Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TPD52 (cancer-related)
Wee Y, Wang T, Liu Y, et al.A pan-cancer study of copy number gain and up-regulation in human oncogenes.
Life Sci. 2018; 211:206-214 [PubMed
] Related Publications
AIM: There has been limited research on CNVs in oncogenes and we conducted a systematic pan-cancer analysis of CNVs and their gene expression changes. The aim of the present study was to provide an insight into the relationships between gene expression and oncogenesis.
MAIN METHODS: We collected all the oncogenes from ONGene database and overlapped with CNVs TCGA tumour samples from Catalogue of Somatic Mutations in Cancer database. We further conducted an integrative analysis of CNV with gene expression using the data from the matched TCGA tumour samples.
KEY FINDINGS: From our analysis, we found 637 oncogenes associated with CNVs in 5900 tumour samples. There were 204 oncogenes with frequent copy number of gain (CNG). These 204 oncogenes were enriched in cancer-related pathways including the MAPK cascade and Ras GTPases signalling pathways. By using corresponding tumour samples data to perform integrative analyses of CNVs and gene expression changes, we identified 95 oncogenes with consistent CNG occurrence and up-regulation in the tumour samples, which may represent the recurrent driving force for oncogenesis. Surprisingly, eight oncogenes shown concordant CNG and gene up-regulation in at least 250 tumour samples: INTS8 (355), ECT2 (326), LSM1 (310), DDHD2 (298), COPS5 (286), EIF3E (281), TPD52 (258) and ERBB2 (254).
SIGNIFICANCE: As the first report about abundant CNGs on oncogene and concordant change of gene expression, our results may be valuable for the design of CNV-based cancer diagnostic strategy.
Zhang Y, Li Y, Wang J, Lei PLong non‑coding RNA ferritin heavy polypeptide 1 pseudogene 3 controls glioma cell proliferation and apoptosis via regulation of the microRNA‑224‑5p/tumor protein D52 axis.
Mol Med Rep. 2018; 18(5):4239-4246 [PubMed
] Free Access to Full Article Related Publications
The aim of the present study was to investigate the potential role and regulatory mechanism of long non‑coding RNA ferritin heavy polypeptide 1 pseudogene 3 (FTH1P3) in glioma development. The expression of FTH1P3 in low‑ and high‑grade glioma tissues was investigated using reverse transcription‑quantitative polymerase chain reaction. FTH1P3 expression was overexpressed or suppressed in U251 glioma cells to examine the involvement of FTH1P3 in glioma cell proliferation and apoptosis using MTT assay and flow cytometry respectively. In addition, the regulatory association between FTH1P3, microRNA (miR)‑224‑5p and tumor protein (TP) D52 was investigated to elucidate the potential underlying mechanisms of FTH1P3 in glioma by luciferase reporter assay. The results revealed that FTH1P3 was up‑regulated in glioma tissues, and FTH1P3 expression in high‑grade glioma tissues was significantly higher compared with that in low‑grade glioma tissues. Upregulation of FTH1P3 promoted glioma cell proliferation and inhibited apoptosis. Furthermore, FTH1P3 inhibited miR‑224‑5p expression, which in turn negatively regulated TPD52 expression. Overexpression of miR‑224‑5p significantly inhibited U251 cell proliferation and induced cellular apoptosis; this effect was clearly reversed following co‑transfection of miR‑224‑5p and TPD52. These data revealed that upregulation of FTH1P3 may have promoted glioma cell proliferation and inhibited apoptosis. Thus, the miR‑224‑5p/TPD52 axis may be a downstream mechanism of FTH1P3 in glioma progression. The findings of the present study may provide a theoretical basis for the study of the treatment of glioma in the future.
Wu Y, Huang J, Xu H, Gong ZOver-expression of miR-15a-3p enhances the radiosensitivity of cervical cancer by targeting tumor protein D52.
Biomed Pharmacother. 2018; 105:1325-1334 [PubMed
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BACKGROUND: Radioresistance is a challenge in the treatment of cervical cancer. Recent studies have reported that microRNAs (miRNAs) mediate radiotherapy resistance and play a vital role in the occurrence and development of cancer. The aim of this study was to investigate whether the expression of miR-15a-3p was correlated with radiosensitivity in cervical cancer.
METHODS: Quantitative real-time PCR experiment was performed to detect the expression of miR-15a-3p in cervical cancer tissues and cells lines. Then, the effect of miR-15a-3p on proliferation in cervical cancer cells radiation-induced were determined by using CCK-8, clonogenic formation and EdU assays. In addition, the TUNEL, flow cytometry analysis and western blotting assays were conducted to evaluate radiation-induced cells apoptosis. A dual-luciferase reporter assay was used to test the target. In addition, tumor xenograft experiment was conducted to test tumor growth in vivo.
RESULTS: In this study, miR-15a-3p was downregulated in cervical cancer tissues and cells lines, however, the expression of miR-15a-3p significantly increased exposed to radiation. Moreover, over-expression of miR-15a-3p inhibited cells proliferation and enhanced cells apoptosis radiation-induced. Further, TPD52 was identified as a direct target of miR-15a-3p. Inhibition of TPD52 could suppress cells proliferation and induce cells apoptosis. Tumor xenograft experiments indicated that over-expression of miR-15a-3p could increase sensitivity to radiation therapy by targeting TPD52.
CONCLUSION: In conclusion, our findings suggested that miR-15a-3p enhanced radiosensitivity in cervical cancer by targeting tumor protein D52, suggesting that miR-15a-3p may be a potential therapeutic target for cervical cancer patients.
Limoni SK, Moghadam MF, Moazzeni SM, et al.Engineered Exosomes for Targeted Transfer of siRNA to HER2 Positive Breast Cancer Cells.
Appl Biochem Biotechnol. 2019; 187(1):352-364 [PubMed
] Related Publications
Exosomes are the best options for gene targeting, because of their natural, nontoxic, non-immunogenic, biodegradable, and targetable properties. By engineering exosome-producing cells, ligands can be expressed fusing with exosomal surface proteins for targeting cancer cell receptors. In the present study, HER2-positive breast cancer cells were targeted with a modified exosome producing engineered HEK293T cell. For this purpose, the HEK293T cells were transduced by a lentiviral vector bearing-LAMP2b-DARPin G3 chimeric gene. Stable cells expressing the fusion protein were selected, and the exosomes produced by these cells were isolated from the culture medium, characterized, and then loaded with siRNA for subsequent delivery to the SKBR3 cells. Our results showed that stable HEK293T cells produced DARPin G3 on the surface of exosomes. These exosomes can bind specifically to HER2/Neu and are capable of delivering siRNA molecules against TPD52 gene into SKBR3 cell line down-regulating the gene expression up to 70%. Present approach is envisaged to facilitate genes and drugs transfer to HER2 cancer cells providing additional option for gene therapy and drug delivery.
Chen Q, Wang P, Fu Y, et al.MicroRNA-217 inhibits cell proliferation, invasion and migration by targeting Tpd52l2 in human pancreatic adenocarcinoma.
Oncol Rep. 2017; 38(6):3567-3573 [PubMed
] Related Publications
MicroRNAs (miRNAs) play important roles in the regulation of various tumor biological processes including proliferation and apoptosis. miR-217 has been implicated in many types of cancer, whereas its expression and potential biological function in human pancreatic adenocarcinoma (HPAC) remain unclear. We aimed to investigate the clinical significance of miR-217 in patients with pancreatic carcinoma and its role and underlying molecular mechanism in HPAC. We collected 15 pairs of pancreatic cancer and normal pancreas tissues to evaluate the expression of miR-217 and tumor protein D52-like 2 (Tpd52l2). Then, we transfected AsPC-1 cells with miR-217 mimics or Tpd52l2 siRNA to detect the effect on cell proliferation, apoptosis, invasion, migration and the cell cycle. In addition, miR-217 mimics and Tpd52l2 expression plasmids were co-transfected into AsPC-1 cells to further investigate the mechanism of miR-217 and Tpd52l2 in HPAC tumorigenesis. Finally, exploration of related signaling pathways was carried out. Herein, we found that the expression of miR-217 was significantly downregulated in HPAC tissues as compared with that observed in adjacent normal tissues. Further functional assays showed that restoration of the expression of miR-217 inhibited cell proliferation, invasion and migration, induced apoptosis, and caused cell cycle arrest of HPAC cells. Notably, Tpd52l2 was identified as a functional target of miR-217 in HPAC. Furthermore, an inverse correlation between miR-217 and Tpd52l2 expression was observed in the HPAC tissues. Downregulation of Tpd52l2 had an effect similar to that following overexpression of miR-217, and upregulation of Tpd52l2 reversed the effects of the overexpression of miR-217. Finally, we found that overexpression of miR-217 or knockdown of Tpd52l2 suppressed the PIK3CA/AKT signaling pathways. In addition, this may explain the effect of miR-217/Tpd52l2 on HPAC development. Taken together, these results suggest a critical role of miR-217 in suppressing proliferation, migration and invasion of HPAC cells by targeting Tpd52l2. Targeting the miR-217/Tpd52l2 axis may be a new therapeutic application with which to treat patients with HPAC in the future.
Cancer cells can have different patterns of exon usage of individual genes when compared to normal tissue, suggesting that alternative splicing may play a role in shaping the tumor phenotype. The discovery and identification of gene variants has increased dramatically with the introduction of RNA-sequencing technology, which enables whole transcriptome analysis of known, as well as novel isoforms. Here we report alternative splicing and transcriptional events among subtypes of invasive ductal carcinoma in The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort. Alternative exon usage was widespread, and although common events were shared among three subtypes, ER+ HER2-, ER- HER2-, and HER2+, many events on the exon level were subtype specific. Additional RNA-seq analysis was carried out in an independent cohort of 43 ER+ HER2- and ER- HER2- primary breast tumors, confirming many of the exon events identified in the TCGA cohort. Alternative splicing and transcriptional events detected in five genes, MYO6, EPB41L1, TPD52, IQCG, and ACOX2 were validated by qRT-PCR in a third cohort of 40 ER+ HER2- and ER- HER2- patients, showing that these events were truly subtype specific.
Kobayashi-Watanabe N, Sato A, Watanabe T, et al.Functional analysis of Discoidin domain receptor 2 mutation and expression in squamous cell lung cancer.
Lung Cancer. 2017; 110:35-41 [PubMed
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OBJECTIVES: Discoidin domain receptor (DDR) 2 mutations have recently been reported to be candidate targets of molecular therapy in lung squamous cell carcinoma (SQCC). However, the status of DDR2 expression and mutations, as well as their precise roles in lung SQCC, have not been clarified. We here report DDR2 mutation and expression status in clinical samples and its role of lung SQCC.
MATERIALS AND METHODS: We investigated DDR2 expression and mutation status in 44 human clinical samples and 7 cell lines. Biological functions of DDR2 were assessed by in vitro cell invasion assay and animal model experiments.
RESULTS: Endogenous DDR2 protein expression levels were high in one cell line, PC-1, and immunohistochemistry of lung cancer tissue array showed high levels of DDR2 protein in 29% of lung SQCC patients. A mutation (T681I) identified in lung SQCC and the cell line EBC-1 was detected among 44 primary lung SQCC samples and 7 lung SQCC cell lines. Although Forced expression of DDR2 and its mutant (T681I) led to induce SQCC cell invasion in vitro, only wild type DDR2 enhanced lung metastasis in an animal model. We also found that ectopic expression of DDR2 induced MMP-1 mRNA expression accompanied by phosphorylation of c-Jun after treatment with its ligand, collagen type I, but DDR2 with the T681I mutation did not, suggesting that T681I mutation is an inactivating mutation.
CONCLUSION: Overexpression of DDR2 might contribute to tumor progression in lung SQCC. The overexpression of DDR2 could be potential molecular target of lung SQCC.
Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of
Distant metastasis is the worst prognostic factor for PCa patients. It has been reported that miR-449a enhances radiosensitivity of prostate cancer cells, but the function of miR449a in metastasis of prostate cancer is mainly unknown. In the present study, we strove to investigate the function and diagnostic value of miR-449a in metastasis of prostate cancer. qRT-PCR was used to quantify the expression of miR449a and PrLZ in PCa cell lines and tissues. we found that miR449a expression was decreased in PCa cell lines. Moreover, miR‑449a was downregulated in PCa tissues, especially in primary lesion tissues of metastatic PCa patients. CCK8, FACS, transwell and tube formation assay were performed to assess growth and metastasis of PCa cells in vitro. Lentivirus mediated miR-449a overexpression suppressed proliferation of LNcap and PC-3, and miR-449a also significantly inhibited invasion and angiogenesis ability of LNcap and PC-3. IHC showed that PrLZ was upregulated in PCa tissues. Luciferase assay and western blotting verified that miR-449a targeted PrLZ expression. Moreover, PrLZ shRNA also significantly suppressed proliferation and metastasis of LNcap and PC-3. In addition, western blotting revealed that miR-449a overexpression and PrLZ shRNA all remarkably inhibited the stemness features in LNcap and PC-3. Furthermore, BALB/c nude mouse subcutaneous xenograft model was uesd to verify the function of miR-449a and PrLZ. Our results showed that miR-449a and PrLZ shRNA significantly suppressed PC-3 tumorigenesis and metastasis in vivo. Our studies suggested that miR-449a decreased in malignant process of PCa and was accompanied by excess expression of PrLZ. The loss of miR-449a caused PrLZ overexpression regulated prostate cancer progression and metastasis via regulating the stemness features of prostate cancer cells. The diagnostic value of miR-449a as a distant metastasis predictor of PCa needs further investigation.
Dasari C, Yaghnam DP, Walther R, Ummanni RTumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells.
Tumour Biol. 2017; 39(5):1010428317698382 [PubMed
] Related Publications
Our previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible underlying mechanism of TPD52 in prostate cancer progression. In LNCaP cells, TPD52 expression was altered by transfecting with either EGFP-TPD52 or specific short hairpin RNA. Overexpression of TPD52 protected LNCaP cells from apoptosis through elevated anti-apoptotic proteins XIAP, Bcl-2, and Cyclin D1, whereas Bax was downregulated. Mechanistically, we found that TPD52 confers transactivation of nuclear factor-κB, thereby enhancing its target gene expression in LNCaP cells. TPD52 promotes LNCaP cell invasion probably via increased matrix metalloproteinase 9 expression and its activity while tissue inhibitor of metalloproteinase expression is significantly downregulated. Notably, TPD52 might be involved in cell adhesion, promoting tumor metastasis by inducing loss of E-cadherin, expression of vimentin and vascular cell adhesion molecule, and additionally activation of focal adhesion kinase. Furthermore, TPD52 directly interacts with nuclear factor-κB p65 (RelA) and promotes accumulation of phosphorylated nuclear factor-κB (p65)
Kato K, Mukudai Y, Motohashi H, et al.Opposite effects of tumor protein D (TPD) 52 and TPD54 on oral squamous cell carcinoma cells.
Int J Oncol. 2017; 50(5):1634-1646 [PubMed
] Related Publications
The tumor protein D52 (TPD52) protein family includes TPD52, -53, -54 and -55. Several reports have shown important roles for TPD52 and TPD53, and have also suggested the potential involvement of TPD54, in D52-family physiological effects. Therefore, we performed detailed expression analysis of TPD52 family proteins in oral squamous cell carcinoma (OSCC). Towards this end, TPD54-overexpressing or knocked-down cells were constructed using OSCC-derived SAS, HSC2 and HSC3 cells. tpd52 or tpd53 was expressed or co-expressed in these cells by transfection. The cells were then analyzed using cell viability (MTT), colony formation, migration, and invasion assays. In OSCC-xenograft experiments, the cells were transplanted into nude mice together with injection of anti-tpd siRNAs. MTT assay of cell monolayers showed little differences in growth of the transfected cells. tpd54 overexpression in SAS cells significantly decreased colony formation in an anchorage-independent manner. Additionally, knock-down of tpd54 enhanced the number of colonies formed and overexpression of tpd52 in tpd54 knock-down cells increased the size of the colonies formed. The chemotaxis assay showed that tpd54 overexpression decreased cell migration. In the OSCC-xenograft in vivo study, tpd54 overexpression slightly attenuated tumor volume in vivo, despite the fact that tumor metastasis or cell survival was not involved. Our results showed that TPD54 not only downregulated anchorage-independent growth and cell migration in vitro, but also attenuated tumor growth in vivo. Based on these results, it is considered that TPD54 might act as a negative regulator of tumor progression in OSCC cells.
Zhang Z, Wang J, Gao R, et al.Downregulation of MicroRNA-449 Promotes Migration and Invasion of Breast Cancer Cells by Targeting Tumor Protein D52 (TPD52).
Oncol Res. 2017; 25(5):753-761 [PubMed
] Related Publications
Our study aimed to investigate whether microRNA-449 (miR-449) plays a key role in regulating the migration and invasion of breast cancer cells via targeting tumor protein D52 (TPD52). The results of the qRT-PCR and Western blotting showed that, in comparison with normal breast tissues and cells, miR-449 was significantly downregulated in breast cancer tissues and cells, while TPD52 was markedly upregulated. After transfection with an miR-449 inhibitor, suppression of miR-449 significantly promoted cell migration and invasion. Also, when miR-449 was overexpressed by transfection with miR-449 mimics, E-cadherin expression significantly increased, and the expression of N-cadherin and vimentin were markedly decreased, whereas the opposite effects were obtained when miR-449 was suppressed by transfection with an miR-449 inhibitor. TPD52 was also confirmed as the direct target of miR-449 via luciferase reporter analysis. Knockdown of TPD52 significantly alleviated the effects of miR-449 overexpression on cell migration and invasion, as well as the expression of E-cadherin, N-cadherin, and vimentin. Our results indicate that downregulation of miR-449 may promote the migration and invasion of breast cancer cells by targeting TPD52. miR-449 may serve as a potential target in the therapy of breast cancer.
Zhao Z, Liu H, Hou J, et al.Tumor Protein D52 (TPD52) Inhibits Growth and Metastasis in Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway.
Oncol Res. 2017; 25(5):773-779 [PubMed
] Related Publications
Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC.
The androgen receptor (AR) is not only a ligand-dependent transcription factor, but also functions as a licensing factor, a component of DNA replication, which is degraded during mitosis. Furthermore, the deregulation of AR activity is involved in the initiation of prostate cancer and contributes to castration resistant prostate cancer (CRPC). While AR degradation is known to occur primarily through a proteasome-mediated pathway, very little is known about how this process is regulated, especially in M phase. PC-1 is an androgen-responsive factor and expresses specificity in prostate cancer, with higher expression noted at G2/M. In this study, PC-1 was shown to interact with AR and E3 ligase CHIP (Carboxy-terminus of Hsc70 Interacting Protein) and to enhance AR/CHIP interactions, thereby decreasing AR stability. Moreover, PC-1 was found to act in conjunction with CHIP in the decreasing of AR via ubiquitination, with the subsequent degradation predominantly occurring during M phase. PC-1 was also found to repress AR transcriptional activity in androgen-dependent and androgen-independent prostate cancer cells and attenuate the growth inhibition of AR. In conclusion, these findings should provide new clues regarding the modulation of AR turnover and activity via PC-1 and reveals an essential role of PC-1 in AR signaling.
Pappalardo MA, Vita R, Di Bari F, et al.Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome.
J Endocrinol Invest. 2017; 40(4):367-376 [PubMed
] Related Publications
PURPOSE: Polycystic ovary syndrome (PCOS) was associated with a number of polymorphisms of genes involved in insulin signaling. So far, they have been studied separately. The aim of this study was to verify the impact of the coexistence of two polymorphisms of insulin signaling.
METHODS: One hundred consecutive PCOS women (diagnosed by Rotterdam criteria) and 45 age-matched healthy women were genotyped for two polymorphisms: Gly972Arg of IRS-1 and Lys121Gln of PC-1. Also, they underwent clinical evaluation, blood sampling for measurement of metabolic and hormonal indices, and a 75-g oral glucose tolerance test (OGTT).
RESULTS: Comparing PCOS women with controls, the rate of homo-/heterozygosity was significantly greater (50 vs. 24.5%, P = 0.004) for IRS-1 polymorphism, but insignificantly greater (20 vs. 13.3%, P = 0.33) for PC-1 polymorphism. In PCOS women, compared with controls, the genotypes IRS-1 hetero/PC-1 wild type (WT) (36 vs. 17.8%, P = 0.03) and IRS-1 hetero/PC-1 hetero (14 vs. 6.7%, P = 0.20) were overrepresented at the expense of IRS-1 WT/PC-1 WT (44 vs. 68.8%, P = 0.005), while IRS-1 WT/PC-1 hetero was similarly represented (6 vs. 6.7%). Based on genotype, metabolic and hormonal indices changed significantly. For instance, six indices (HOMA-IR, fasting insulin, insulin area under the curve at OGTT, triglycerides, total and calculated free testosterone) were the highest in IRS-1 hetero/PC-1 WT women.
CONCLUSIONS: Genetic variations in insulin signaling contribute to the extent and the variability of metabolic and hormonal derangement.
The development of targeted molecular therapies has greatly benefited patients with lung adenocarcinomas. In contrast, these treatments have had little benefit in the management of lung squamous cell carcinoma (lung SCC). Therefore, new treatment options based on current genomic approaches are needed for lung SCC. Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness. Downregulation of microRNA-218 (miR-218) was frequently observed in our miRNA expression signatures of cancers, and previous studies have shown an antitumor function of miR-218 in several types of cancers. However, the impact of miR-218 on lung SCC is still ambiguous. The present study investigated the antitumor roles of miR-218 in lung SCC to identify the target genes regulated by this miRNA. Ectopic expression of miR-218 greatly inhibited cancer cell migration and invasion in the lung SCC cell lines EBC-1 and SK-MES-1. Through a combination of in silico analysis and gene expression data searching, tumor protein D52 (TPD52) was selected as a putative target of miR-218 regulation. Moreover, direct binding of miR-218 to the 3'-UTR of TPD52 was observed by dual luciferase reporter assay. Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines. Furthermore, the downstream pathways mediated by TPD52 involved critical regulators of genomic stability and mitotic checkpoint genes. Taken together, our data showed that downregulation of miR-218 enhances overexpression of TPD52 in lung SCC cells, promoting cancer cell aggressiveness. Identification of tumor-suppressive miRNA-mediated RNA networks of lung SCC will provide new insights into the potential mechanisms of the molecular pathogenesis of the disease.
Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.
Sharma P, Bhunia S, Poojary SS, et al.Global methylation profiling to identify epigenetic signature of gallbladder cancer and gallstone disease.
Tumour Biol. 2016; 37(11):14687-14699 [PubMed
] Related Publications
Promoter methylation in various tumor suppressor genes is reported to influence gallbladder carcinogenesis. Here, we aimed to identify methylation status in gallbladder cancer (GBC) by performing a comprehensive genome-wide DNA methylation profiling. The methylation status of 485,577 CpG sites were investigated using Illumina's Infinium Human Methylation 450 BeadChip array in 24 tissues (eight each of tumor, adjacent non-tumor, and gallstone). About 33,443 differentially methylated sites (DMRs) were obtained in the whole human genome, of which 24,188 (72 %) were hypermethylated and 9255 (28 %) were hypomethylated. The data also revealed that majority of the DMRs are localized on the proximal promoter region [Transcription start sites (TSS200, TSS1500) and 5' untranslated region (5'UTR)] and first exon. Exclusion of first exon detected a total of 10,123 (79 %) hypermethylated and 2703 (21 %) hypomethylated sites. Comparative analysis of the later with our differential proteomics data resulted in identification of 7 hypermethylated or down-regulated (e.g., FBN1, LPP, and SOD3) and 61 hypomethylated or up-regulated markers (e.g., HBE1, SNRPF, TPD52) for GBC. These genes could be further validated on the basis of their methylation/expression status in order to identify their utility to be used as biomarker/s for early diagnosis and management of GBC.
Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA), increases susceptibility to prostate cancer (PCa) in rodent models. Here, we used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays to identify treatment-associated methylome changes in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally (PND1, 3, and 5) treated with 25 µg/pup or 2,500 µg EB/kg body weight (BW) or 0.1 µg BPA/pup or 10 µg BPA/kg BW. We identified 111 EB-associated and 86 BPA-associated genes, with 20 in common, that have significant differentially methylated regions. Pathway analysis revealed cancer as the top common disease pathway. Bisulfite sequencing validated the differential methylation patterns observed by array analysis in 15 identified candidate genes. The methylation status of 7 (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes exhibited an inverse correlation with gene expression in tissue samples. Cell-based assays, using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) rat prostate cells, added evidence of DNA methylation-mediated gene expression of 6 genes (exception: Paqr4). Functional connectivity of these genes was linked to embryonic stem cell pluripotency. Furthermore, clustering analyses using the dataset from The Cancer Genome Atlas revealed that expression of this set of 7 genes was associated with recurrence-free survival of PCa patients. In conclusion, our study reveals that gene-specific promoter methylation changes, resulting from early-life EDC exposure in the rat, may serve as predictive epigenetic biomarkers of PCa recurrence, and raises the possibility that such exposure may impact human disease.
BACKGROUND: MicroRNA-224 (miR-224) and microRNA-452 (miR-452) are closely located on the human chromosome Xq28 region. miR-224 functions as a tumour suppressor by targeting tumour protein D52 (TPD52) in prostate cancer (PCa). Here, we aimed to investigate the functional significance of miR-452 in PCa cells.
METHODS: Functional studies of PCa cells were performed using transfection with mature miRNAs or siRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-452 levels and overall patient survival was estimated by the Kaplan-Meier method.
RESULTS: Expression of miR-452 was significantly downregulated in PCa tissues. Transfection with mature miR-452 inhibited the migration and invasion of PCa cells. Kaplan-Meier survival curves showed that low expression of miR-452 predicted a short duration of progression to castration-resistant PCa. WW domain-containing E3 ubiquitin protein ligase-1 (WWP1) was a direct target of miR-452, and knockdown of WWP1 inhibited the migration and invasion of PCa cells. WWP1 was upregulated in PCa clinical specimens.
CONCLUSIONS: Regulation of the miR-452-WWP1 axis contributed to PCa cell migration and invasion, and elucidation of downstream signalling of this axis will provide new insights into the mechanisms of PCa oncogenesis and metastasis.
Mechanisms of abnormal protein phosphorylation that regulate cell invasion and metastasis in pancreatic cancer remain obscure. In this study, we used high-throughput phosphorylation array to test two pancreatic cancer cell lines (PC-1 cells with a low, and PC-1.0 cells with a high potential for invasion and metastasis). We noted that a total of 57 proteins revealed a differential expression (fold change ≥ 2.0). Six candidate proteins were further validated by western blot with results found to be accordance with the array. Of 57 proteins, 32 up-regulated proteins (e.g. CaMK1-α and P90RSK) were mainly involved in ErbB and neurotrophin signaling pathways as determined using DAVID software, while 25 down-regulated proteins (e.g. BID and BRCA1) were closely involved in apoptosis and p53 signaling pathways. Moreover, four proteins (AKT1, Chk2, p53 and P70S6K) with different phosphorylation sites were found, not only among up-regulated, but also among down-regulated proteins. Importantly, specific phosphorylation sites can affect cell biological functions. CentiScaPe software calculated topological characteristics of each node in the protein-protein interaction (PPI) network: we found that AKT1 owns the maximum node degrees and betweenness in the up-regulation protein PPI network (26 nodes, average path length: 1.89, node degrees: 6.62±4.18, betweenness: 22.23±35.72), and p53 in the down-regulation protein PPI network (17 nodes, average path length: 2.04, node degrees: 3.65±2.47, betweenness: 16.59±29.58). In conclusion, the identification of abnormal protein phosphorylation related to invasion and metastasis may allow us to identify new biomarkers in an effort to develop novel therapeutic drug targets for pancreatic cancer treatment.
Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-β1 exposure of A549 cells. Nintedanib was able to reverse TGF-β1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.
Tang NY, Chueh FS, Yu CC, et al.Benzyl isothiocyanate alters the gene expression with cell cycle regulation and cell death in human brain glioblastoma GBM 8401 cells.
Oncol Rep. 2016; 35(4):2089-96 [PubMed
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Glioblastoma multiforme (GBM) is a highly malignant devastating brain tumor in adults. Benzyl isothiocyanate (BITC) is one of the isothiocyanates that have been shown to induce human cancer cell apoptosis and cell cycle arrest. Herein, the effect of BITC on cell viability and apoptotic cell death and the genetic levels of human brain glioblastoma GBM 8401 cells in vitro were investigated. We found that BITC induced cell morphological changes, decreased cell viability and the induction of cell apoptosis in GBM 8401 cells was time-dependent. cDNA microarray was used to examine the effects of BITC on GBM 8401 cells and we found that numerous genes associated with cell death and cell cycle regulation in GBM 8401 cells were altered after BITC treatment. The results show that expression of 317 genes was upregulated, and two genes were associated with DNA damage, the DNA-damage-inducible transcript 3 (DDIT3) was increased 3.66-fold and the growth arrest and DNA-damage-inducible α (GADD45A) was increased 2.34-fold. We also found that expression of 182 genes was downregulated and two genes were associated with receptor for cell responses to stimuli, the EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) was inhibited 2.01-fold and the TNF receptor-associated protein 1 (TRAP1) was inhibited 2.08-fold. BITC inhibited seven mitochondria ribosomal genes, the mitochondrial ribosomal protein; tumor protein D52 (MRPS28) was inhibited 2.06-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein L23 (MRPL23) decreased 2.08-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein S12 (MRPS12) decreased 2.08-fold, the mitochondria ribosomal protein L12 (MRPL12) decreased 2.25-fold and the mitochondria ribosomal protein S34 (MRPS34) was decreased 2.30-fold in GBM 8401 cells. These changes of gene expression can provide the effects of BITC on the genetic level and are potential biomarkers for glioblastoma therapy.
Li G, Yao L, Zhang J, et al.Tumor-suppressive microRNA-34a inhibits breast cancer cell migration and invasion via targeting oncogenic TPD52.
Tumour Biol. 2016; 37(6):7481-91 [PubMed
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The tumor protein D52 (TPD52) is an oncogene overexpressed in breast cancer. Although the oncogenic effects of TPD52 are well recognized, how its expression and the role in migration/invasion is still not clear. This study tried to explore the regulative role of microRNA-34a (miR-34a), a tumor suppressive miRNA, on TPD52 expression in breast cancer. The expression of miR-34a was found significantly decreased in breast cancer specimens with lymph node metastases and breast cancer cell lines. The clinicopathological characteristics analyzed showed that lower expression levels of miR-34a were associated with advanced clinical stages. Moreover, TPD52 was demonstrated as one of miR-34a direct targets in human breast cancer cells. miR-34a was further found significantly repress epithelial-mesenchymal transition (EMT) and inhibit breast cancer cell migration and invasion via TPD52. These findings indicate that miR-34a inhibits breast cancer progression and metastasis through targeting TPD52. Consequently, our data strongly suggested that oncogenic TPD52 pathway regulated by miR-34a might be useful to reveal new therapeutic targets for breast cancer.
Ross-Adams H, Lamb AD, Dunning MJ, et al.Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.
EBioMedicine. 2015; 2(9):1133-44 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome.
METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone.
FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions.
INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.
Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.
Zhu L, Liu J, Ma S, Zhang SLong Noncoding RNA MALAT-1 Can Predict Metastasis and a Poor Prognosis: a Meta-Analysis.
Pathol Oncol Res. 2015; 21(4):1259-64 [PubMed
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Elevated expression of MALAT-1 was found in various cancers, and correlated with metastasis and prognostic. This meta-analysis collected all relevant articles and explored correlation of MALAT-1 with lymph node metastasis (LNM), distant metastasis (DM), and overall survival (OS). A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, Medline, CNKI, CBM, and the Cochrane Library. The odds ratios (OR) of LNM and DM and hazard ratio (HR) of OS were calculated to assess the association strength. Eight studies with a total of 845 patients were included in the meta-analysis. Six different types of cancer were evaluated, with 2 non-small cell lung cancer (NSCLC), 1 colorectal cancer (CRC), 1 gastric cancer (GC), 2 pancreatic cancer (PC), 1 clear cell renal cell carcinoma (ccRCC), and 1 osteosarcoma (OSA). Compared with low MALAT-1 expression, high MALAT-1 expression correlated with more LNM (OR = 2.08, 95 %CI: 1.00-4.32, p = 0.05) by a random-effects model (I (2) = 71 %, p = 0.004). A similar result was seen between MALAT-1 expression and DM, the OR was 3.52 (95 %CI: 1.06-11.71, p = 0.04) adopting a random-effects model (I (2) = 59 %, p = 0.04). Additionally, our analysis showed a poorer OS in patients with high MALAT-1 expression than those with low MALAT-1 expression (HR = 2.12, 95 %CI: 1.60-2.82, p < 0.001) adopting a random-effects model (I (2) = 56 %, p = 0.04). MALAT-1 may serve as a molecular marker for cancer metastasis and prognosis.
Nepomuceno AI, Shao H, Jing K, et al.In-depth LC-MS/MS analysis of the chicken ovarian cancer proteome reveals conserved and novel differentially regulated proteins in humans.
Anal Bioanal Chem. 2015; 407(22):6851-63 [PubMed
] Free Access to Full Article Related Publications
Ovarian cancer (OVC) remains the most lethal gynecological malignancy in the world due to the combined lack of early-stage diagnostics and effective therapeutic strategies. The development and application of advanced proteomics technology and new experimental models has created unique opportunities for translational studies. In this study, we investigated the ovarian cancer proteome of the chicken, an emerging experimental model of OVC that develops ovarian tumors spontaneously. Matched plasma, ovary, and oviduct tissue biospecimens derived from healthy, early-stage OVC, and late-stage OVC birds were quantitatively characterized by label-free proteomics. Over 2600 proteins were identified in this study, 348 of which were differentially expressed by more than twofold (p ≤ 0.05) in early- and late-stage ovarian tumor tissue specimens relative to healthy ovarian tissues. Several of the 348 proteins are known to be differentially regulated in human cancers including B2M, CLDN3, EPCAM, PIGR, S100A6, S100A9, S100A11, and TPD52. Of particular interest was ovostatin 2 (OVOS2), a novel 165-kDa protease inhibitor found to be strongly upregulated in chicken ovarian tumors (p = 0.0005) and matched plasma (p = 0.003). Indeed, RT-quantitative PCR and Western blot analysis demonstrated that OVOS2 mRNA and protein were also upregulated in multiple human OVC cell lines compared to normal ovarian epithelia (NOE) cells and immunohistochemical staining confirmed overexpression of OVOS2 in primary human ovarian cancers relative to non-cancerous tissues. Collectively, these data provide the first evidence for involvement of OVOS2 in the pathogenesis of both chicken and human ovarian cancer.
An important strategy for improving advanced PCa treatment is targeted therapies combined with chemotherapy. PC-1, a prostate Leucine Zipper gene (PrLZ), is specifically expressed in prostate tissue as an androgen-induced gene and is up-regulated in advanced PCa. Recent work confirmed that PC-1 expression promotes PCa growth and androgen-independent progression. However, how this occurs and whether this can be used as a biomarker is uncertain. Here, we report that PC-1 overexpression confers PCa cells resistance to rapamycin treatment by antagonizing rapamycin-induced cytostasis and autophagy (rapamycin-sensitivity was observed in PC-1-deficient (shPC-1) C4-2 cells). Analysis of the mTOR pathway in PCa cells with PC-1 overexpressed and depressed revealed that eukaryotic initiation factor 4E-binding protein 1(4E-BP1) was highly regulated by PC-1. Immunohistochemistry assays indicated that 4E-BP1 up-regulation correlates with increased PC-1 expression in human prostate tumors and in PCa cells. Furthermore, PC-1 interacts directly with 4E-BP1 and stabilizes 4E-BP1 protein via inhibition of its ubiquitination and proteasomal degradation. Thus, PC-1 is a novel regulator of 4E-BP1 and our work suggests a potential mechanism through which PC-1 enhances PCa cell survival and malignant progression and increases chemoresistance. Thus, the PC-1-4E-BP1 interaction may represent a therapeutic target for treating advanced PCa.
Wang SY, Feng LY, Meng ZQBicluster and pathway enrichment analysis related to tumor progression of hepatocellular carcinoma.
Eur Rev Med Pharmacol Sci. 2015; 19(7):1191-7 [PubMed
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OBJECTIVE: Hepatocellular carcinoma is one of the most aggressive cancers with poor prognosis worldwide. Tumor progression remains a significant cause of high mortality in patients with hepatocellular carcinoma. However, the molecular mechanism underlying tumor progression of hepatocellular carcinoma has not been completely unraveled currently. The aim of this study was to gain insight into the molecular mechanisms of tumor progression of hepatocellular carcinoma.
MATERIALS AND METHODS: We performed microarray analysis on 24 tissue specimens obtained at the time of surgical resection or liver transplantation from 24 patients with hepatocellular carcinoma downloaded from the Gene Expression Omnibus database.
RESULTS: Our analysis indicated that several differentially expressed genes might play crucial roles in the progression of hepatocellular carcinoma, such as GADD45G, SPTBN1, CDC27, TPD52 and INSIG1. GADD45G and SPTBN1 not only contribute to tumor progression in hepatocellular carcinoma, but also correlate with poor prognosis in esophageal squamous cell carcinoma and pancreatic cancer respectively. Futhermore, we performed pathway enrichment analysis and found enriched pathways, including "Proteasome", "Alanine, aspartate and glutamate metabolism", "TGF-beta signaling pathway", "Wnt signaling pathway", and so on.
CONCLUSIONS: Our findings confirmed the presence of multiple molecular alterations during tumor progression and indicated the differentially expressed genes might be involved in tumor progression though multiple pathways. Genes GADD45G and SPTBN1 might correlate with poor prognosis in hepatocellular carcinoma as has already been shown for other malignancies of the gastrointestinal tract.