Bladder Cancer - Molecular Biology

Overview

A diverse range of different chromosomal abnormalities have been reported in bladder cancer cells. The most frequently detected genetic abnormality in transitional cell carcinoma (TCC) of bladder is LOH on chromosome 9.

Abnormalities in genes regulating cell cycle control are often seen in advanced bladder cancers, particularly mutations in TP53 and proteins of the G1 checkpoint, especially RB1, CDKN2A (p16) and cyclin D1 (CCND1).

Overexpression of p73 is also common in bladder cancers and some studies have shown that this is associated with disease progression. Differential mucin expression have also been reported in bladder cancers. However, there are conflicting reports about expression specific mucins; MUC1, MUC2 and MUC7.

Uroplakins (membrane proteins) are expressed in both normal and cancerous urothelium and can act as a marker for the detection of metastases and circulating TCC cells.

Gene-Environment Interactions: A number of studies have investigated genes that might modulate the susceptibility to bladder cancer associated with cigarette smoking. These include the NAT1, NAT2, and GSTM1 genes.

See also: Bladder Cancer - clinical resources (22)

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (352)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Bladder Cancer
509
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Bladder Cancer
197
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A Deletion
-CDKN2A deletion in Bladder Cancer
159
BIRC5 17q25.3 API4, EPR-1 -BIRC5 and Bladder Cancer
150
GSTM1 1p13.3 MU, H-B, GST1, GTH4, GTM1, MU-1, GSTM1-1, GSTM1a-1a, GSTM1b-1b -GSTM1 and Bladder Cancer
147
NAT2 8p22 AAC2, PNAT, NAT-2 -NAT2 and Bladder Cancer
143
TNF 6p21.33 DIF, TNFA, TNFSF2, TNLG1F, TNF-alpha -TNF and Bladder Cancer
104
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Bladder Cancer
71
MTOR 1p36.22 SKS, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 -MTOR and Bladder Cancer
65
CDKN1A 6p21.2 P21, CIP1, SDI1, WAF1, CAP20, CDKN1, MDA-6, p21CIP1 -CDKN1A Expression in Bladder Cancer
60
GSTP1 11q13.2 PI, DFN7, GST3, GSTP, FAEES3, HEL-S-22 -GSTP1 and Bladder Cancer
58
CASP3 4q35.1 CPP32, SCA-1, CPP32B -CASP3 and Bladder Cancer
50
BAX 19q13.33 BCL2L4 -BAX and Bladder Cancer
49
XRCC1 19q13.31 RCC -XRCC1 and Bladder Cancer
45
AR Xq12 KD, AIS, AR8, TFM, DHTR, SBMA, HYSP1, NR3C4, SMAX1, HUMARA -AR and Bladder Cancer
44
CD44 11p13 IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CDW44, CSPG8, HCELL, HUTCH-I, ECMR-III -CD44 and Bladder Cancer
42
PROC 2q13-q14 PC, APC, PROC1, THPH3, THPH4 -PROC and Bladder Cancer
41
KIT 4q12 PBT, SCFR, C-Kit, CD117 -KIT and Bladder Cancer
41
ERBB2 17q12 NEU, NGL, HER2, TKR1, CD340, HER-2, MLN 19, HER-2/neu -ERBB2 and Bladder Cancer
37
PIK3CA 3q26.32 MCM, CWS5, MCAP, PI3K, CLOVE, MCMTC, PI3K-alpha, p110-alpha -PIK3CA and Bladder Cancer
36
MMP9 20q13.12 GELB, CLG4B, MMP-9, MANDP2 -MMP9 and Bladder Cancer
32
AKT1 14q32.33 AKT, PKB, RAC, CWS6, PRKBA, PKB-ALPHA, RAC-ALPHA -AKT1 and Bladder Cancer
31
NAT1 8p22 AAC1, MNAT, NATI, NAT-1 -NAT1 and Bladder Cancer
30
SRC 20q11.23 ASV, SRC1, THC6, c-SRC, p60-Src -SRC and Bladder Cancer
29
MUC1 1q22 EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC Overexpression
-MUC1 and Bladder Cancer
26
VEGFA 6p21.1 VPF, VEGF, MVCD1 -VEGF Expression in Bladder Cancer
26
CDKN1B 12p13.1 KIP1, MEN4, CDKN4, MEN1B, P27KIP1 -CDKN1B and Bladder Cancer
26
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS and Bladder Cancer
23
EZH2 7q36.1 WVS, ENX1, EZH1, KMT6, WVS2, ENX-1, EZH2b, KMT6A -EZH2 and Bladder Cancer
23
IL10 1q32.1 CSIF, TGIF, GVHDS, IL-10, IL10A -Interleukin-10 and Bladder Cancer
21
CDK4 12q14.1 CMM3, PSK-J3 -CDK4 and Bladder Cancer
21
CD82 11p11.2 R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27 -CD82 and Bladder Cancer
18
RUNX3 1p36.11 AML2, CBFA3, PEBP2aC -RUNX3 and Bladder Cancer
18
CDH1 16q22.1 UVO, CDHE, ECAD, LCAM, Arc-1, CD324 -CDH1 and Bladder Cancer
18
H19 11p15.5 ASM, BWS, WT2, ASM1, D11S813E, LINC00008, NCRNA00008 -H19 and Bladder Cancer
18
FHIT 3p14.2 FRA3B, AP3Aase -FHIT and Bladder Cancer
17
STAT3 17q21.2 APRF, HIES, ADMIO, ADMIO1 -STAT3 and Bladder Cancer
17
XIAP Xq25 API3, ILP1, MIHA, XLP2, BIRC4, IAP-3, hIAP3, hIAP-3 -XIAP and Bladder Cancer
16
E2F3 6p22.3 E2F-3 -E2F3 and Bladder Cancer
16
FGFR1 8p11.23 CEK, FLG, HH2, OGD, ECCL, FLT2, KAL2, BFGFR, CD331, FGFBR, FLT-2, HBGFR, N-SAM, FGFR-1, HRTFDS, bFGF-R-1 -FGFR1 and Bladder Cancer
15
HIF1A 14q23.2 HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA, HIF-1-alpha -HIF1A and Bladder Cancer
15
CDKN2B 9p21.3 P15, MTS2, TP15, CDK4I, INK4B, p15INK4b -CDKN2B and Bladder Cancer
14
FGFR2 10q26.13 BEK, JWS, BBDS, CEK3, CFD1, ECT1, KGFR, TK14, TK25, BFR-1, CD332, K-SAM -FGFR2 and Bladder Cancer
14
AURKA 20q13.2 AIK, ARK1, AURA, BTAK, STK6, STK7, STK15, PPP1R47 -AURKA and Bladder Cancer
14
CCNB1 5q13.2 CCNB -CCNB1 and Bladder Cancer
14
VEGFC 4q34.3 VRP, Flt4-L, LMPH1D -VEGFC and Bladder Cancer
13
GPX1 3p21.31 GPXD, GSHPX1 -GPX1 and Bladder Cancer
13
ERCC1 19q13.32 UV20, COFS4, RAD10 -ERCC1 and Bladder Cancer
13
IGF2 11p15.5 GRDF, IGF-II, PP9974, C11orf43 -IGF2 and Bladder Cancer
12
KRT5 12q13.13 K5, CK5, DDD, DDD1, EBS2, KRT5A -KRT5 and Bladder Cancer
11
TIMP3 22q12.3 SFD, K222, K222TA2, HSMRK222 -TIMP3 and Bladder Cancer
11
PRC1 15q26.1 ASE1 -PRC1 and Bladder Cancer
11
KRT20 17q21.2 K20, CD20, CK20, CK-20, KRT21 -KRT20 and Bladder Cancer
11
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Bladder Cancer
11
STAG2 Xq25 SA2, SA-2, SCC3B, NEDXCF, bA517O1.1 GWS
-STAG2 and Bladder Cancer
11
SNAI1 20q13.13 SNA, SNAH, SNAIL, SLUGH2, SNAIL1, dJ710H13.1 -SNAI1 and Bladder Cancer
10
TGFA 2p13 TFGA -TGFA and Bladder Cancer
10
FAS 10q23.31 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Bladder Cancer
9
CLMP 11q24.1 ACAM, ASAM, CSBM, CSBS -CLMP and Bladder Cancer
9
TACC3 4p16.3 ERIC1, ERIC-1 -TACC3 and Bladder Cancer
9
ICAM1 19p13.2 BB2, CD54, P3.58 -ICAM1 and Bladder Cancer
9
BMI1 10p12.2 PCGF4, RNF51, FLVI2/BMI1, flvi-2/bmi-1 -BMI1 and Bladder Cancer
9
JUN 1p32.1 AP1, p39, AP-1, cJUN, c-Jun -c-Jun and Bladder Cancer
9
FASLG 1q24.3 APTL, FASL, CD178, CD95L, ALPS1B, CD95-L, TNFSF6, TNLG1A, APT1LG1 -FASLG and Bladder Cancer
9
TGFBR1 9q22.33 AAT5, ALK5, ESS1, LDS1, MSSE, SKR4, ALK-5, LDS1A, LDS2A, TGFR-1, ACVRLK4, tbetaR-I -TGFBR1 and Bladder Cancer
9
NME1 17q21.33 NB, AWD, NBS, GAAD, NDKA, NM23, NDPKA, NDPK-A, NM23-H1 -NME1 and Bladder Cancer
8
CEACAM5 19q13.2 CEA, CD66e -CEACAM5 and Bladder Cancer
8
TERC 3q26.2 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Bladder Cancer
8
XRCC6 22q13.2 ML8, KU70, TLAA, CTC75, CTCBF, G22P1 -XRCC6 and Bladder Cancer
7
NOS2 17q11.2 NOS, INOS, NOS2A, HEP-NOS -NOS2 and Bladder Cancer
7
KLF4 9q31.2 EZF, GKLF -KLF4 and Bladder Cancer
7
EPHX1 1q42.12 MEH, EPHX, EPOX, HYL1 -EPHX1 and Bladder Cancer
7
AKT2 19q13.2 PKBB, PRKBB, HIHGHH, PKBBETA, RAC-BETA -AKT2 and Bladder Cancer
7
HLA-A 6p22.1 HLAA -HLA-A and Bladder Cancer
7
PPARG 3p25.2 GLM1, CIMT1, NR1C3, PPARG1, PPARG2, PPARgamma -PPARG and Bladder Cancer
7
GAPDH 12p13.31 G3PD, GAPD, HEL-S-162eP -GAPDH and Bladder Cancer
7
CDH13 16q23.3 CDHH, P105 -CDH13 and Bladder Cancer
7
KRT7 12q13.13 K7, CK7, SCL, K2C7 -KRT7 and Bladder Cancer
7
EDNRB 13q22.3 ETB, ET-B, ETB1, ETBR, ETRB, HSCR, WS4A, ABCDS, ET-BR, HSCR2 -EDNRB and Bladder Cancer
6
GSTO1 10q25.1 P28, SPG-R, GSTO 1-1, GSTTLp28, HEL-S-21 -GSTO1 and Bladder Cancer
6
LGALS3 14q22.3 L31, GAL3, MAC2, CBP35, GALBP, GALIG, LGALS2 -LGALS3 and Bladder Cancer
6
FSCN1 7p22.1 HSN, SNL, p55, FAN1 -FSCN1 and Bladder Cancer
6
HPRT1 Xq26.2-q26.3 HPRT, HGPRT -HPRT1 and Bladder Cancer
6
BIRC7 20q13.33 KIAP, LIVIN, MLIAP, RNF50, ML-IAP -BIRC7 and Bladder Cancer
6
CAMP 3p21.31 LL37, CAP18, CRAMP, HSD26, CAP-18, FALL39, FALL-39 -CAMP and Bladder Cancer
6
CCND2 12p13.32 MPPH3, KIAK0002 -CCND2 and Bladder Cancer
6
LGALS1 22q13.1 GBP, GAL1 -LGALS1 and Bladder Cancer
6
DAPK1 9q21.33 DAPK -DAPK1 and Bladder Cancer
6
XRCC4 5q14.2 SSMED -XRCC4 and Bladder Cancer
6
CCR2 3p21.31 CKR2, CCR-2, CCR2A, CCR2B, CD192, CKR2A, CKR2B, CMKBR2, MCP-1-R, CC-CKR-2 -CCR2 and Bladder Cancer
6
ERCC6 10q11.23 CSB, CKN2, COFS, ARMD5, COFS1, POF11, RAD26, UVSS1 -ERCC6 and Bladder Cancer
6
COMT 22q11.21 HEL-S-98n -COMT and Bladder Cancer
6
ARHGDIB 12p12.3 D4, GDIA2, GDID4, LYGDI, Ly-GDI, RAP1GN1, RhoGDI2 -ARHGDIB and Bladder Cancer
6
PRKDC 8q11.21 HYRC, p350, DNAPK, DNPK1, HYRC1, IMD26, XRCC7, DNA-PKcs -PRKDC and Bladder Cancer
6
TIMP2 17q25.3 DDC8, CSC-21K -TIMP2 and Bladder Cancer
6
MALAT1 11q13.1 HCN, NEAT2, PRO2853, LINC00047, NCRNA00047 -MALAT1 and Bladder Cancer
5
HAS3 16q22.1 -HAS3 and Bladder Cancer
5
RALA 7p14.1 RAL -RALA and Bladder Cancer
5
HAS1 19q13.41 HAS -HAS1 and Bladder Cancer
5
POLB 8p11.21 -POLB and Bladder Cancer
5
TEP1 14q11.2 TP1, TLP1, p240, TROVE1, VAULT2 -TEP1 and Bladder Cancer
5
MIR10A 17q21.32 MIRN10A, mir-10a, miRNA10A, hsa-mir-10a -miR-10a and Bladder Cancer
5
LARS 5q32 LRS, LEUS, LFIS, ILFS1, LARS1, LEURS, PIG44, RNTLS, HSPC192, hr025Cl -LARS and Bladder Cancer
5
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Bladder Cancer
5
STAR 8p11.23 STARD1 -STAR and Bladder Cancer
5
MMP3 11q22.2 SL-1, STMY, STR1, CHDS6, MMP-3, STMY1 -MMP3 and Bladder Cancer
5
NOS3 7q36.1 eNOS, ECNOS -NOS3 and Bladder Cancer
5
MAGEA3 Xq28 HIP8, HYPD, CT1.3, MAGE3, MAGEA6 -MAGEA3 and Bladder Cancer
5
HGF 7q21.11 SF, HGFB, HPTA, F-TCF, DFNB39 -HGF and Bladder Cancer
5
TSC2 16p13.3 LAM, TSC4, PPP1R160 -TSC2 and Bladder Cancer
5
S100A8 1q21.3 P8, MIF, NIF, CAGA, CFAG, CGLA, L1Ag, MRP8, CP-10, MA387, 60B8AG -S100A8 and Bladder Cancer
4
LRIG1 3p14 LIG1, LIG-1 -LRIG1 and Bladder Cancer
4
GDF15 19p13.11 PDF, MIC1, PLAB, MIC-1, NAG-1, PTGFB, GDF-15 -GDF15 and Bladder Cancer
4
CDK1 10q21.2 CDC2, CDC28A, P34CDC2 -CDK1 and Bladder Cancer
4
TP73 1p36.32 P73 -TP73 Overexpression in Bladder Cancer
4
GSTM3 1p13.3 GST5, GSTB, GTM3, GSTM3-3 -GSTM3 and Bladder Cancer
4
GSTO2 10q25.1 GSTO 2-2, bA127L20.1 -GSTO2 and Bladder Cancer
4
S100A9 1q21.3 MIF, NIF, P14, CAGB, CFAG, CGLB, L1AG, LIAG, MRP14, 60B8AG, MAC387 -S100A9 and Bladder Cancer
4
CCR5 3p21.31 CKR5, CCR-5, CD195, CKR-5, CCCKR5, CMKBR5, IDDM22, CC-CKR-5 -CCR5 and Bladder Cancer
4
EREG 4q13.3 ER, Ep, EPR -EREG and Bladder Cancer
4
FLT1 13q12.3 FLT, FLT-1, VEGFR1, VEGFR-1 -FLT1 Expression in Bladder Cancer
4
PIK3R1 5q13.1 p85, AGM7, GRB1, IMD36, p85-ALPHA -PIK3R1 and Bladder Cancer
4
CKS2 9q22.2 CKSHS2 -CKS2 and Bladder Cancer
4
FGF1 5q31.3 AFGF, ECGF, FGFA, ECGFA, ECGFB, FGF-1, HBGF1, HBGF-1, GLIO703, ECGF-beta, FGF-alpha -FGF1 and Bladder Cancer
4
VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and Bladder Cancer
4
GNAS 20q13.32 AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, PITA3, C20orf45 -GNAS and Bladder Cancer
4
LAMC2 1q25.3 B2T, CSF, EBR2, BM600, EBR2A, LAMB2T, LAMNB2 -LAMC2 and Bladder Cancer
4
CCNA1 13q13.3 CT146 -CCNA1 and Bladder Cancer
4
MGEA5 10q24.32 OGA, MEA5, NCOAT -MGEA5 and Bladder Cancer
3
MTRR 5p15.31 MSR, cblE -MTRR and Bladder Cancer
3
MUC7 4q13.3 MG2 -MUC7 and Bladder Cancer
3
HDAC2 6q21 HD2, RPD3, YAF1 -HDAC2 and Bladder Cancer
3
XRCC5 2q35 KU80, KUB2, Ku86, NFIV, KARP1, KARP-1 -XRCC5 and Bladder Cancer
3
HDAC4 2q37.3 HD4, AHO3, BDMR, HDACA, HA6116, HDAC-4, HDAC-A -HDAC4 and Bladder Cancer
3
COL18A1 21q22.3 KS, KNO, KNO1 -COL18A1 and Bladder Cancer
3
MMP14 14q11.2 MMP-14, MMP-X1, MT-MMP, MT1MMP, MTMMP1, WNCHRS, MT1-MMP, MT-MMP 1 -MMP14 and Bladder Cancer
3
NOX1 Xq22.1 MOX1, NOH1, NOH-1, GP91-2 -NOX1 and Bladder Cancer
3
RAF1 3p25.2 NS5, CRAF, Raf-1, c-Raf, CMD1NN -RAF1 and Bladder Cancer
3
ADGRB1 8q24.3 BAI1, GDAIF -BAI1 and Bladder Cancer
3
VIP 6q25.2 PHM27 -VIP and Bladder Cancer
3
MAP2K6 17q24.3 MEK6, MKK6, MAPKK6, PRKMK6, SAPKK3, SAPKK-3 -MAP2K6 and Bladder Cancer
3
UBE2C 20q13.12 UBCH10, dJ447F3.2 -UBE2C and Bladder Cancer
3
FGF4 11q13.3 HST, KFGF, HST-1, HSTF1, K-FGF, HBGF-4 -FGF4 and Bladder Cancer
3
SFRP2 4q31.3 FRP-2, SARP1, SDF-5 -SFRP2 and Bladder Cancer
3
ACTB 7p22.1 BRWS1, PS1TP5BP1 -ACTB and Bladder Cancer
3
PDGFRB 5q32 IMF1, KOGS, IBGC4, JTK12, PDGFR, PENTT, CD140B, PDGFR1, PDGFR-1 -PDGFRB and Bladder Cancer
3
SMAD2 18q21.1 JV18, MADH2, MADR2, JV18-1, hMAD-2, hSMAD2 -SMAD2 and Bladder Cancer
3
IGFBP5 2q35 IBP5 -IGFBP5 and Bladder Cancer
3
CALCA 11p15.2 CT, KC, PCT, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Bladder Cancer
3
XAF1 17p13.1 BIRC4BP, XIAPAF1, HSXIAPAF1 -XAF1 and Bladder Cancer
3
RHOA 3p21.31 ARHA, ARH12, RHO12, RHOH12 -RHOA and Bladder Cancer
3
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Bladder Cancer
3
KRT14 17q21.2 K14, NFJ, CK14, EBS3, EBS4 -KRT14 and Bladder Cancer
3
UGT2B7 4q13.2 UGT2B9, UDPGTH2, UDPGT2B7, UDPGTh-2, UDPGT 2B7, UDPGT 2B9 -UGT2B7 and Bladder Cancer
3
DEK 6p22.3 D6S231E -DEK and Bladder Cancer
3
CD47 3q13.1-q13.2 IAP, OA3, MER6 -CD47 and Bladder Cancer
3
NCOA1 2p23 SRC1, KAT13A, RIP160, F-SRC-1, bHLHe42, bHLHe74 -NCOA1 and Bladder Cancer
2
RREB1 6p24.3 HNT, FINB, LZ321, Zep-1, RREB-1 -RREB1 and Bladder Cancer
2
S100P 4p16.1 MIG9 -S100P and Bladder Cancer
2
HLA-G 6p22.1 MHC-G -HLA-G and Bladder Cancer
2
MCM5 22q12.3 CDC46, MGORS8, P1-CDC46 -MCM5 and Bladder Cancer
2
PTPRF 1p34.2 LAR, BNAH2 -PTPRF and Bladder Cancer
2
PLAT 8p11.21 TPA, T-PA -PLAT and Bladder Cancer
2
TNFSF15 9q32 TL1, TL1A, VEGI, TNLG1B, VEGI192A -TNFSF15 expression in Bladder Cancer
2
FH 1q43 MCL, FMRD, HsFH, LRCC, HLRCC, MCUL1 -FH and Bladder Cancer
2
ITGB3 17q21.32 GT, CD61, GP3A, BDPLT2, GPIIIa, BDPLT16 -ITGB3 and Bladder Cancer
2
CUL3 2q36.2 CUL-3, PHA2E -CUL3 and Bladder Cancer
2
ANXA1 9q21.13 ANX1, LPC1 -ANXA1 and Bladder Cancer
2
RXRA 9q34.2 NR2B1 -RXRA and Bladder Cancer
2
IRF8 16q24.1 ICSBP, IRF-8, ICSBP1, IMD32A, IMD32B, H-ICSBP -IRF8 and Bladder Cancer
2
ANXA5 4q27 PP4, ANX5, ENX2, RPRGL3, HEL-S-7 -ANXA5 and Bladder Cancer
2
GLI2 2q14 CJS, HPE9, PHS2, THP1, THP2 -GLI2 and Bladder Cancer
2
SRPX Xp11.4 DRS, ETX1, SRPX1, HEL-S-83p -SRPX and Bladder Cancer
2
RRM1 11p15.4 R1, RR1, RIR1 -RRM1 and Bladder Cancer
2
MAP2K4 17p12 JNKK, MEK4, MKK4, SEK1, SKK1, JNKK1, SERK1, MAPKK4, PRKMK4, SAPKK1, SAPKK-1 -MAP2K4 and Bladder Cancer
2
E2F2 1p36.12 E2F-2 -E2F2 and Bladder Cancer
2
BCL2L2 14q11.2 BCLW, BCL-W, PPP1R51, BCL2-L-2 -BCL2L2 and Bladder Cancer
2
TBX2 17q23.2 -TBX2 and Bladder Cancer
2
TACSTD2 1p32.1 EGP1, GP50, M1S1, EGP-1, TROP2, GA7331, GA733-1 -TACSTD2 and Bladder Cancer
2
RAD23B 9q31.2 P58, HR23B, HHR23B -RAD23B and Bladder Cancer
2
FGF7 15q21.2 KGF, HBGF-7 -FGF7 and Bladder Cancer
2
CTAG1B Xq28 CTAG, ESO1, CT6.1, CTAG1, LAGE-2, LAGE2B, NY-ESO-1 -CTAG1B and Bladder Cancer
2
EWSR1 22q12.2 EWS, EWS-FLI1, bK984G1.4 -EWSR1 and Bladder Cancer
2
WWOX 16q23.1-q23.2 FOR, WOX1, EIEE28, FRA16D, SCAR12, HHCMA56, PRO0128, SDR41C1, D16S432E -WWOX and Bladder Cancer
2
DAB2IP 9q33.2 AIP1, AIP-1, AF9Q34, DIP1/2 -DAB2IP and Bladder Cancer
2
MAPK1 22q11.22 ERK, p38, p40, p41, ERK2, ERT1, ERK-2, MAPK2, PRKM1, PRKM2, P42MAPK, p41mapk, p42-MAPK -MAPK1 and Bladder Cancer
2
NUMB 14q24.2-q24.3 S171, C14orf41, c14_5527 -NUMB and Bladder Cancer
2
RHEB 7q36.1 RHEB2 -RHEB and Bladder Cancer
2
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Bladder Cancer
2
CDKN2D 19p13.2 p19, INK4D, p19-INK4D -CDKN2D and Bladder Cancer
2
MMP8 11q22.2 HNC, CLG1, MMP-8, PMNL-CL -MMP8 and Bladder Cancer
2
RALB 2q14.2 -RALB and Bladder Cancer
2
HYAL1 3p21.31 MPS9, NAT6, LUCA1, HYAL-1 -HYAL1 and Bladder Cancer
2
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Bladder Cancer
2
FEZ1 11q24.2 UNC-76 -FEZ1 and Bladder Cancer
2
CYP2A13 19q13.2 CPAD, CYP2A, CYPIIA13 -CYP2A13 and Bladder Cancer
2
SPINK1 5q32 TCP, PCTT, PSTI, TATI, Spink3 -SPINK1 and Bladder Cancer
2
TAGLN 11q23.3 SM22, SMCC, TAGLN1, WS3-10 -TAGLN and Bladder Cancer
2
CEACAM1 19q13.2 BGP, BGP1, BGPI -CEACAM1 and Bladder Cancer
2
NQO2 6p25.2 QR2, DHQV, DIA6, NMOR2 -NQO2 and Bladder Cancer
2
KISS1R 19p13.3 HH8, CPPB1, GPR54, AXOR12, KISS-1R, HOT7T175 -KISS1R and Bladder Cancer
2
TBX3 12q24.21 UMS, XHL, TBX3-ISO -TBX3 and Bladder Cancer
2
MIR34A 1p36.22 mir-34, MIRN34A, mir-34a, miRNA34A -MIR34A and Bladder Cancer
2
TLR3 4q35.1 CD283, IIAE2 -TLR3 and Bladder Cancer
2
BUB1 2q14 BUB1A, BUB1L, hBUB1 -BUB1 and Bladder Cancer
2
KLF5 13q22.1 CKLF, IKLF, BTEB2 -KLF5 and Bladder Cancer
2
IMP3 15q24.2 BRMS2, MRPS4, C15orf12 -IMP3 and Bladder Cancer
2
LAMB3 1q32.2 AI1A, LAM5, LAMNB1, BM600-125KDA -LAMB3 and Bladder Cancer
2
GLI3 7p14.1 PHS, ACLS, GCPS, PAPA, PAPB, PAP-A, PAPA1, PPDIV, GLI3FL, GLI3-190 -GLI3 and Bladder Cancer
2
JAG1 20p12.2 AGS, AHD, AWS, HJ1, AGS1, DCHE, CD339, JAGL1 -JAG1 and Bladder Cancer
2
GATA2 3q21.3 DCML, IMD21, NFE1B, MONOMAC -GATA2 and Bladder Cancer
2
HOXD10 2q31.1 HOX4, HOX4D, HOX4E, Hox-4.4 -HOXD10 and Bladder Cancer
2
MAD2L1 4q27 MAD2, HSMAD2 -MAD2L1 and Bladder Cancer
2
CXCL5 4q13.3 SCYB5, ENA-78 -CXCL5 and Bladder Cancer
2
SMARCA4 19p13.2 BRG1, CSS4, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A -SMARCA4 and Bladder Cancer
2
FLNA Xq28 FLN, FMD, MNS, OPD, ABPX, CSBS, CVD1, FGS2, FLN1, NHBP, OPD1, OPD2, XLVD, XMVD, FLN-A, ABP-280 -FLNA and Bladder Cancer
2
MMP12 11q22.2 ME, HME, MME, MMP-12 -MMP12 and Bladder Cancer
2
IL4R 16p12.1 CD124, IL4RA, IL-4RA -IL4R and Bladder Cancer
2
MBD2 18q21.2 DMTase, NY-CO-41 -MBD2 and Bladder Cancer
2
MCM2 3q21 BM28, CCNL1, CDCL1, cdc19, D3S3194, MITOTIN -MCM2 and Bladder Cancer
2
SDC4 20q13.12 SYND4 -SDC4 and Bladder Cancer
2
ERCC4 16p13.12 XPF, RAD1, FANCQ, XFEPS, ERCC11 -ERCC4 and Bladder Cancer
2
RHOBTB2 8p21.3 DBC2 -RHOBTB2 and Bladder Cancer
2
NOX4 11q14.3 KOX, KOX-1, RENOX -NOX4 and Bladder Cancer
2
IL17C 16q24.2 CX2, IL-17C -IL17C and Bladder Cancer
2
AQP3 9p13.3 GIL, AQP-3 -AQP3 and Bladder Cancer
2
AIM1 6q21 ST4, CRYBG1 -AIM1 and Bladder Cancer
2
BCHE 3q26.1-q26.2 E1, CHE1, CHE2 -BCHE and Bladder Cancer
2
EPHB4 7q22.1 HTK, MYK1, HFASD, TYRO11 -EPHB4 and Bladder Cancer
2
MCM4 8q11.21 NKCD, CDC21, CDC54, NKGCD, hCdc21, P1-CDC21 -MCM4 and Bladder Cancer
2
ENDOU 12q13.1 P11, PP11, PRSS26 -ENDOU and Bladder Cancer
1
ESPL1 12q13.13 ESP1, SEPA GWS
-ESPL1 and Bladder Cancer
1
SMPD1 11p15.4 ASM, NPD, ASMASE -SMPD1 and Bladder Cancer
1
LDLR 19p13.2 FH, FHC, LDLCQ2 -LDLR and Bladder Cancer
1
LASP1 17q12 MLN50, Lasp-1 -LASP1 and Bladder Cancer
1
SPRR2B 1q21.3 -SPRR2B and Bladder Cancer
1
TANK 2q24.2 ITRAF, TRAF2, I-TRAF -TANK and Bladder Cancer
1
TRAF6 11p12 RNF85, MGC:3310 -TRAF6 and Bladder Cancer
1
AGTR2 Xq23 AT2, ATGR2, MRX88 -AGTR2 and Bladder Cancer
1
BMPR2 2q33-q34 BMR2, PPH1, BMPR3, BRK-3, POVD1, T-ALK, BMPR-II -BMPR2 and Bladder Cancer
1
BUB3 10q26.13 BUB3L, hBUB3 -BUB3 and Bladder Cancer
1
MUC5B 11p15.5 MG1, MUC5, MUC9, MUC-5B -MUC5B and Bladder Cancer
1
CXCL11 4q21.1 IP9, H174, IP-9, b-R1, I-TAC, SCYB11, SCYB9B -CXCL11 and Bladder Cancer
1
EEF1E1 6p24.3 P18, AIMP3 -EEF1E1 and Bladder Cancer
1
NEFL 8p21.2 NFL, NF-L, NF68, CMT1F, CMT2E, PPP1R110 -NEFL and Bladder Cancer
1
SMARCA2 9p24.3 BRM, SNF2, SWI2, hBRM, NCBRS, Sth1p, BAF190, SNF2L2, SNF2LA, hSNF2a -SMARCA2 and Bladder Cancer
1
S100B 21q22.3 NEF, S100, S100-B, S100beta -S100B and Bladder Cancer
1
MIRLET7D 9q22.32 LET7D, let-7d, MIRNLET7D, hsa-let-7d -None and Bladder Cancer
1
CEBPB 20q13.13 TCF5, IL6DBP, NF-IL6, C/EBP-beta -CEBPB and Bladder Cancer
1
ATP7B 13q14.3 WD, PWD, WC1, WND -ATP7B and Bladder Cancer
1
GNL3 3p21.1 NS, E2IG3, NNP47, C77032 -GNL3 and Bladder Cancer
1
HDAC6 Xp11.23 HD6, JM21, CPBHM, PPP1R90 -HDAC6 and Bladder Cancer
1
EML4 2p21 C2orf2, ELP120, EMAP-4, EMAPL4, ROPP120 -EML4 and Bladder Cancer
1
POLI 18q21.2 RAD30B, RAD3OB -POLI and Bladder Cancer
1
WRN 8p12 RECQ3, RECQL2, RECQL3 -WRN and Bladder Cancer
1
CREB3L1 11p11.2 OASIS -CREB3L1 and Bladder Cancer
1
ADH1C 4q23 ADH3 -ADH1C and Bladder Cancer
1
RIN1 11q13.2 -RIN1 and Bladder Cancer
1
MAD1L1 7p22.3 MAD1, PIG9, TP53I9, TXBP181 -MAD1L1 and Bladder Cancer
1
MEG3 14q32.2 GTL2, FP504, prebp1, PRO0518, PRO2160, LINC00023, NCRNA00023, onco-lncRNA-83 -MEG3 and Bladder Cancer
1
IL23R 1p31.3 -IL23R and Bladder Cancer
1
S100A1 1q21.3 S100, S100A, S100-alpha -S100A1 and Bladder Cancer
1
YWHAZ 8q22.3 HEL4, YWHAD, KCIP-1, HEL-S-3, HEL-S-93, 14-3-3-zeta -YWHAZ and Bladder Cancer
1
ACVRL1 12q13.13 HHT, ALK1, HHT2, ORW2, SKR3, ALK-1, TSR-I, ACVRLK1 -ACVRL1 and Bladder Cancer
1
PLK2 5q11.2 SNK, hSNK, hPlk2 -PLK2 and Bladder Cancer
1
BCL2L12 19q13.33 -BCL2L12 and Bladder Cancer
1
HSD3B2 1p12 HSDB, HSD3B, SDR11E2 -HSD3B2 and Bladder Cancer
1
KIAA1524 3q13.13 p90, CIP2A -KIAA1524 and Bladder Cancer
1
MTSS1 8q24.13 MIM, MIMA, MIMB -MTSS1 and Bladder Cancer
1
TRIM24 7q33-q34 PTC6, TF1A, TIF1, RNF82, TIF1A, hTIF1, TIF1ALPHA -TRIM24 and Bladder Cancer
1
IL27 16p12.1-p11.2 p28, IL30, IL-27, IL27A, IL-27A, IL27p28 -IL27 and Bladder Cancer
1
FGFR4 5q35.2 TKF, JTK2, CD334 -FGFR4 and Bladder Cancer
1
NONO Xq13.1 P54, NMT55, NRB54, MRXS34, P54NRB, PPP1R114 -NONO and Bladder Cancer
1
HDAC3 5q31.3 HD3, RPD3, RPD3-2 -HDAC3 and Bladder Cancer
1
ARF1 1q42.13 PVNH8 -ARF1 and Bladder Cancer
1
PSIP1 9p22.3 p52, p75, PAIP, DFS70, LEDGF, PSIP2 -PSIP1 and Bladder Cancer
1
CASP1 11q22.3 ICE, P45, IL1BC -CASP1 and Bladder Cancer
1
TNFRSF25 1p36.31 DR3, TR3, DDR3, LARD, APO-3, TRAMP, WSL-1, GEF720, WSL-LR, PLEKHG5, TNFRSF12 -TNFRSF25 and Bladder Cancer
1
TPTE 21p11.2 CT44, PTEN2 -TPTE and Bladder Cancer
1
TNKS 8p23.1 TIN1, ARTD5, PARPL, TINF1, TNKS1, pART5, PARP5A, PARP-5a -TNKS and Bladder Cancer
1
DLEC1 3p22.2 F56, DLC1, DLC-1, CFAP81 -DLEC1 and Bladder Cancer
1
MSI2 17q22 MSI2H -MSI2 and Bladder Cancer
1
OPCML 11q25 OPCM, OBCAM, IGLON1 -OPCML and Bladder Cancer
1
HLA-E 6p21.3 MHC, QA1, EA1.2, EA2.1, HLA-6.2 -HLA-E and Bladder Cancer
1
ELN 7q11.23 WS, WBS, SVAS -ELN and Bladder Cancer
1
CASP2 7q34 ICH1, NEDD2, CASP-2, NEDD-2, PPP1R57 -CASP2 and Bladder Cancer
1
PTPRD 9p24.1-p23 HPTP, PTPD, HPTPD, HPTPDELTA, RPTPDELTA -PTPRD and Bladder Cancer
1
ANO1 11q13.3 DOG1, TAOS2, ORAOV2, TMEM16A -ANO1 and Bladder Cancer
1
CSF3R 1p34.3 SCN7, CD114, GCSFR -CSF3R and Bladder Cancer
1
IRAK1 Xq28 IRAK, pelle -IRAK1 and Bladder Cancer
1
CHRNB4 15q25.1 -CHRNB4 and Bladder Cancer
1
S100A3 1q21.3 S100E -S100A3 and Bladder Cancer
1
DRD2 11q23.2 D2R, D2DR -DRD2 and Bladder Cancer
1
NUMA1 11q13.4 NUMA, NMP-22 -NUMA1 and Bladder Cancer
1
IDO1 8p11.21 IDO, INDO, IDO-1 -IDO1 and Bladder Cancer
1
IRF7 11p15.5 IMD39, IRF7A, IRF7B, IRF7C, IRF7H, IRF-7H -IRF7 and Bladder Cancer
1
CBX7 22q13.1 -CBX7 and Bladder Cancer
1
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Bladder Cancer
1
NRG1 8p12 GGF, HGL, HRG, NDF, ARIA, GGF2, HRG1, HRGA, SMDF, MST131, MSTP131, NRG1-IT2 -NRG1 and Bladder Cancer
1
RASAL1 12q24.13 RASAL -RASAL1 and Bladder Cancer
1
KAT5 11q13.1 TIP, ESA1, PLIP, TIP60, cPLA2, HTATIP, ZC2HC5, HTATIP1 -KAT5 and Bladder Cancer
1
MSI1 12q24 -MSI1 and Bladder Cancer
1
LHCGR 2p21 HHG, LHR, LCGR, LGR2, ULG5, LHRHR, LSH-R, LH/CGR, LH/CG-R -LHCGR and Bladder Cancer
1
AMFR 16q13 GP78, RNF45 -AMFR and Bladder Cancer
1
IRF9 14q12 p48, IRF-9, ISGF3, ISGF3G -IRF9 and Bladder Cancer
1
DGCR8 22q11.21 Gy1, pasha, DGCRK6, C22orf12 -DGCR8 and Bladder Cancer
1
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Bladder Cancer
1
CASP5 11q22.3 ICH-3, ICEREL-III, ICE(rel)III -CASP5 and Bladder Cancer
1
IL17A 6p12.2 IL17, CTLA8, IL-17, CTLA-8, IL-17A -IL17A and Bladder Cancer
1
MIR106A Xq26.2 mir-106, MIRN106A, mir-106a -MIR106A and Bladder Cancer
1
KLK6 19q13.41 hK6, Bssp, Klk7, SP59, PRSS9, PRSS18 -KLK6 and Bladder Cancer
1
IL12B 5q33.3 CLMF, NKSF, CLMF2, IMD28, IMD29, NKSF2, IL-12B -IL12B and Bladder Cancer
1
PPP2CB 8p12 PP2CB, PP2Abeta -PPP2CB and Bladder Cancer
1
ITGA6 2q31.1 CD49f, VLA-6, ITGA6B -ITGA6 and Bladder Cancer
1
PGK1 Xq21.1 PGKA, MIG10, HEL-S-68p -PGK1 and Bladder Cancer
1
RCVRN 17p13.1 RCV1 -RCVRN and Bladder Cancer
1
LTB 6p21.33 p33, TNFC, TNFSF3, TNLG1C -LTB and Bladder Cancer
1
FABP5 8q21.13 EFABP, KFABP, E-FABP, PAFABP, PA-FABP -FABP5 and Bladder Cancer
1
EIF4EBP1 8p11.23 BP-1, 4EBP1, 4E-BP1, PHAS-I -EIF4EBP1 and Bladder Cancer
1
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Bladder Cancer
1
S100A7 1q21.3 PSOR1, S100A7c -S100A7 and Bladder Cancer
1
SLC7A5 16q24.2 E16, CD98, LAT1, 4F2LC, MPE16, D16S469E -SLC7A5 and Bladder Cancer
1
UGT2B17 4q13.2 BMND12, UDPGT2B17 -UGT2B17 and Bladder Cancer
1
MYOD1 11p15.1 PUM, MYF3, MYOD, bHLHc1 -MYOD1 and Bladder Cancer
1
LRIG3 12q14.1 LIG3 -LRIG3 and Bladder Cancer
1
TYK2 19p13.2 JTK1, IMD35 -TYK2 and Bladder Cancer
1
HTRA1 10q26.13 L56, HtrA, ARMD7, ORF480, PRSS11, CARASIL, CADASIL2 -HTRA1 and Bladder Cancer
1
PBRM1 3p21.1 PB1, BAF180 -PBRM1 and Bladder Cancer
1
SNRPE 1q32.1 SME, Sm-E, HYPT11, snRNP-E -SNRPE and Bladder Cancer
1
KLK5 19q13.41 SCTE, KLKL2, KLK-L2 -KLK5 and Bladder Cancer
1
CAV2 7q31.2 CAV -CAV2 and Bladder Cancer
1
MYCL 1p34.2 LMYC, L-Myc, MYCL1, bHLHe38 -MYCL and Bladder Cancer
1
PDCD6 5p15.33 ALG2, ALG-2, PEF1B -PDCD6 and Bladder Cancer
1
NRP2 2q33.3 NP2, NPN2, PRO2714, VEGF165R2 -NRP2 and Bladder Cancer
1
FOXO4 Xq13.1 AFX, AFX1, MLLT7 -FOXO4 and Bladder Cancer
1
GRASP 12q13.13 TAMALIN -GRASP and Bladder Cancer
1
IL12A 3q25.33 P35, CLMF, NFSK, NKSF1, IL-12A -IL12A and Bladder Cancer
1
AIFM1 Xq26.1 AIF, AUNX1, CMT2D, CMTX4, COWCK, DFNX5, NADMR, NAMSD, PDCD8, COXPD6 -AIFM1 and Bladder Cancer
1
PPP1R13L 19q13.32 RAI, RAI4, IASPP, NKIP1 -PPP1R13L and Bladder Cancer
1
HOXA13 7p15.2 HOX1, HOX1J -HOXA13 and Bladder Cancer
1
SOD1 21q22.11 ALS, SOD, ALS1, IPOA, hSod1, HEL-S-44, homodimer -SOD1 and Bladder Cancer
1
SLCO1B1 12p12.1 LST1, HBLRR, LST-1, OATP2, OATPC, OATP-C, OATP1B1, SLC21A6 -SLCO1B1 and Bladder Cancer
1
FGF19 11q13.3 -FGF19 and Bladder Cancer
1
ALOX5 10q11.21 5-LO, 5LPG, LOG5, 5-LOX -ALOX5 and Bladder Cancer
1
ATIC 2q35 PURH, AICAR, AICARFT, IMPCHASE, HEL-S-70p -ATIC and Bladder Cancer
1
SLCO1B3 12p12.2 LST3, HBLRR, LST-2, OATP8, OATP-8, OATP1B3, SLC21A8, LST-3TM13 -SLCO1B3 and Bladder Cancer
1
NSD3 8p11.23 KMT3F, KMT3G, WHISTLE, WHSC1L1, pp14328 -WHSC1L1 and Bladder Cancer
1
TES 7q31.2 TESS, TESS-2 -TES and Bladder Cancer
1
ITGB4 17q25.1 CD104, GP150 -ITGB4 and Bladder Cancer
PDLIM4 5q31.1 RIL -PDLIM4 and Bladder Cancer
MAPK3 16p11.2 ERK1, ERT2, ERK-1, PRKM3, P44ERK1, P44MAPK, HS44KDAP, HUMKER1A, p44-ERK1, p44-MAPK -MAPK3 and Bladder Cancer
TUBE1 6q21 TUBE, dJ142L7.2 -TUBE1 and Bladder Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Yang FL, Hong K, Zhao GJ, et al.
[Construction of prognostic model and identification of prognostic biomarkers based on the expression of long non-coding RNA in bladder cancer via bioinformatics].
Beijing Da Xue Xue Bao Yi Xue Ban. 2019; 51(4):615-622 [PubMed] Related Publications
OBJECTIVE: To construct the prognostic model and identify the prognostic biomarkers based on long non-coding RNA (lncRNA) in bladder cancer.
METHODS: The lncRNA expression data and corresponding clinical data of bladder cancer were collected from The Cancer Genome Atlas (TCGA) database. The software Perl and R, and R packages were used for data integration, extraction, analysis and visualization. Detailly, R package "edgeR" was utilized to screen differentially expressed lncRNA in bladder cancer tissues compared with the normal bladder samples. The univariate Cox regression and the least absolute shrinkage and selection operator (Lasso) regression were performed to identify key lncRNA that were utilized to construct the prognostic model by the multivariate Cox regression. According to the median value of the risk score, all patients were divided into the high-risk group and low-risk group to perform the Kaplan-Meier (K-M) survival curves, receiver operating characteristic (ROC) curve and C-index, estimating the prognostic power of the prognostic model. In addition, the hazard ratio (HR) and 95% confidence interval (CI) of each key lncRNA were also calculated by the multivariate Cox regression. Moreover, we performed the K-M survival analysis for each significant key lncRNA from the result of the multivariate Cox regression.
RESULTS: A total of 691 lncRNA were identified as differentially expressed lncRNA, and 35 lncRNA signatures were initially considered associated with the prognosis of bladder cancer, where in 23 lncRNA were identified as key lncRNA associated with the prognosis. The overall survival time in years of the low-risk group was obviously longer than that of the high-risk group [(2.85±2.72) years vs. (1.58±1.51) years, P<0.001]. The area under the ROC curve (AUC) was 0.813 (3-year survival) and 0.778 (5-year survival) respectively, and the C-index was 0.73. In addition, HR and 95%CI of each key lncRNA were calculated by the multivariate Cox regression and 11 lncRNA were significant. Furthermore, K-M survival analysis revealed the independent prognostic value of 3 lncRNA, including AL589765.1 (P=0.004), AC023824.1 (P=0.022)and PKN2-AS1 (P=0.016).
CONCLUSION: The present study successfully constructed the prognostic model based on the expression level of 23 lncRNA and finally identified one protective prognostic biomarker AL589765.1, and two adverse prognostic biomarkers including AC023824.1 and PKN2-AS1 in bladder cancer.

Yang F, Zhou Q, Meng L, Xing N
IMP3 is a biomarker for non-muscle-invasive urothelial carcinoma of the bladder associated with an aggressive phenotype.
Medicine (Baltimore). 2019; 98(27):e16009 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is one of the most common malignancies of urinary tract. The current study aimed to investigate the role of insulin-like growth factor II messenger RNA binding protein 3 (IMP3) expression in the prognostic evaluation of non-muscle- invasive urothelial carcinoma of the bladder.Immunohistochemistry (IHC) was carried out to examine IMP3 protein expression in specimens from 183 cases of non-muscle-invasive urothelial carcinoma, 20 cases of muscle-invasive urothelial carcinoma and 20 benign tissues adjacent to cancer tissue.The expression of IMP3 was not detected in the adjacent benign tissues. The expression intensity of IMP3 in muscle-invasive samples was significantly higher than that in non-muscle-invasive urothelial carcinoma specimens (P = .008). IMP3 expression was significantly related with advanced tumor stage (P < .001), advanced tumor grade (P = .004), and tumor recurrence (P < .001) in non-muscle-invasive urothelial carcinomas. Kaplan-Meier analysis showed that IMP3-positive patients had much lower disease-free (P < .001), progression-free (P = .002) and metastasis-free (P = .019) survival rates compared with those with IMP3-negative tumors. By multivariable Cox analysis, we also found that IMP3 expression in non-muscle- invasive urothelial carcinomas proved to be an independent unfavorable prognostic factor of disease-free survival (HR: 2.52; 95% CI, 1.39-4.56; P = .002), progression- free survival (HR: 5.19; 95% CI, 1.54-17.46; P = .008) and metastasis-free survival (HR: 4.87; 95% CI, 1.08-22.02; P = .040).Our results demonstrate that the expression of IMP3 in non-muscle- invasive bladder cancer can serve as an independent predictor that will help recognize the subgroup of patients with a high ability to relapse, progress, and metastasize and who might get the maximum benefit from an early and more aggressive treatment strategy.

Blanca A, Sanchez-Gonzalez A, Requena MJ, et al.
Expression of miR-100 and miR-138 as prognostic biomarkers in non-muscle-invasive bladder cancer.
APMIS. 2019; 127(8):545-553 [PubMed] Related Publications
microRNA alterations are involved in bladder cancer tumorigenesis. The aim of the current study was to evaluate the potential role of miR-100 and miR-138 as prognostic biomarkers in Ta/T1 non-muscle-invasive bladder cancer (NMIBC). We assessed a quantitative RT-PCR analysis of miR-100 and miR-138 in 50 bladder tumor samples (stage Ta/T1) and four healthy adjacent tissues. Western blot analysis was used to measure protein expression of FGFR3 and cyclin D3 in order to know whether these targets can be regulated by miR-100 and miR-138, respectively. The statistical analysis included non-parametric tests (Mann-Whitney U and Kruskal-Wallis) and univariate survival analysis by Kaplan-Meier method and the log-rank test. Low expression of miR-138 characterized recurrent tumors (p = 0.043), and higher expression levels were associated with longer recurrence-free survival (p = 0.012). However, low miR-100 expression correlated with longer progression-free survival (marginal significance; p = 0.053) and cancer-specific overall survival (p = 0.006). Additionally, higher levels of miR-100 were associated with negative FGFR3 protein expression (p = 0.032) and higher levels of miR-138 were associated with positive cyclin D3 protein expression (p = 0.037). Our results support miR-138 and miR-100 as prognostic biomarkers in patients with NMIBC.

Ma QY, Li SY, Li XZ, et al.
Long non-coding RNA DILC suppresses bladder cancer cells progression.
Gene. 2019; 710:193-201 [PubMed] Related Publications
Accumulative researches have demonstrated the critical functions of long non-coding RNAs (lncRNAs) in the progression of malignant tumors, including bladder cancer (BC). Our previous studies showed that lnc-DILC was an important tumor suppressor gene in both liver cancer and colorectal cancer. However, the role of lnc-DILC in BC remains to be elucidated. In the present study, we for first found that lnc-DILC was downregulated in human bladder cancer tissues. Lnc-DILC overexpression suppressed the proliferation, metastasis and expansion of bladder cancer stem cells (CSCs). Mechanically, lnc-DILC suppressed BC cells progression via STAT3 pathway. Special STAT3 inhibitor S3I-201 diminished the discrepancy of growth, metastasis and self-renewal ability between lnc-DILC-overexpression BC cells and their control cells, which further confirmed that STAT3 was acquired for lnc-DILC-disrupted BC cell growth, metastasis and self-renewal. Taken together, our results suggest that lnc-DILC is a novel bladder tumor suppressor and indicate that lnc-DILC inhibits BC progression via inactivating STAT3 signaling.

Pietilä M, Sahgal P, Peuhu E, et al.
SORLA regulates endosomal trafficking and oncogenic fitness of HER2.
Nat Commun. 2019; 10(1):2340 [PubMed] Free Access to Full Article Related Publications
The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

Wang X, Lyu J, Ji A, et al.
Jarid2 enhances the progression of bladder cancer through regulating PTEN/AKT signaling.
Life Sci. 2019; 230:162-168 [PubMed] Related Publications
AIMS: Jumonji AT-rich interactive domain 2 (Jarid2) is an interacting component of PRC2 which catalyzes methylation of H3K27 (H3K27me3) and causes the downregulation of PTEN. In the present study, we aimed to explore whether Jarid2 could interact with H3K27me3 to regulate PTEN expression in bladder cancer.
MAIN METHODS: Jarid2 expression in bladder cancer tissues and cells were determined by western blotting and RT-PCR. CCK-8, flow cytometry, transwell chamber and in vivo xenograft assays were performed to assess cell growth, apoptosis, migration and tumorigenesis, respectively. Chromatin immunoprecipitation (ChIP) assay was used to assess the methylation of PTEN.
KEY FINDINGS: Jarid2 expression was increased in bladder cancer tissues and cells. Downregulation of Jarid2 with shRNA transfection obviously inhibited the proliferation, migration and tumorigenesis of bladder cancer T24 and HT-1376 cells and induced cell apoptosis. Jarid2 downregulation decreased the expression of p-AKT and increased PTEN expression. Besides, Jarid2 down-regulation repressed the epithelial-mesenchymal transition (EMT), whereas knockdown of PTEN impaired this effect. Moreover, upregulation of Jarid2 increased the combination of PTEN promoter and H3K27me3, and 5-aza-CdR rescued it. Meanwhile, 5-aza-CdR administration abolished Jarid2 roles in the promotion of EMT process and AKT activation, as well as the reduction of PTEN expression.
SIGNIFICANCE: Overall, the present study elaborated that Jarid2 facilitated the progression of bladder cancer through H3K27me3-mediated PTEN downregulation and AKT activation, which might provide a new mechanism for Jarid2 in promoting bladder cancer progression.

Nakamura Y, Miyata Y, Takehara K, et al.
The Pathological Significance and Prognostic Roles of Thrombospondin-1, and -2, and 4N1K-peptide in Bladder Cancer.
Anticancer Res. 2019; 39(5):2317-2324 [PubMed] Related Publications
BACKGROUND/AIM: Thrombospondins (TSPs) play a role as inhibitors of angiogenesis under various pathological conditions. The aim of the study was to evaluate the pathological significance and prognostic role of the 4N1K-peptide (KRFYVVMWKK), which is derived from TSP-1 and -2, in bladder cancer.
MATERIALS AND METHODS: Two-hundred and six bladder cancer tissues were examined for expression of TSP-1, TSP-2, and 4N1K-peptide by immunohistochemistry. Cancer cell proliferation, apoptosis, angiogenesis and matrix metalloproteinase (MMP)-9 immunoreactivity were also examined.
RESULTS: Expression of TSP-2 and 4N1K-peptide was negatively associated with T stage, metastasis, and grade. TSP-2 expression was negatively associated with cancer cell proliferation and MMP-9 expression, whereas 4N1K-peptide was significantly associated with apoptosis, angiogenesis, and MMP-9 expression. Multivariate analysis showed that 4N1K-peptide expression was a significant predictor of metastasis (hazard ratio=3.90, p=0.002).
CONCLUSION: TSP-2 and 4N1K peptide played important roles in malignant aggressiveness and progression of bladder cancer via complex mechanisms involving cell proliferation, apoptosis, angiogenesis, and MMP-9.

Zhang C, Wang W, Lin J, et al.
lncRNA CCAT1 promotes bladder cancer cell proliferation, migration and invasion.
Int Braz J Urol. 2019 May-Jun; 45(3):549-559 [PubMed] Related Publications
OBJECTIVE: To study the expression patterns of long noncoding RNA (lncRNA) colon cancer-associated transcript 1 (CCAT1) and the changes in cell proliferation, apoptosis, migration and invasion induced by silencing CCAT1 in bladder cancer cells.
MATERIALS AND METHODS: The expression levels of CCAT1 were determined using realtime quantitative polymerase chain reaction in cancerous tissues and paired normal tissues from 34 patients with bladder cancer. The relationship between clinical characteristics and CCAT1 expression was analyzed. And then we conducted cell experiments. Bladder urothelial carcinoma cell lines T24 and 5637 cells were transfected with CCAT1 small interfering RNA (siRNA) or scramble siRNA. Cell proliferation and apoptosis changes were determined using a Cell Counting Kit-8 (CCK-8) assay and a fl ow cytometry assay. Migration and invasion changes were measured using a wound healing assay and a trans-well assay. microRNAs (miRNAs) were predicted by Starbase 2.0, and their differential expression levels were studied.
RESULTS: CCAT1 was signifi cantly upregulated in bladder cancer (P < 0.05). CCAT1 upregulation was positively related to tumor stage (P = 0.004), tumor grade (P = 0.001) and tumor size (P = 0.042). Cell proliferation, migration and invasion were promoted by abnormally expressed CCAT1. miRNAs miR-181b-5p, miR-152-3p, miR-24-3p, miR-148a-3p and miR-490-3p were potentially related to the aforementioned functions of CCAT1.
CONCLUSION: CCAT1 plays an oncogenic role in urothelial carcinoma of the bladder. In addition, CCAT1 may be a potential therapeutic target in this cancer.

Yang PJ, Hsieh MJ, Hung TW, et al.
Effects of Long Noncoding RNA H19 Polymorphisms on Urothelial Cell Carcinoma Development.
Int J Environ Res Public Health. 2019; 16(8) [PubMed] Free Access to Full Article Related Publications
Urothelial cell carcinoma (UCC) is one of the major malignancies of the genitourinary tract, and it is induced by carcinogenic epidemiological risk factors. H19 is one of the most crucial long noncoding RNAs (lncRNAs) and is involved in various types of bladder cancer. In this study, we examined H19 single-nucleotide polymorphisms (SNPs) to investigate UCC susceptibility and clinicopathological characteristics. Using real-time polymerase chain reaction, we analyzed five SNPs of H19 in 431 UCC patients and 431 controls without cancer. The results showed that patients with UCC carrying the H19 rs217727 CT + TT and rs2107425 CT + TT genetic variants had a high risk of developing muscle invasive tumors (pT2-T4) (

Deng S, Ren ZJ, Jin T, et al.
Contribution of prostate stem cell antigen variation rs2294008 to the risk of bladder cancer.
Medicine (Baltimore). 2019; 98(16):e15179 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Number of studies have been performed to evaluate the relationship between prostate stem cell antigen (PSCA) variation rs2294008 and bladder cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association.
METHODS: Pubmed, Web of science, Embase, China biology medical literature database (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang and Weipu databases were searched before June 30, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0.
RESULTS: Ten studies involved 14,021 cases and 26,871 controls. Overall, significant association was observed between the PSCA gene variant rs2294008 polymorphism and bladder cancer (T vs C: OR = 1.16, 95%CI = 1.12-1.20; TT vs CC: OR = 1.32, 95%CI = 1.24-1.41; TT vs CT+CC: OR = 1.15, 95%CI = 1.09-1.22; TT+CT vs CC: OR = 1.27, 95%CI = 1.21-1.34). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.23, 95%CI = 1.15-1.31) and Caucasians (T vs C: OR = 1.14, 95%CI = 1.10-1.18). The sensitivity analysis confirmed the reliability and stability of the meta-analysis.
CONCLUSION: Our meta-analysis supports that the PSCA gene variant rs2294008 polymorphism might contribute to individual susceptibility to bladder cancer.

Zhang Q, Mao Z, Sun J
NF-κB inhibitor, BAY11-7082, suppresses M2 tumor-associated macrophage induced EMT potential via miR-30a/NF-κB/Snail signaling in bladder cancer cells.
Gene. 2019; 710:91-97 [PubMed] Related Publications
BACKGROUND: Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer.
METHODS: In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer.
RESULTS: First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as β-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082.
CONCLUSION: Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.

Mao W, Huang X, Wang L, et al.
Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression.
J Exp Clin Cancer Res. 2019; 38(1):169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FGFR3 plays an important role in the development of bladder cancer (BCa). Hsa_circ_0068871 is a circRNA generated from several exons of FGFR3. However, the potential functional role of hsa_circ_0068871 in BCa remains largely unknown. Here we aim to evaluate the role of hsa_circ_0068871 in BCa.
METHODS: We selected miR-181a-5p as the potential target miRNA of hsa_circ_0068871. The expression levels of hsa_circ_0068871 and miR-181a-5p were examined in BCa tissues and paired adjacent normal tissues by quantitative real-time PCR. To characterize the function of hsa_circ_0068871, BCa cell lines were stably infected with lentivirus targeting hsa_circ_0068871, followed by examinations of cell proliferation, migration and apoptosis. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0068871 in BCa. Biotinylated RNA probe pull-down assay, fluorescence in situ hybridization and luciferase reporter assay were conducted to confirm the relationship between hsa_circ_0068871, miR-181a-5p and FGFR3.
RESULTS: Hsa_circ_0068871 is over-expressed in BCa tissues and cell lines, whereas miR-181a-5p expression is repressed. Depletion of has_circ_0068871 or upregulation of miR-181a-5p inhibited the proliferation and migration of BCa cells in vitro and in vivo. Mechanistically, hsa_circ_0068871 upregulated FGFR3 expression and activated STAT3 by targeting miR-181a-5p to promote BCa progression.
CONCLUSIONS: Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote BCa progression, and it may serve as a potential biomarker.

Liu P, Li X, Guo X, et al.
Circular RNA DOCK1 promotes bladder carcinoma progression via modulating circDOCK1/hsa-miR-132-3p/Sox5 signalling pathway.
Cell Prolif. 2019; 52(4):e12614 [PubMed] Related Publications
OBJECTIVES: To reveal the role of circular RNA (circRNA) DOCK1 (circDOCK1) as a potential biomarker and therapeutic target and its competing endogenous RNA mechanism in bladder carcinoma (BC).
METHODS: The next-generation sequencing (NGS) technology was introduced to screen the circRNA expression profiles of BC using microarray. qPCR and Western blots assay were employed to measure the gene expression in different groups. Cell counting kit-8, EdU and transwell assays were applied to detect the cell viability, proliferation and migration potential, respectively. Luciferase reporter assay was used to test the binds between hsa-miR-132-3p/Sox5. Xenografted tumour growth of nude mice was performed to test the role of circDOCK1 in vivo.
RESULTS: CircDOCK1 was upregulated in BC tissues and cell lines. Repression of circDOCK1 reduced cell viability, inhibited cell proliferation and curbed the cell migration potential of BC cell. CircDOCK1 played its role via regulation of circDOCK1/hsa-miR-132-3p/Sox5 pathway in BC cells. Suppression circDOCK1 inhibited the tumour growth in vivo.
CONCLUSION: In this study, we revealed that circDOCK1 affected the progression of BC via modulation of circDOCK1/hsa-miR-132-3p/Sox5 pathway both in vitro and in vivo and providing a potential biomarker and therapeutic targets for BC.

Sugita S, Yoshino H, Yonemori M, et al.
Tumor‑suppressive microRNA‑223 targets WDR62 directly in bladder cancer.
Int J Oncol. 2019; 54(6):2222-2236 [PubMed] Related Publications
miRNA‑223 (miR‑223) has been reported to function not only as a tumor suppressor, but also as an oncogenic microRNA (miRNA or miR) in various cancer cells. Therefore, the functional role of miR‑223 has not been elucidated to date, at least to the best of our knowledge. We previously performed the deep sequencing analysis of clinical bladder cancer (BC) specimens. It was revealed that miR‑223 expression was significantly downregulated in BC, suggesting that miR‑223 functions as a tumor suppressor miRNA in BC. The aim of this study was to investigate the functional roles of miR‑223 and to identify its targets in BC. The expression levels of miR‑223 were significantly decreased in our clinical BC specimens. The Cancer Genome Atlas (TCGA) database indicated that miR‑223 expression was related to lymphovascular invasion and distant metastasis. The restoration of miR‑223 expression significantly inhibited tumor aggressiveness and induced apoptosis via caspase‑3/7 activation in BC cells. WD repeat domain 62 (WDR62), a candidate target of miR‑223 according to in silico analyses, has been previously proposed to play a role in neurodevelopment. Direct binding between WDR62 and miR‑223 was confirmed by luciferase assay. The TCGA database revealed positive associations between WDR62 mRNA expression and a higher tumor grade and stage in BC. The knockdown of WDR62 significantly inhibited tumor aggressiveness and induced the apoptosis of BC cells. On the whole, the findings of this study reveal a novel miR‑223 target, oncogenic WDR62, and provided insight into the oncogenesis of BC.

Han Y, Zheng Q, Tian Y, et al.
Identification of a nine-gene panel as a prognostic indicator for recurrence with muscle-invasive bladder cancer.
J Surg Oncol. 2019; 119(8):1145-1154 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Bladder cancer is one of the most common and highly recurrent cancers worldwide. Recurrence-associated genes may potentially predict cancer recurrence. We aimed to construct a recurrence-associated gene panel to improve the prognostic prediction of bladder cancer.
METHODS: Based on DNA sequencing and clinical data from the TCGA-BLCA project, we identified 10 potential driver genes significantly associated with recurrence of bladder cancer. We performed multivariable logistic regression analysis to construct an optimized recurrence prediction model with nine recurrence-associated genes (EME1, AKAP9, ZNF91, PARD3, STAG2, ZFP36L2, METTL3, POLR3B, and MUC7) and clinical information as the independent variables.
RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.80 in this model, much higher than that of the baseline model (AUC = 0.73) and the same trend was also validated in its subset. Decision curve analysis also revealed that there is a significant net benefit gained by adding nine genes mutation to the baseline model. Furthermore, Kaplan-Meier survival analysis showed that eight out of the nine genes (excluding MUC7) had good effects on the overall prognosis of patients.
CONCLUSIONS: This nine-gene panel will most likely be a useful tool for prognostic evaluation and will facilitate the personalized management of patients with bladder cancer.

Amir H, Khan MA, Feroz S, et al.
CARLo-7-A plausible biomarker for bladder cancer.
Int J Exp Pathol. 2019; 100(1):25-31 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Cancer is defined as undifferentiated and unchecked growth of cells damaging the surrounding tissue. Cancers manifest altered gene expression. Gene expression is regulated by a diverse array of non-protein-coding RNA. Aberrant expression of long non-coding RNAs (lncRNAs) has been recently found to have functional consequences in cancers. In the current study, we report CARLo-7 as the only bladder cancer-specific lncRNA from the CARLos cluster. The expression of this lncRNA correlates with bladder cancer grade. We propose that CARLo-7 has an oncogenic potential and might be regulator of cell proliferation. Furthermore, by comparison the expression of proto-oncogene MYC, which is the only well-annotated gene close to the cancer - associated linkage disequilibrium blocks of this region, does not show a pronounced change in expression between the low- and high-grade tumours. Our results indicate that CARlo-7 can act as a prognostic marker for bladder cancer.

Chen J, Cao L, Li Z, Li Y
SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake.
Hum Cell. 2019; 32(2):193-201 [PubMed] Related Publications
Bladder cancer (BC) is one of the most common tumors. Metabolic reprogramming is a feature of neoplasia and tumor growth. Understanding the metabolic alterations in bladder cancer may provide new directions for bladder cancer treatment. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators. In pancreatic cancer, the loss of SIRT1 is accompanied by a decreased expression of proteins in the glycolysis pathway, such as GLUT1, and cancer cell proliferation. Thus, we hypothesize that SIRT1 may interact with GLUT1 to modulate the proliferation and glycolysis phenotype in bladder cancer. In the present study, the expression of SIRT1 and GLUT1 was upregulated in BC tissues and cell lines and positively correlated in tissue samples. SIRT1 overexpression or GLUT1 overexpression alone was sufficient to promote cell proliferation and glucose uptake in BC cells. EX527, a specific inhibitor of SIRT1, exerted an opposing effect on bladder cancer proliferation and glucose uptake. The effect of EX527 could be partially reversed by GLUT1 overexpression. More importantly, SIRT1 overexpression significantly promoted the transcriptional activity and expression of GLUT1, indicating that SIRT1 increases the transcription activity and expression of GLUT1, therefore, promoting the cell proliferation and glycolysis in BC cells. Our study first reported that SIRT1/GLUT1 axis promotes bladder cancer progression via regulation of glucose uptake.

Sekino Y, Sakamoto N, Ishikawa A, et al.
Transcribed ultraconserved region Uc.63+ promotes resistance to cisplatin through regulation of androgen receptor signaling in bladder cancer.
Oncol Rep. 2019; 41(5):3111-3118 [PubMed] Related Publications
Cisplatin (CDDP)‑based combination chemotherapy is the standard for muscle‑invasive bladder cancer (MIBC). However, nearly all patients undergoing CDDP chemotherapy become refractory due to the development of CDDP resistance. Therefore, clarification of the mechanisms of CDDP resistance is urgently needed. The transcribed ultraconserved regions (T‑UCRs) are a novel class of non‑coding RNAs that are highly conserved across species and are associated with carcinogenesis and cancer progression. In addition, emerging evidence has shown the involvement of androgen receptor (AR) signals in urothelial carcinoma (UC) progression. The aim of the present study was to investigate the expression of transcribed ultraconserved region Uc.63+, and to analyze the effects of Uc.63+ on AR expression and CDDP resistance in UC. Quantitative reverse transcription‑polymerase chain reaction (qRT‑PCR) revealed that the expression of Uc.63+ was higher in UC tissues than that in non‑neoplastic bladder tissues and 15 types of normal tissue. An MTT assay revealed that Uc.63+ was involved in cell proliferation. Western blotting demonstrated that the expression of AR was disrupted by the overexpression or knockdown of Uc.63+ in AR‑positive UMUC3 cells. Furthermore, knockdown of Uc.63+ increased sensitivity to CDDP in UMUC3 cells. Conversely, overexpression of Uc.63+ had no effect on CDDP sensitivity in AR‑negative RT112 cells. Additionally, we observed that the expression of Uc.63+ was increased in CDDP‑resistant UMUC3 cells (UMUC3‑CR) in comparison with that in parental UMUC3 cells. Knockdown of Uc.63+ re‑sensitized the UMUC3‑CR cells to CDDP. These results indicated that Uc.63+ may be a promising therapeutic target to overcome CDDP resistance in UC.

Groves A, Gleeson M, Spigelman AD
NTHL1-associate polyposis: first Australian case report.
Fam Cancer. 2019; 18(2):179-182 [PubMed] Related Publications
While familial adenomatous polyposis accounts for approximately 1% of all colorectal cancer, the genetic cause underlying the development of multiple colonic adenomas remains unsolved in many patients. Adenomatous polyposis syndromes can be divided into: familial adenomatous polyposis, MUTYH-associated polyposis, polymerase proofreading associated polyposis and the recently described NTHL1-associated polyposis (NAP). NAP is characterised by recessive inheritance, attenuated adenomatous polyposis, colonic cancer(s) and possible extracolonic malignancies. To date, 11 cases have been reported as having germline homozygous or compound heterozygous mutations in the base excision repair gene NTHL1. Here we present a further case of a 65-year-old male with a history of adenomatous polyposis and bladder cancer, who has a previously described homozygous nonsense variant in the NTHL1 gene. This case is consistent with the emerging phenotype previously described of multiple colorectal adenomas and at least one primary tumour, adding to the small but growing body of literature about NAP.

Feng J, Chen K, Dong X, et al.
Genome-wide identification of cancer-specific alternative splicing in circRNA.
Mol Cancer. 2019; 18(1):35 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Circular RNA (circRNA) is a group of RNA families generated by RNA circularization, which was discovered ubiquitously across different cancers. However, the internal structure of circRNA is difficult to determine due to alternative splicing that occurs in its exons and introns. Furthermore, cancer-specific alternative splicing of circRNA is less likely to be identified. Here, we proposed a de novo algorithm, CircSplice, that could identify internal alternative splicing in circRNA and compare differential circRNA splicing events between different conditions ( http://gb.whu.edu.cn/CircSplice or https://github.com/GeneFeng/CircSplice ). By applying CircSplice in clear cell renal cell carcinoma and bladder cancer, we detected 4498 and 2977 circRNA alternative splicing (circ-AS) events in the two datasets respectively and confirmed the expression of circ-AS events by RT-PCR. We further inspected the distributions and patterns of circ-AS in cancer and adjacent normal tissues. To further understand the potential functions of cancer-specific circ-AS, we classified those events into tumor suppressors and oncogenes and performed pathway enrichment analysis. This study is the first comprehensive view of cancer-specific circRNA alternative splicing, which could contribute significantly to regulation and functional research of circRNAs in cancers.

Song Y, Yang Y, Liu L, Liu X
Association between five polymorphisms in vascular endothelial growth factor gene and urinary bladder cancer risk: A systematic review and meta-analysis involving 6671 subjects.
Gene. 2019; 698:186-197 [PubMed] Related Publications
BACKGROUND: Vascular endothelial growth factor (VEGF) gene plays a key role in angiogenesis and tumor growth. The relationship between VEGF gene polymorphisms and bladder cancer (BCa) risk was studied extensively in recent years. However, the currently available results are controversial. To ascertain whether VEGF polymorphisms are associated with the susceptibility to BCa, we conducted this systematic review and meta-analysis.
MATERIALS AND METHODS: Relevant studies were collected systemically from PubMed, Medline, Embase, Web of Science databases and the Cochrane Library. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using random or fixed effects models by Stata statistical software. This systematic review protocol was registered at International prospective register of systematic reviews (PROSPERO) under number CRD42018099279.
RESULTS: A total of eight articles including twenty case-control studies with 3206 BCa cases and 3645 controls were enrolled for this meta-analysis. By pooling all eligible studies, we found that rs3025039, rs833052 and rs25648 polymorphisms were significantly associated with BCa risk. However, in subgroup analyses by stage, we identified a decreased association between the rs699947 A-allele and Muscle-invasive Bladder Cancer (MIBC) under allele contrast, homozygous and recessive genetic models (A vs C: OR = 0.76; AA vs CC: OR = 0.49, 95%CI = 0.27-0.90, I
CONCLUSION: Our meta-analysis suggested that rs3025039 (C > T), rs833052 (C > A) and rs25648 (C > T) polymorphisms of VEGF gene increased susceptibility to BCa risk. And our study also demonstrated homozygous TT genotype in rs3025039, homozygous AA genotype in rs833052 and homozygous TT genotype in rs25648 were significantly relevant to elevated BCa risk. In the meanwhile, it is worth noting that rs699947 (C > A) A-allele should be thought as a protective factor for MIBC.

Humayun-Zakaria N, Arnold R, Goel A, et al.
Tropomyosins: Potential Biomarkers for Urothelial Bladder Cancer.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Despite the incidence and prevalence of urothelial bladder cancer (UBC), few advances in treatment and diagnosis have been made in recent years. In this review, we discuss potential biomarker candidates: the tropomyosin family of genes, encoded by four loci in the human genome. The expression of these genes is tissue-specific. Tropomyosins are responsible for diverse cellular roles, most notably based upon their interplay with actin to maintain cellular processes, integrity and structure. Tropomyosins exhibit a large variety of splice forms, and altered isoform expression levels have been associated with cancer, including UBC. Notably, tropomyosin isoforms are detectable in urine, offering the potential for non-invasive diagnosis and risk-stratification. This review collates the basic knowledge on tropomyosin and its isoforms, and discusses their relationships with cancer-related phenomena, most specifically in UBC.

Maia MC, Hansen A, Alves C, Salah S
Biomarkers in Non-Schistosomiasis-related squamous cell carcinoma of the urinary bladder: A review.
Crit Rev Oncol Hematol. 2019; 135:76-84 [PubMed] Related Publications
Non-urothelial (NU) histologies represent less than 10% of bladder cancers, with squamous cell carcinoma (SCC) being the most common subtype (approximately 5%). Bladder SCCs are subdivided into Schistosoma-related or non-Schistosoma-related tumors, with the latter being the most frequent subtype in the western world. Typically, these patients have been excluded or under-represented in clinical trials and thus little is known about treatment efficacy in bladder SCC. To address this paucity of data, extrapolation from urothelial carcinoma (UC) trials can be performed but this approach has inherent limitations. In the era of precision medicine, efforts to characterize the genomic and molecular profiles of bladder tumors may yield evidence to support new targets for effective therapies. We reviewed the available data on biomarkers of bladder SCC and provide suggestions on how these may influence therapeutic testing and clinical trials in the future.

Tsui KH, Hou CP, Chang KS, et al.
Metallothionein 3 Is a Hypoxia-Upregulated Oncogene Enhancing Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells.
Int J Mol Sci. 2019; 20(4) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (

Morra F, Merolla F, Criscuolo D, et al.
CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer.
J Exp Clin Cancer Res. 2019; 38(1):90 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells.
METHODS: The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis.
RESULTS: P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels.
CONCLUSIONS: In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients.

Fus ŁP, Pihowicz P, Koperski Ł, et al.
HIF-1α expression is inversely associated with tumor stage, grade and microvessel density in urothelial bladder carcinoma.
Pol J Pathol. 2018; 69(4):395-404 [PubMed] Related Publications
Urothelial bladder carcinoma (UBC) is the most common urinary tract malignancy. The most important histopathological factors affecting prognosis are cancer stage and grade. Studies show that microvessel density (MVD) reflecting angiogenesis is also associated with clinicopathological features and affects the outcome in UBC. One of the most important regulators of angiogenesis is hypoxia inducible factor 1 (HIF-1). Previous reports describing expression of the HIF-1α subunit in UBC showed unclear and inconsistent results. Our study attempted do evaluate the association between HIF-1α expression and tumor stage, grade, lymph nodes status and MVD in UBC. We performed immunohistochemical staining in 99 UBC cases, including 38 non-muscle invasive (NMIBC) and 61 muscle invasive tumors (MIBC). We observed inverse relationships between HIF-1α immunoreactivity score (IRS) and tumor stage, grade and MVD. Significantly lower HIF-1α IRS values were observed in MIBC and high grade cancers. We found a significant negative correlation between HIF-1α IRS and MVD. These results suggest that HIF-1α pathway is not involved in UBC growth and progression, and that angiogenesis in high grade MIBC is not regulated by HIF-1. Our findings contradict previous reports regarding HIF-1α, MVD and UBC which shows the necessity of additional molecular studies in this field.

Su H, Tao T, Yang Z, et al.
Circular RNA cTFRC acts as the sponge of MicroRNA-107 to promote bladder carcinoma progression.
Mol Cancer. 2019; 18(1):27 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Circular RNA (circRNA) represents a broad and diverse endogenous RNAs that can regulate gene expression in cancer. However, the regulation and function of bladder cancer (BC) circRNAs remain largely unknown.
METHODS: Here we generated circRNA microarray data from three BC tissues and paired non-cancerous matched tissues, and detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. We subsequently performed functional analyses in cell lines and an animal model to support clinical findings. Mechanistically, we demonstrated that cTFRC could directly bind to miR-107 and relieve suppression for target TFRC expression.
RESULTS: We detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. Knock down of cTFRC inhibited invasion and proliferation of BC cell lines in vitro and tumor growth in vivo. Furthermore, the expression of cTFRC correlated with TFRC and negatively correlated with miR-107 both in BC cell lines and BC clinical samples. In addition, up-regulation of cTFRC promoted TFRC expression and contributed to an epithelial to mesenchymal transition phenotype in BC cells. Finally, we found that cTFRC acts as a competing endogenous RNA (ceRNA) for miR-107 to regulate TFRC expression.
CONCLUSIONS: cTFRC may exert regulatory functions in BC and may be a potential marker of BC diagnosis or progression.

Tan Y, Zhang T, Zhou L, et al.
MiR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.
Med Sci Monit. 2019; 25:1323-1335 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND Chemoresistance is a main limitation in chemotherapy for therapeutic cancer. MicroRNA (miRNA) has been indicated in the progression and tumorigenesis of many types of cancer, but the effect of miR-34b-3p in bladder cancer (BCa) cells is still unknown. MATERIAL AND METHODS This research compared the multidrug-sensitive (5637) BCa cell line and the multidrug-resistant (EJ) BCa cell line. We found that CCND2 (G1/S-specific cyclin-D2) and P2RY1 (purinergic receptor P2Y1) were the targets of miR-34b-3p, as further validated by qRT-PCR (quantitative real-time polymerase chain reaction) and western blot analysis. RESULTS Forced reversal of the levels of miR-34b-3p or CCND2/P2RY1 changed the chemoresistance profiles in both 5637 cells and EJ cells. Further experiments suggested that the CCND2 gene and the P2RY1 gene act in concert to negatively correlate with miR-34b-3p effect on BCa multidrug-chemoresistance. CONCLUSIONS These results not only reveal new players regulating BCa chemoresistance, but also provide clues for effective chemotherapy for BCa patients.

Wu S, Ou T, Xing N, et al.
Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer.
Nat Commun. 2019; 10(1):720 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conduct whole-genome and targeted sequencing in urothelial bladder carcinomas (UBCs, the most common type of bladder cancer). Recurrent mutations in noncoding regions affecting gene regulatory elements and structural variations (SVs) leading to gene disruptions are prevalent. Notably, we find recurrent ADGRG6 enhancer mutations and FRS2 duplications which are associated with higher protein expression in the tumor and poor prognosis. Functional assays demonstrate that depletion of ADGRG6 or FRS2 expression in UBC cells compromise their abilities to recruit endothelial cells and induce tube formation. Moreover, pathway assessment reveals recurrent alterations in multiple angiogenesis-related genes. These results illustrate a multidimensional genomic landscape that highlights noncoding mutations and SVs in UBC tumorigenesis, and suggest ADGRG6 and FRS2 as novel pathological angiogenesis regulators that would facilitate vascular-targeted therapies for UBC.

Deng S, He SY, Zhao P, Zhang P
The role of oncostatin M receptor gene polymorphisms in bladder cancer.
World J Surg Oncol. 2019; 17(1):30 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Oncostatin M receptor (OSMR) represents a part of the interleukin-six (IL6) cytokine group that was discovered recently to be closely associated with cell's growth and differentiation, inflammation, and enhancement of metastatic capacity. A comprehensive study suggests a close relationship between OSMR and papillary thyroid cancer, colorectal cancer, breast cancer, and other tumors. However, the relationship between OSMR and bladder cancer has yet to be determined.
METHODS: Three hundred six patients (including 142 patients with muscle-invasive bladder cancer and 164 patients with non-muscle-invasive bladder cancer) as well as 459 normal controls were included in this study. Two tag SNPs of OSMR, rs2278329, and rs2292016 were genotyped by TaqMan® SNP Genotyping Assay method and then the associations with bladder cancer were analyzed, as well as risk factors and prognosis.
RESULTS: Patients with bladder cancer and controls did not differ significantly in terms of genotype frequencies and allele frequency distribution of rs2278329 (P = 0.77, OR = 0.97) and rs2292016 (P = 0.39, OR = 1.20) respectively. For rs2278329, no differences were found in terms of risk factors in stratified analyses. However, rs2292016 was associated with recurrence and tumor grade. GT/TT was found to increase the risk of relapse compared to the patients without allele T (GG genotype) (P = 0.016, OR = 1.878, 95% CI = 1.12-3.14) with the T allele of rs2292016 being a risk factor for recurrence (P = 0.032, OR = 0.67, 95% CI = 0.47-0.97). Besides, patients with GT genotype often present with high-grade bladder cancer (P = 0.003, OR = 2.33, 95% CI = 1.32-4.17). Multiple Cox regression analysis showed that rs2278329 and rs2292016 were related to the recurrence-free survival and overall survival in non muscle invasive bladder cancer (NMIBC) patients. For rs2278329, GA genotype could affect recurrence-free survival (P = 0.01, OR = 2.16, 95% CI = 1.17-3.98). For rs2292016, TT/GT genotype had a lower risk of death compared with GG homozygote genotype, and T was a protective factor for overall survival in bladder cancer (P = 0.029, OR = 0.22, 95% CI = 0.06-0.86).
CONCLUSIONS: OSMR genotype frequencies were found to be associated with higher recurrence in bladder cancer, and it may serve as a biomarker candidate gene to predict prognosis of this disease. Further validation of OSMR as biomarker is required.

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Chromosome Y Loss in Bladder Cancer

Khaled HM, Aly MS, Magrath IT
Loss of Y chromosome in bilharzial bladder cancer.
Cancer Genet Cytogenet. 2000; 117(1):32-6 [PubMed] Related Publications
Bilharzial bladder cancer is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. In a previous study, using centromere probes specific for chromosomes 3, 4, 7-11, 16, and 17, we demonstrated that monosomy of chromosome 9 (48.4%), and numerical aberrations of chromosome 17 (19.4%) were the most common observed imbalances. The present study extends the establishment of the baseline cytogenetic profile of this type of malignancy. Interphase cytogenetics by fluorescence in situ hybridization with the use of a panel of centromere-associated DNA probes for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, X, and Y was performed on paraffin-embedded bladder specimens from 25 Egyptian patients affected with bilharzial bladder cancer. No numerical aberrations were detected in the 25 cases for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, and X. However, loss of chromosome Y was observed in 7 of the 17 male cases studied (41.2%). No significant correlation was observed between loss of the Y chromosome and any of the different clinicopathologic characteristics of these cases. These data suggest that loss of the Y chromosome is the second frequent event that can occur in bilharzial bladder cancer. A molecular genetic model of bilharzial bladder cancer is evolving.

Sauter G, Moch H, Wagner U, et al.
Y chromosome loss detected by FISH in bladder cancer.
Cancer Genet Cytogenet. 1995; 82(2):163-9 [PubMed] Related Publications
To examine the significance of Y chromosome losses in bladder cancer, fluorescence in situ hybridization (FISH) was used to determine its prevalence and associations with known parameters of malignancy. Cells were dissociated from formalin-fixed paraffin-embedded bladder tumors from 68 male patients and from 11 post-mortem bladder washes of male patients with a negative bladder cancer history, and were examined by FISH using centromeric probes for chromosomes X, Y, 7, 9, and 17. Nullisomy for chromosome Y was seen in 23 of 68 tumors (34%), monosomy in 28 of 68 tumors (41%), and polysomy in 17 of 68 tumors (25%). There was no association between chromosome Y loss and tumor grade, stage, tumor growth fraction (Ki67 LI), p53 immunostaining, and presence of p53 deletions. Patient age was higher for tumors with a Y loss (73.5 +/- 12.0 years) than for tumors without Y loss (66.6 +/- 10.8 years; p = 0.0207). In one normal bladder wash, a distinct subpopulation (38% of cells) with Y nullisomy was seen. These data suggest that Y loss is a frequent event that can occur early in bladder cancer, although there is no evidence for a role of Y loss in tumor progression.

del(9q) in Bladder Cancer

Loss of heterozygosity (LOH) on chromosome arm 9 is the most frequent genetic alteration in transitional cell carcinomas. Candidate tumor suppressor genes/loci have been proposed, including: CDKN2 and DBCCR1.

Habuchi T, Yoshida O, Knowles MA
A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC.
Hum Mol Genet. 1997; 6(6):913-9 [PubMed] Related Publications
Loss of heterozygosity (LOH) on chromosome 9q is the most frequent genetic alteration in transitional cell carcinoma (TCC) of the bladder, implicating the presence of a tumour suppressor gene or genes on 9q. To define the location of a tumour suppressor locus on 9q in TCC, we screened 156 TCCs of the bladder and upper urinary tract by detailed deletion mapping using 31 microsatellite markers on 9q. Partial deletions of 9q were found in 10 TCCs (6%), and LOH at all informative loci on 9q was found in 77 TCCs (49%). In five low grade superficial bladder tumours, the partial deletion was localized to D9S195 located at 9q32-33, with retention of heterozygosity at all other informative loci including D9S103, D9S258, D9S275 and GSN. We constructed a yeast artificial chromosome (YAC) contig covering the deleted region in these five tumours and placed another four unmapped microsatellite markers on this contig map. Using these markers, we further defined the common deleted region to the interval between D9S1848 and AFMA239XA9. The region is covered by a single YAC (852e11), whose size is estimated to be 840 kb. Our data should expedite further fine mapping and identification of the candidate tumour suppressor gene at 9q32-33.

Habuchi T, Luscombe M, Elder PA, Knowles MA
Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33.
Genomics. 1998; 48(3):277-88 [PubMed] Related Publications
Loss of heterozygosity (LOH) on chromosome 9q is the most frequent genetic alteration in transitional cell carcinoma (TCC) of the bladder, indicating the presence of one or more relevant tumor suppressor genes. We previously mapped one of these putative tumor suppressor loci to 9q32-q33 and localized the candidate region within a single YAC 840 kb in size. This locus has been designated DBC1 (for deleted in bladder cancer gene 1). We have identified a novel gene, DBCCR1, in this candidate region by searching for expressed sequence tags (ESTs) that map to YACs spanning the region. Database searching using the entire DBCCR1 cDNA sequence identified several human ESTs and a few homologous mouse. ESTs. However, the predicted 761-amino-acid sequence had no significant homology to known protein sequences. Mutation analysis of the coding region and Southern blot analysis detected neither somatic mutations nor gross genetic alterations in primary TCCs. Although DBCCR1 was expressed in multiple normal human tissues including urothelium, mRNA expression was absent in 5 of 10 (50%) bladder cancer cell lines. Methylation analysis of the CpG island at the 5' region of the gene and the induction of de novo expression by a demethylating agent indicated that this island might be a frequent target for hypermethylation and that hypermethylation-based silencing of the gene occurs in TCC. These findings make DBCCR1 a good candidate for DBC1.

Knowles MA
Identification of novel bladder tumour suppressor genes.
Electrophoresis. 1999; 20(2):269-79 [PubMed] Related Publications
Many genetic alterations have recently been identified in transitional cell carcinoma (TCC) of the bladder. These include alterations to known proto-oncogenes and tumour suppressor genes and the identification of multiple sites of nonrandom chromosomal deletion which are predicted to define the location of as yet unidentified tumour suppressor genes. This review summarises recent efforts to define the location of novel bladder tumour suppressor genes using loss of heterozygositiy (LOH) and homozygous deletion analyses and to isolate the genes targeted by these deletions. For three of the four regions of deletion on chromosome 9, the most frequently deleted chromosome in TCC, candidate genes have been identified. It is anticipated that the identification of the genes and/or genetic regions which are frequently altered in TCC will provide useful tools for diagnosis, prediction of prognosis, patient monitoring and novel therapies.

van Tilborg AA, Groenfeld LE, van der Kwast TH, Zwarthoff EC
Evidence for two candidate tumour suppressor loci on chromosome 9q in transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in bladder tumour cell lines.
Br J Cancer. 1999; 80(3-4):489-94 [PubMed] Free Access to Full Article Related Publications
The most frequent genetic alterations in transitional cell carcinoma (TCC) of the bladder involve loss of heterozygosity (LOH) on chromosome 9p and 9q. The LOH on chromosome 9p most likely targets the CDKN2 locus, which is inactivated in about 50% of TCCs. Candidate genes that are the target for LOH on chromosome 9q have yet to be identified. To narrow the localization of one or more putative tumour suppressor genes on this chromosome that play a role in TCC of the bladder, we examined 59 tumours with a panel of microsatellite markers along the chromosome. LOH was observed in 26 (44%) tumours. We present evidence for two different loci on the long arm of chromosome 9 where potential tumour suppressor genes are expected. These loci are delineated by interstitial deletions in two bladder tumours. Our results confirm the results of others and contribute to a further reduction of the size of these regions, which we called TCC1 and TCC2. These regions were examined for homozygous deletions with EST and STS markers. No homozygous deletions were observed in 17 different bladder tumour cell lines.

Simoneau M, Aboulkassim TO, LaRue H, et al.
Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31.
Oncogene. 1999; 18(1):157-63 [PubMed] Related Publications
The most common genetic alteration identified in transitional cell carcinoma (TCC) of the bladder is loss of heterozygosity (LOH) on chromosome 9. However, localization of tumor suppressor genes on 9q has been hampered by the low frequency of subchromosomal deletions. We have analysed 139 primary, initial low stage TCC of the bladder using a panel of 28 microsatellite markers spanning chromosome 9 at an average distance of 5 Mb, following a primer-extension preamplification (PEP) technique. Sixty-seven (48%) tumors showed LOH at one or more loci and partial deletions were detected in 62 (45%) tumors; apparent monosomy 9 was detected in only five (4%) tumors. Deletions were more frequent on 9q (44%) than on 9p (23%), the latter being mostly associated with 9q deletion, suggesting that alteration of genes on 9q may be an early event associated with superficial papillary tumors. Combined data from the cases with partial 9q deletions displayed four candidate regions for tumor suppressor loci, based on the frequency of deletion observed and tumors with unique deletions at these sites. In two tumors, the unique partial deletion comprised D9S12 at 9q22.3, a region encompassing loci for the Gorlin syndrome and multiple self-healing squamous epithelioma gene. In two other tumors, the single LOH was identified at the D9S172 locus at 9q31-32 where the dysautonia and Fukuyama-type congenital muscular dystrophy genes have been located. One tumor showed unique LOH at the GSN locus at 9q33, a region frequently deleted in other sporadic tumors while the fourth region of deletion was observed at 9q34 between ASS and ABL-1, in two tumors. This region is frequently deleted in tumors and encompasses the locus for the hereditary hemorrhagic telangiectasia gene. These findings suggest four target regions on 9q within which suppressor genes for TCC may reside.

Uroplakins and Bladder Cancer

Uroplakins are membrane proteins specific to mammalian urothelium. These are expressed in both normal and cancerous urothelium. Mutations have rarely been reported, however, uroplakins act as a useful marker for detecting metastases and circulating TCC cells. The uroplakin family includes: UKP1A, UKP1B, UKP2 and UKP3.
Moll R, Wu XR, Lin JH, Sun TT
Uroplakins, specific membrane proteins of urothelial umbrella cells, as histological markers of metastatic transitional cell carcinomas.
Am J Pathol. 1995; 147(5):1383-97 [PubMed] Free Access to Full Article Related Publications
Uroplakins (UPs) Ia, Ib, II, and III, transmembrane proteins constituting the asymmetrical unit membrane of urothelial umbrella cells, are the first specific urothelial differentiation markers described. We investigated the presence and localization patterns of UPs in various human carcinomas by applying immunohistochemistry (avidin-biotin-peroxidase complex method), using rabbit antibodies against UPs II and III, to paraffin sections. Positive reactions for UP III (sometimes very focal) were noted in 14 of the 16 papillary noninvasive transitional cell carcinomas (TCCs) (88%), 29 of the 55 invasive TCCs (53%), and 23 of the 35 TCC metastases (66%). Different localization patterns of UPs could be distinguished, including superficial membrane staining like that found in normal umbrella cells (in papillary carcinoma), luminal (microluminal) membrane staining (in papillary and invasive carcinoma), and, against expectations, peripheral membrane staining (in invasive carcinoma). Non-TCC carcinomas of various origins (n = 177) were consistently negative for UPs. The presence of UPs in metastatic TCCs represents a prime example of even advanced tumor progression being compatible with the (focal) expression of highly specialized differentiation repertoires. Although of only medium-grade sensitivity, UPs do seem to be highly specific urothelial lineage markers, thus operating up interesting histodiagnostic possibilities in cases of carcinoma metastases of uncertain origin.

Wu RL, Osman I, Wu XR, et al.
Uroplakin II gene is expressed in transitional cell carcinoma but not in bilharzial bladder squamous cell carcinoma: alternative pathways of bladder epithelial differentiation and tumor formation.
Cancer Res. 1998; 58(6):1291-7 [PubMed] Related Publications
Uroplakins (UPs) are integral membrane proteins that are synthesized as the major differentiation products of mammalian urothelium. We have cloned the human UP-II gene and localized it on chromosome 11q23. A survey of 50 transitional cell carcinomas (TCCs) revealed a UP-II polymorphism but no tumor-specific mutations. Immunohistochemical staining using rabbit antisera against a synthetic peptide of UP-II and against total UPs showed UP reactivity in 39.5% (17 of 43 cases) of conventional TCCs, 12.8% (5 of 39) of bilharzial-related TCCs, and 2.7% (1 of 36) of bilharzial-related squamous cell carcinomas (SCCs). The finding that fewer bilharzial TCCs express UPs than conventional TCCs (12.8 versus 40%) raised the possibility that the former are heterogeneous, expressing SCC features to varying degrees. Our data strongly support the hypothesis that urothelium can undergo at least three pathways of differentiation: (a) urothelium-type pathway; (b) epidermis-type pathway; and (c) glandular-type pathway, characterized by the production of UPs, K1/K10 keratins, and secreted glycoproteins, respectively. Vitamin A deficiency and mesenchymal factors may play a role in determining the relative contributions of these pathways to urothelial differentiation as well as to the formation of TCC, SCC, and adenocarcinoma, or a mixture thereof.

Yuasa T, Yoshiki T, Tanaka T, et al.
Expression of uroplakin Ib and uroplakin III genes in tissues and peripheral blood of patients with transitional cell carcinoma.
Jpn J Cancer Res. 1998; 89(9):879-82 [PubMed] Free Access to Full Article Related Publications
Uroplakins (UPs), urothelium-specific transmembrane proteins, are present only in urothelial cells. We have determined the nucleotide sequences of human UP-Ib and UP-III and synthesized specific primer pairs. The two UP genes were expressed in both cancerous and noncancerous urothelial taken from all patients examined by reverse transcription-polymerase chain reaction (RT-PCR). These genes were also detected in the peripheral blood of 3 patients with metastatic transitional cell carcinoma (TCC), but not in that from 9 patients with non-metastatic TCC or 3 healthy volunteers. The sensitivity of our assay was sufficient to detect one cancer cell in 5 ml of peripheral blood. Detection of UP gene-expression in blood by RT-PCR may provide helpful information for the diagnosis and management of TCC.

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