CADM1

Gene Summary

Gene:CADM1; cell adhesion molecule 1
Aliases: BL2, ST17, IGSF4, NECL2, RA175, TSLC1, IGSF4A, Necl-2, SYNCAM, sgIGSF, sTSLC-1, synCAM1
Location:11q23.2
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cell adhesion molecule 1
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplasm Invasiveness
  • Tumor Suppressor Gene
  • RTPCR
  • Messenger RNA
  • Immunoglobulins
  • Cancer Gene Expression Regulation
  • Skin Cancer
  • Down-Regulation
  • Viral Load
  • Staging
  • Promoter Regions
  • Transfection
  • Gene Silencing
  • Papillomavirus Infections
  • Tumor Markers
  • CADM1
  • DNA Methylation
  • Apoptosis
  • Proteins
  • Cell Adhesion
  • Loss of Heterozygosity
  • CpG Islands
  • Vaginal Smears
  • Western Blotting
  • Cell Proliferation
  • Gene Expression Profiling
  • RT-PCR
  • Transcription
  • Immunohistochemistry
  • Mice, Inbred BALB C
  • Microfilament Proteins
  • Membrane Proteins
  • Cervical Intraepithelial Neoplasia
  • Chromosome 11
  • Urogenital System
  • Non-Small Cell Lung Cancer
  • Lung Cancer
  • Cell Adhesion Molecules
  • Squamous Cell Carcinoma
  • Polymerase Chain Reaction
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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).

Latest Publications: CADM1 (cancer-related)

De Strooper LM, van Zummeren M, Steenbergen RD, et al.
CADM1, MAL and miR124-2 methylation analysis in cervical scrapes to detect cervical and endometrial cancer.
J Clin Pathol. 2014; 67(12):1067-71 [PubMed] Related Publications
AIMS: Gene promoter hypermethylation is recognised as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. The current study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer.
METHODS: A series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, cervical intraepithelial neoplasia grade 3 (CIN3) (n=16) or CIN2 (n=32), and women without evidence of CIN2 or worse (n=120) were assessed for methylation of CADM1, MAL and miR124-2. Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylation-specific PCR.
RESULTS: All samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI 58.0% to 94.4%) of women with endometrial cancer scored positive for DNA methylation for at least one of the three genes. In women without cancer, methylation frequencies increased significantly with severity of disease from 19.2% (23/120; 95% CI 12.1% to 26.2%) in women without CIN2 or worse to 37.5% (12/32; 95% CI 20.7% to 54.3%) and 68.8% (11/16; 95% CI 46.0% to 91.5%) in women with CIN2 and CIN3, respectively. Overall methylation positivity and the number of methylated genes increased proportionally to the lesion severity.
CONCLUSIONS: DNA methylation analysis of CADM1, MAL and miR124-2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas.

Wikman H, Westphal L, Schmid F, et al.
Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients.
Oncotarget. 2014; 5(10):3076-87 [PubMed] Free Access to Full Article Related Publications
Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.

Kobayashi S, Nakano K, Watanabe E, et al.
CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma.
Clin Cancer Res. 2014; 20(11):2851-61 [PubMed] Related Publications
PURPOSE: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development.
EXPERIMENTAL DESIGN: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis.
RESULTS: HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts.
CONCLUSION: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.

Vasiljević N, Scibior-Bentkowska D, Brentnall AR, et al.
Credentialing of DNA methylation assays for human genes as diagnostic biomarkers of cervical intraepithelial neoplasia in high-risk HPV positive women.
Gynecol Oncol. 2014; 132(3):709-14 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Testing for high risk human papillomavirus (HR-HPV) is increasing; however due to limitations in specificity there remains a need for better triage tests. Research efforts have focused recently on methylation of human genes which show promise as diagnostic classifiers.
METHODS: Methylation of 26 genes: APC, CADM1, CCND2, CDH13, CDKN2A, CTNNB1, DAPK1, DPYS, EDNRB, EPB41L3, ESR1, GSTP1, HIN1, JAM3, LMX1, MAL, MDR1, PAX1, PTGS2, RARB, RASSF1, SLIT2, SOX1, SPARC, TERT and TWIST1 was measured by pyrosequencing in cytology specimens from a pilot set of women with normal or cervical intraepithelial neoplasia grade 3 (CIN3) histology. Six genes were selected for testing in Predictors 1, a colposcopy referral study comprising 799 women. The three genes EPB41L3, DPYS and MAL were further tested in a second colposcopy referral study, Predictors 2, comprising 884 women.
RESULTS: The six genes selected from the pilot: EPB41L3, EDNRB, LMX1, DPYS, MAL and CADM1 showed significantly elevated methylation in CIN2 and CIN3 (CIN2/3) versus ≤CIN1 in Predictors 1 (p<0.01). Highest methylation was observed in cancer tissues. EPB41L3 methylation was the best single classifier of CIN2/3 in both HR-HPV positive (p<0.0001) and negative samples (p=0.02). Logistic regression modeling showed that other genes did not add significantly to EPB41L3 and in Predictors 2, its classifier value was validated with AUC 0.69 (95% CI 0.65-0.73).
CONCLUSION: Several methylated genes show promise for detecting CIN2/3 of which EPB41L3 seems the best. Methylated human gene biomarkers used in combination may be clinically useful for triage of women with HR-HPV infections.

Hesselink AT, Heideman DA, Steenbergen RD, et al.
Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy.
Int J Cancer. 2014; 135(4):880-6 [PubMed] Related Publications
Methylation markers were studied for their suitability to triage human papillomavirus (HPV)-positive women by testing self-collected cervico-vaginal lavage specimens. For this purpose, we analyzed 355 hrHPV-positive self-collected specimens with three methylation markers, that is, CADM1-m18, MAL-m1 and miR-124-2 by quantitative methylation-specific PCR. The areas under the receiver-operating characteristic (ROC) curve for end-point cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were 0.637 for CADM1-m18, 0.767 for MAL-m1 and 0.762 for miR-124-2. This indicates that CADM1-m18 is not suitable as single marker. By varying the thresholds of both markers in the bi-marker panels CADM1-m18/MAL-m1, CADM1-m18/miR-124-2 and MAL-m1/miR-124-2 upper and lower ROC curves were obtained, depicting the maximum and minimum CIN3+ sensitivity, respectively, at given specificity. For all these bi-marker combinations, the upper curves were similar. However, for the MAL-m1/miR-124-2 panel, the distance between upper and lower ROC curves was closest and this panel displayed the highest assay thresholds, indicating that this combination was most robust. At clinical specificities of 50 and 70%, the MAL-m1/miR-124-2 sensitivity for detection of CIN3+ ranged from 77.0 to 87.8% and from 64.9 to 71.6%, respectively. At 70% specificity thresholds no carcinomas were missed. By comparison, the CIN3+ sensitivity of HPV16/18 genotyping on the self-sampled lavage specimens was 58.1% (95%CI: 46.6-68.8) at a specificity of 87.7% (95%CI: 83.2-91.2). In conclusion, methylation analysis is a promising triage tool that in combination with HPV-DNA testing offers feasible, full molecular screening on self-collected cervico-vaginal lavage specimens.

Qiu Y, Luo X, Kan T, et al.
TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1.
Mol Biosyst. 2014; 10(3):679-85 [PubMed] Related Publications
UNLABELLED: Transforming growth factor β (TGF-β) plays important roles in tumor metastasis by regulating miRNAs expression. miR-182 is an important molecule in the regulation of cancer progression. The aim of the study is to assess the role of miR-182 in TGF-β-induced cancer metastasis. In the present study, we found that miR-182 levels are significantly upregulated in GBC tissues compared with normal controls, and miR-182 expression is remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. TGF-β induces miR-182 expression in GBC cells, and overexpression of miR-182 promotes GBC cell migration and invasion, whereas miR-182 inhibition suppresses TGF-β-induced cancer cell migration and invasion. The blockage of miR-182 by a specific inhibitor effectively inhibits pulmonary metastases in vivo. We further identified that the cell adhesion molecule1 (CADM1) is a new target gene of miR-182. miR-182 negatively regulates CADM1 expression in vitro and in vivo. Importantly, re-expression of CADM1 in GBC cells partially abrogates miR-182-induced cell invasion.
CONCLUSIONS: miR-182 is an important mediator of GBC metastasis, thus offering a new target for the development of therapeutic agents against GBC.

Győrffy B, Surowiak P, Budczies J, Lánczky A
Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer.
PLoS One. 2013; 8(12):e82241 [PubMed] Free Access to Full Article Related Publications
In the last decade, optimized treatment for non-small cell lung cancer had lead to improved prognosis, but the overall survival is still very short. To further understand the molecular basis of the disease we have to identify biomarkers related to survival. Here we present the development of an online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to identify biomarkers related to survival. We searched the caBIG, GEO and TCGA repositories to identify samples with published gene expression data and survival information. Univariate and multivariate Cox regression analysis, Kaplan-Meier survival plot with hazard ratio and logrank P value are calculated and plotted in R. The complete analysis tool can be accessed online at: www.kmplot.com/lung. All together 1,715 samples of ten independent datasets were integrated into the system. As a demonstration, we used the tool to validate 21 previously published survival associated biomarkers. Of these, survival was best predicted by CDK1 (p<1E-16), CD24 (p<1E-16) and CADM1 (p = 7E-12) in adenocarcinomas and by CCNE1 (p = 2.3E-09) and VEGF (p = 3.3E-10) in all NSCLC patients. Additional genes significantly correlated to survival include RAD51, CDKN2A, OPN, EZH2, ANXA3, ADAM28 and ERCC1. In summary, we established an integrated database and an online tool capable of uni- and multivariate analysis for in silico validation of new biomarker candidates in non-small cell lung cancer.

Casadio V, Molinari C, Calistri D, et al.
DNA Methylation profiles as predictors of recurrence in non muscle invasive bladder cancer: an MS-MLPA approach.
J Exp Clin Cancer Res. 2013; 32:94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although non muscle invasive bladder cancer (NMIBC) generally has a good long-term prognosis, up to 80% of patients will nevertheless experience local recurrence after the primary tumor resection. The search for markers capable of accurately identifying patients at high risk of recurrence is ongoing. We retrospectively evaluated the methylation status of a panel of 24 tumor suppressor genes (TIMP3, APC, CDKN2A, MLH1, ATM, RARB, CDKN2B, HIC1, CHFR, BRCA1, CASP8, CDKN1B, PTEN, BRCA2, CD44, RASSF1, DAPK1, FHIT, VHL, ESR1, TP73, IGSF4, GSTP1 and CDH13) in primary lesions to obtain information about their role in predicting local recurrence in NMIBC.
METHODS: Formaldehyde-fixed paraffin-embedded (FFPE) samples from 74 patients operated on for bladder cancer were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA): 36 patients had relapsed and 38 were disease-free at the 5-year follow up. Methylation status was considered as a dichotomous variable and genes showing methylation ≥20% were defined as "positive".
RESULTS: Methylation frequencies were higher in non recurring than recurring tumors. A statistically significant difference was observed for HIC1 (P = 0.03), GSTP1 (P = 0.02) and RASSF1 (P = 0.03). The combination of the three genes showed 78% sensitivity and 66% specificity in identifying recurrent patients, with an overall accuracy of 72%.
CONCLUSIONS: Our preliminary data suggest a potential role of HIC1, GSTP1 and RASSF1 in predicting local recurrence in NMIBC. Such information could help clinicians to identify patients at high risk of recurrence who require close monitoring during follow up.

Guerrero-Setas D, Pérez-Janices N, Ojer A, et al.
Differential gene hypermethylation in genital lichen sclerosus and cancer: a comparative study.
Histopathology. 2013; 63(5):659-69 [PubMed] Related Publications
AIMS: Lichen sclerosus (LS) is a chronic inflammatory disease of the genital skin of unknown aetiology. The role of LS in penile squamous cell carcinogenesis is not well characterized. HPV has been implicated in both, as have epigenetic changes. The presence of HPV and hypermethylation of the MGMT, p16, RASSF1, RASSF2, TSLC1 and TSP1 genes were studied in penile LS; MGMT, RASSF2 and TSLC1 hypermethylation in penile cancer and TSLC1 hypermethylation in vulvar LS and cancer extends previous results reported by our group.
METHODS AND RESULTS: Thirty-seven HPV genotypes and hypermethylation were evaluated by PCR/reverse-line-blot and methylation-specific PCR respectively, in 27 preputial LS, 24 penile SCC, 30 vulvar SCC, 21 vulvar LS and 22 normal skin cases. HPV66 was present in 3.7% of penile LS cases, and p16 and RASSF2 hypermethylation were more frequent in penile cancer than in penile LS. p16, RASSF1, RASSF2 and TSP1 hypermethylation were similar in penile and vulvar LS.
CONCLUSIONS: Gene hypermethylation is a common event in penile LS, and occurs approximately as frequently as in vulvar LS. Certain genes can be hypermethylated as an early or late event in LS or cancer, respectively. This suggests a possible sequential role for these alterations in the transition from benign to malignant lesions.

Masuda H, Baggerly KA, Wang Y, et al.
Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes.
Clin Cancer Res. 2013; 19(19):5533-40 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and colleagues is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.
EXPERIMENTAL DESIGN: We revalidated the Lehmann and colleagues experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathologic response data. We classified the TNBC samples by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model. We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden (RCB) index.
RESULTS: TNBC subtype and pCR status were significantly associated (P = 0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P = 0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like).
CONCLUSIONS: Classifying TNBC by 7 subtypes predicts high versus low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC.

Zhang X, Li W, Kang Y, et al.
SynCAM, a novel putative tumor suppressor, suppresses growth and invasiveness of glioblastoma.
Mol Biol Rep. 2013; 40(9):5469-75 [PubMed] Related Publications
SynCAM, also named by TSLC1, SgIGSF and IGSF4, was identified as a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule. However, the role of SynCAM in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in glioblastoma. SynCAM was silenced in 72 % (5/7) glioblastoma cell lines. A significant downregulation was also detected in paired glioblastoma tumors compared with adjacent non-cancerous tissues. In contrast, SynCAM was readily expressed in various normal adult brain tissues. Ectopic expression of SynCAM in the silenced cancer cell line T98G significantly reduced colony formation and cell proliferation, induced cell cycle arrests and repressed cell invasive ability. Nude mice were subcutaneously injected into the flank with T98G cells and treated with normal saline, pcDNA3.1 (vector) or pcDNA3.1-SynCAM, respectively. Treatment with pcDNA3.1-SynCAM retarded growth in the xenografts, which contributed to a 58 % decrease in tumor volume compared to controls. In conclusion, our results suggest that SynCAM suppressions growth of glioblastoma and may serve as a novel functional tumor-suppressor gene.

Xu PW, Xu HY, Liu XN, et al.
Aberrant promoter methylation of cell adhesion-related genes associated with clinicopathologic features in non-small cell lung cancer in China.
Cancer Biomark. 2013; 13(2):115-22 [PubMed] Related Publications
PURPOSE: The aim of this study was to investigate the methylation status of three cell adhesion-related genes including CDH1, TSLC1 and TIMP3 in non-small cell lung cancer and explore its association with clinicopathologic features and various environmental risk factors.
METHODS: We detected the aberrant methylation presence of these genes by methylation-specific polymerase chain reaction and analyzed the potential correlations with multivariate logistic regression model as well as stepwise logistic regression.
RESULTS: For CDH1, promoter methylation was less frequent in adenosquamous carcinomas than adenocarcinomas (OR=0.35, 95%CI=0.13-0.96); pickled food increased the methylation frequency (OR=2.23, 95%CI=1.09-4.54) while light smoking and fruit intake decreased that (OR=0.43, 95%CI=0.19-0.97; OR=0.37, 95%CI=0.15-0.95). For TSLC1, males and toxin exposure increased methylation frequency (OR=6.25, 95%CI=1.05-37.13; OR=2.42, 95%CI=1.01-5.77) while light smoking and radiation exposure decreased that (OR=0.14, 95%CI=0.03-0.60; OR=0.17, 95%CI=0.04-0.87). For TIMP3, males showed lower methylation frequency than females (OR=0.18, 95%CI=0.04-0.88) while central lung cancer, heavy smoking and radiation exposure presented higher aberrant DNA methylation status (OR=2.19, 95%CI=1.07-4.52; OR=6.99, 95%CI=1.32-37.14; OR=2.30, 95%CI=1.04-5.08).
CONCLUSIONS: Aberrant promoter methylation of cell adhesion-related tumor suppressor genes in lung cancer displayed varieties of gene-specific correlations with clinicopathologic features and various environmental risk factors.

Liu D, Feng X, Wu X, et al.
Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma.
Tumour Biol. 2013; 34(6):3773-83 [PubMed] Related Publications
Tumor suppressor in lung cancer 1 (TSLC1) is tightly implicated in a variety of biological processes and plays critical roles in tumor development and progression. However, the roles of TSLC1 in cutaneous squamous cell carcinoma (CSCC) remain to be unraveled. Here, we reported the TSLC1 gene that was significantly downregulated in CSCC tissues and cells, and survival times of patients with TSLC1 at a low level were markedly lower than that at a high level (P = 0.0070). A stepwise investigation demonstrated that an elevated TSLC1 level evoked obvious proliferation and invasion inhibitions and arrested cell cycle at G0/G1 phase in A431 cells. Moreover, increase of caspase-3 activity mediated by elevated TSLC1 level induced cell apoptosis in A431 cells. Most notably, upregulation of TSLC1 expression reduced the numbers of colony formation and tumorigenicity. Collectively, our results presented herein suggest that TSLC1 as tumor suppressor may play prominent roles in development and progression of CSCC via regulation of different biological processes.

Litjens RJ, Hopman AH, van de Vijver KK, et al.
Molecular biomarkers in cervical cancer diagnosis: a critical appraisal.
Expert Opin Med Diagn. 2013; 7(4):365-77 [PubMed] Related Publications
INTRODUCTION: It is expected that in the near future high-risk human papillomavirus (hr-HPV) testing will be implemented as the primary cervical cancer screening method in some countries. However, only a fraction of hr-HPV positive women will have a clinically relevant lesion. As a result, there is an urgent need for additional biomarkers that can detect these lesions and that can at the same time be applied to cytological specimens. This overview evaluates the most promising cytological biomarkers.
AREAS COVERED: Cytological biomarkers that can be used are being discussed in view of their molecular background. The most promising biomarkers are p16(INK4a)/Ki-67 dual immunostaining; methylation of the promoter region of the cell adhesion molecule 1 (CADM1) gene and the T-lymphocyte maturation associated protein (MAL) gene and viral integration. Their sensitivity, specificity and limitations are discussed in detail and their diagnostic accuracy is evaluated.
EXPERT OPINION: The most promising cytological biomarkers for cervical cancer screening are p16(INK4a)/Ki-67 dual immunostaining, methylation of CADM1 and MAL and viral integration. Although some of the biomarkers are very promising for this purpose, no studies have evaluated how accurately these biomarkers classify or predict the outcome. Additional clinical trials are needed to determine the true clinical value of these promising cytological biomarkers.

Molinari C, Casadio V, Foca F, et al.
Gene methylation in rectal cancer: predictive marker of response to chemoradiotherapy?
J Cell Physiol. 2013; 228(12):2343-9 [PubMed] Related Publications
Although numerous studies have focused on the link between CpG island methylator phenotypes and the development of colorectal cancer, few studies have dealt specifically with methylation profiling in rectal cancer and its role in predicting response to neoadjuvant chemoradiotherapy (NCRT). We characterized methylation profiles in normal and neoplastic tissue samples from patients with rectal cancer and assessed the role of this molecular profile in predicting chemoradioactivity. We evaluated 74 pretreatment tumor samples and 16 apparently normal tissue biopsies from rectal cancer patients submitted to NCRT. The methylation profile of 24 different tumor suppressor genes was analyzed from FFPE samples by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methylation status was studied in relation to tissue type and clinical pathological parameters, in particular, pathological response evaluated by tumor regression grade (TRG). ESR1, CDH13, RARB, IGSF4, and APC genes showed high methylation levels in tumor samples (range 18.92-49.77) with respect to normal tissue. Methylation levels of the remaining genes were low and similar in both normal (range 1.91-14.56) and tumor tissue (range 1.84-11). Analysis of the association between methylation and response to therapy in tumor samples showed that only TIMP3 methylation status differed significantly within the four TRG classes (ANOVA, P < 0.05). Results from the present explorative study suggest that quantitative epigenetic classification of rectal cancer by MS-MLPA clearly distinguishes tumor tissue from apparently normal mucosa. Conversely, with the exception of TIMP3 gene, the methylation of selected genes does not seem to correlate with response to NCRT.

Minami A, Shimono Y, Mizutani K, et al.
Reduction of the ST6 β-galactosamide α-2,6-sialyltransferase 1 (ST6GAL1)-catalyzed sialylation of nectin-like molecule 2/cell adhesion molecule 1 and enhancement of ErbB2/ErbB3 signaling by microRNA-199a.
J Biol Chem. 2013; 288(17):11845-53 [PubMed] Free Access to Full Article Related Publications
Nectin-like molecule 2 (Necl-2)/cell adhesion molecule 1 (CADM1) is shown to be down-regulated by the promoter hypermethylation and/or loss of heterozygosity at chromosome 11q23.2 in many types of cancers, including lung and breast cancers, and is proposed to serve as a tumor suppressor. However, the incidence of these epigenetic and genetic abnormalities of Necl-2 is 30-60% in these cancers, and other mechanisms for the suppression of Necl-2 are presumed to be present. We previously showed that Necl-2 interacts in cis with ErbB3 and suppresses the heregulin (HRG)-induced ErbB2/ErbB3 signaling for cell movement and death. We studied here the relationship between Necl-2 and microRNA-199a (miR-199a) that is up-regulated or down-regulated in a variety of cancers. miR-199a did not directly target the Necl-2 mRNA or affect its mRNA level in human lung cancer A549 cells and human embryonic kidney HEK293 cells. Necl-2 was at least sialylated by the sialyltransferase ST6 β-galactosamide α-2,6-sialyltransferase 1 (ST6GAL1). miR-199a targeted ST6GAL1 and reduced both the sialylation and the protein level of Necl-2. In addition, miR-199a enhanced the HRG-induced ErbB2/ErbB3 signaling. These results indicate that the suppressive role of Necl-2 in the HRG-induced ErbB2/ErbB3 signaling is regulated by miR-199a at least through the reduction of the ST6GAL1-catalyzed sialylation of Necl-2 and/or through the reduction of the protein level of Necl-2 presumably by the protein degradation.

Lei W, Liu HB, Wang SB, et al.
Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model.
Acta Pharmacol Sin. 2013; 34(4):531-40 [PubMed] Free Access to Full Article Related Publications
AIM: The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions.
METHODS: The recombinant virus Ad·sp-E1A(Δ24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A(Δ24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A(Δ24)-TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses.
RESULTS: Infection of A549 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A(Δ24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A(Δ24)-TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A(Δ24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues.
CONCLUSION: The oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.

Bierkens M, Hesselink AT, Meijer CJ, et al.
CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease.
Int J Cancer. 2013; 133(6):1293-9 [PubMed] Related Publications
Combined detection of cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation-associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high-risk human papillomavirus (hrHPV)-positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV-positive women with no underlying high-grade disease, high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN-grade of the corresponding biopsy and second to CIN-grade stratified by the presence of 'normal' or 'abnormal' cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with ≤ CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV-positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and ≥ 5 years). Methylation levels were determined by quantitative methylation-specific PCR and normal cytology scrapes of hrHPV-positive women with histologically ≤ CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3- and 6.2-fold in CIN2/3, respectively, and 143.5- and 454.9-fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5- and 13.6-fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer.

Lee E, Lee BB, Ko E, et al.
Cohypermethylation of p14 in combination with CADM1 or DCC as a recurrence-related prognostic indicator in stage I esophageal squamous cell carcinoma.
Cancer. 2013; 119(9):1752-60 [PubMed] Related Publications
BACKGROUND: The objective of this study was to discover molecular biomarkers associated with the recurrence of esophageal squamous cell carcinoma (ESCC).
METHODS: The authors retrospectively analyzed the hypermethylation status of 11 genes using methylation-specific polymerase chain reaction (PCR) and the expression of epidermal growth factor receptor (EGFR), O-6 methylguanine-DNA methyltransferase (MGMT), tumor protein 53 (p53), and transforming growth factor β (TGFβ) using immunohistochemistry in 329 formalin-fixed, paraffin-embedded ESCCs.
RESULTS: Recurrence was identified in 151 of 329 ESCCs (46%) at a median follow-up of 4.5 years. The recurrence was associated with hypermethylation of the genes cell adhesion molecule 1 (CADM1) (P = .003), deleted in colon carcinoma (DCC) (P = .04), or cyclin-dependent kinase inhibitor 2A (p14) (P = .02) in patients with stage I ESCC. Thirty-six of 37 Stage I ESCCs (97%) that had cohypermethylation of at least 2 of the 3 genes had hypermethylation of p14 plus either CADM1 or DCC or both CADM1 and DCC. The 5-year recurrence-free survival (RFS) rates were 93% in patients who had stage I disease without hypermethylation of the 3 genes and 56% in those who had cohypermethylation of p14 in combination with CADM1 and/or DCC. Patients who had stage I ESCC with cohypermethylation of p14 in combination with DCC and/or CADM1 had 7.13 times (95% confidence interval, 1.61-31.64 times; P = .009) poorer RFS compared with those who had no hypermethylation of the 3 genes after adjusting confounding factors. Hypermethylation of the other 8 genes and altered expression of 4 proteins were not associated with recurrence across pathologic stages.
CONCLUSIONS: The current results suggested that cohypermethylation of p14 in combination with DCC and/or CADM1 may be an independent prognostic factor for recurrence in patients with stage I ESCC.

Snellenberg S, De Strooper LM, Hesselink AT, et al.
Development of a multiplex methylation-specific PCR as candidate triage test for women with an HPV-positive cervical scrape.
BMC Cancer. 2012; 12:551 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Quantitative methylation-specific PCR (qMSP) analysis for determining the methylation status of (candidate) tumor suppressor genes has potential as objective and valuable test to triage high-risk human papillomavirus (hrHPV) positive women in cervical screening. Particularly combined methylation analysis of a panel of genes shows most promising clinical performance, with sensitivity levels that equal or exceed that of cytology. However, the wide application of such methylation marker panels is hampered by the lack of effective multiplex assays allowing simultaneous methylation detection of various targets in a single reaction. Here, we designed and analyzed a multiplex qMSP assay for three genes whose methylation was previously found to be informative for cervical (pre)cancer (i.e. CADM1, MAL and hsa-miR-124-2) as well as a reference gene β-actin. Based on our experience, we discuss the optimization of the parameters that provide a practical approach towards multiplex qMSP design.
METHODS: Primers and PCR reagents were optimized for multiplex qMSP purposes and the resulting assay was analytically validated on serial dilutions of methylated DNA in unmethylated DNA, and compared with singleplex counterparts on hrHPV-positive cervical scrapings.
RESULTS: Upon optimization, including primer redesign and primer limiting assays, the multiplex qMSP showed the same analytical performance as the singleplex qMSPs. A strong correlation between the obtained normalized ratios of the singleplex and multiplex qMSPs on cervical scrapes was found for all three markers: CADM1 (R(2) = 0.985), MAL (R(2) = 0.986) and hsa-miR-124-2 (R(2) = 0.944).
CONCLUSION: Multiplex qMSP offers a promising approach for high-throughput diagnostic analysis of the methylation status of multiple genes, which after proper design and validation can be equally specific, sensitive and reproducible as its singleplex versions.

Cosialls AM, Santidrián AF, Coll-Mulet L, et al.
Epigenetic profile in chronic lymphocytic leukemia using methylation-specific multiplex ligation-dependent probe amplification.
Epigenomics. 2012; 4(5):491-501 [PubMed] Related Publications
AIM: To analyze the methylation status of 35 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in chronic lymphocytic leukemia (CLL).
MATERIALS & METHODS: The DNA of 37 samples from patients with CLL, six healthy donors, and Jurkat and Ramos cell lines was analyzed by MS-MLPA.
RESULTS: Our results confirm that hypermethylation is a common and not randomly distributed event in CLL, and some genes, such as WT1, CDH13, IGSF4/TSLC1, GATA5, DAPK1 and RARB, are hypermethylated in more than 25% of the analyzed samples. Importantly, MS-MLPA also detected hypermethylation of some genes not reported previously in CLL, and their methylation status was confirmed by bisulfite sequencing.
CONCLUSION: These results indicate that MS-MLPA is a useful technique for the detection of methylation in CLL samples. Selecting CLL-specific methylation targets in order to generate a CLL-specific MS-MLPA probe set could enhance its usefulness as a tool in studies of risk stratification and guiding the best therapeutic decision.

You Y, Wang SH, Zhang JF, Zheng SY
TSLC1 expression discriminates cutaneous melanomas from dysplastic nevi.
Melanoma Res. 2012; 22(6):430-5 [PubMed] Related Publications
Cutaneous melanoma is a malignant tumor of melanocytes that causes the majority of skin cancer-related deaths. However, sometimes, discrimination between dysplastic nevi and early melanomas is difficult, even for experienced pathologists. Besides histology, the silencing of tumor suppressor genes aids in the diagnosis of melanoma. We have shown previously that tumor suppressor in lung cancer 1 (TSLC1) is a tumor suppressor gene, and its silencing through aberrant promoter methylation is associated with the generation of cutaneous melanoma. To examine TSLC1 expression in melanocytic skin lesions to determine whether it can serve as a diagnostic marker in histologically questionable lesions. Cytoplasmic localization of the expression of the TSLC1 gene was detected by immunohistochemistry; the levels of TSLC1 mRNA and protein were detected by quantitative real-time reverse transcription-PCR and western blot, respectively. Using immunohistochemistry, the average TSLC1 expression levels in cutaneous melanomas decreased approximately 3.6-fold (n=20) as compared with dysplastic nevi (n=30) and 3.7-fold as compared with normal skin (n=25). The average expression levels of TSLC1 mRNA and protein in dysplastic nevi lesions and normal skin were significantly higher than the levels in cutaneous melanomas. No significant changes in TSLC1 mRNA and protein expressions were found between normal skin and dysplastic nevi. Our results show that a loss of TSLC1 frequently occurs in cutaneous melanoma, and indicate that it could serve as a diagnostic marker for cutaneous melanoma in histologically questionable lesions.

Botling J, Edlund K, Lohr M, et al.
Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation.
Clin Cancer Res. 2013; 19(1):194-204 [PubMed] Related Publications
PURPOSE: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.
EXPERIMENTAL DESIGN: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).
RESULTS: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.
CONCLUSIONS: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

Faraji F, Pang Y, Walker RC, et al.
Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity.
PLoS Genet. 2012; 8(9):e1002926 [PubMed] Free Access to Full Article Related Publications
Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity, which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.

Ballester M, Gonin J, Rodenas A, et al.
Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2.
Hum Reprod. 2012; 27(11):3179-86 [PubMed] Related Publications
STUDY QUESTION: How is the expression of nectins and nectin-like molecules (Necls) detected by immunostaining altered by endometriosis?
SUMMARY ANSWER: Our results suggest that Nectin-1, -3, -4 and Necl-2 may contribute to the pathogenesis of endometriosis. Immunostaining of nectins and Necls varies according to the anatomical location of endometriosis.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Nectin and Necl molecules are immunoglobulin-like cell adhesion molecules involved in apoptosis, cell proliferation and in metastases. Previous studies have demonstrated the involvement of adhesion molecules in the development of endometriotic lesions but no data exist on immunostaining of nectins and Necls molecules in endometriosis.
DESIGN, PARTICIPANTS AND SETTING: This retrospective study was conducted in a tertiary-care hospital (Tenon Hospital, Paris, France). Samples were collected from 55 women undergoing endometrial biopsy or surgery for endometriosis and 20 controls having hysterectomy or endometrial biopsy for other reasons; multiple samples were collected from 15 women. We studied the immunostaining of Nectin-1, -3, -4 and Necl-2 in secretory and proliferative endometrium from women with (n = 20) or without endometriosis (i.e. control group, n = 20), and in peritoneal (n = 20), ovarian (n = 20) and colorectal endometriosis (n = 20).
MAIN RESULTS: Semi-quantitative immunostaining demonstrated that (1) Necl-2 staining was stronger in all types of endometriotic lesions than in the eutopic endometrium from patients with endometriosis (P < 0.0125) and in ovarian endometriotic cysts compared with other locations (P < 0.001); (2) Nectin-3 staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.03) and in all endometriotic lesions compared with the eutopic endometrium from patients with endometriosis (P < 0.0125); (3) Nectin-4, staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.04) and (4) Nectin-1 staining was significantly increased in colorectal endometriosis compared with other locations (P = 0.004).
BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: We did not assess the pattern of expression in endometriosis of all nectins and Necl molecules. Indeed, Necl-5 is implicated in many pathophysiological processes such as cell movement and proliferation with potential relevance to endometriosis. GENERALISABILITY TO OTHER POPULATIONS: At present, few data on implication of nectins and Necl molecules in endometriosis exist. Hence, our results should be confirmed by further quantitative studies at protein or RNA levels.
STUDY FUNDING/COMPETING INTEREST(S): No funding source. All the authors declare no conflict of interest.

Zhang J, Ning J, Geng J, et al.
Down-regulation of tumor suppressor in lung cancer 1 (TSLC1) expression correlates with poor prognosis in patients with colon cancer.
J Mol Histol. 2012; 43(6):715-21 [PubMed] Related Publications
Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, has been reported to be frequently inactivated in a variety of human malignant tumors. The aim of this study was to detect TSLC1 expression in human colon cancer and to analyze its association with prognosis of patients with colon cancer. Using quantitative real-time PCR and Western blot analysis, we found significantly decreased expression of TSLC1 in primary colon tumor tissues (n = 30) compared with adjacent normal tissues. Immunohistochemistry analysis also found decreased TSLC1 expression in 41.3 % (33/80) colon tumor tissues. In clinicopathological analysis, loss of TSLC1 expression significantly correlated with female gender and lymph node metastasis of colon cancer patients (P < 0.05). In addition, decreased expression of TSLC1 in tumors was found to be closely associated with a poor prognosis (P = 0.037, log-rank test), and multivariate analysis showed that lower TSLC1 protein expression was an independent prognostic factor for colon cancer patients. Our study suggests that down-regulated expression of TSLC1 may play an important role in the progression of colon cancer and TSLC1 expression may serve as a useful marker for the prognostic evaluation of patients with colon cancer.

Huang Y, Song H, Hu H, et al.
Trichosanthin inhibits DNA methyltransferase and restores methylation-silenced gene expression in human cervical cancer cells.
Mol Med Rep. 2012; 6(4):872-8 [PubMed] Related Publications
Epigenetic silencing of tumor suppressor genes is a well-established oncogenic process and the reactivation of tumor suppressor genes that have been silenced by promoter methylation is an attractive molecular target for cancer therapy. In this study, we investigated the demethylation activity of trichosanthin (TCS, the main bioactive component isolated from a Chinese medicinal herb) and its possible mechanism of action in cervical cancer cell lines. HeLa human cervical adenocarcinoma and CaSki human cervical squamous carcinoma cells were treated with various concentrations (0, 20, 40 and 80 µg/ml) of TCS for 48 h and the mRNA and protein expression levels of the tumor suppressor genes adenomatous polyposis coli (APC) and tumor suppressor in lung cancer 1 (TSLC1) were detected using reverse transcription (RT)-PCR and western blotting, respectively. We analyzed the methylation status of APC and TSLC1 using methylation-specific PCR (MSP). The expression levels and enzyme activity of DNA methyltransferase 1 (DNMT1) were also examined. The mRNA and protein expression levels of APC and TSLC1 were increased following treatment with various concentrations (0, 20, 40 and 80 µg/ml) of TCS for 48 h. The expression of the APC gene increased 2.55±0.29-, 3.44±0.31- and 4.36±0.14-fold, respectively. The expression of the TSLC1 gene increased 2.28±0.15-, 4.23±0.88- and 6.09±0.23-fold, respectively. MSP detection showed that TCS induced demethylation in HeLa and CaSki cells and that this demethylation activity was accompanied by the decreased expression of DNMT1 and reduced DNMT1 enzyme activity. Our experimental results demonstrate for the first time that TCS is capable of restoring the expression of methylation-silenced tumor suppressor genes and is potentially useful as a demethylation agent for the clinical treatment of human cervical cancer.

Nakahata S, Morishita K
CADM1/TSLC1 is a novel cell surface marker for adult T-cell leukemia/lymphoma.
J Clin Exp Hematop. 2012; 52(1):17-22 [PubMed] Related Publications
CADM1/TSLC1 (Cell adhesion molecule 1/Tumor suppressor in lung cancer 1) is a cell adhesion molecule that was originally identified as a tumor suppressor in lung cancer. CADM1/TSLC1 expression is reduced in a variety of cancers via promoter methylation, and this reduction is associated with poor prognosis and enhanced metastatic potential. In contrast, we observed that CADM1/TSLC1 is highly and ectopically expressed in all primary adult T-cell leukemia/lymphoma (ATLL) cells and in most human T-cell leukemia virus type (HTLV)-1-infected T-cell and ATLL cell lines. No expression, however, was detected in CD4+ T cells or in several other non-HTLV-1-infected leukemia cells. Moreover, we identified that high CADM1/TSLC1 expression plays an important role in enhanced cell-cell adhesion to the vascular endothelium, tumor growth and the ability of ATLL cells to infiltrate organs. We developed various antibodies as diagnostic tools to identify CADM1+ ATLL cells. Using flow cytometry, we determined that CADM1/TSLC1 is present on the surface of ATLL cells. The percentage of CD4+CADM1+ cells in the peripheral blood of HTLV-1 carriers and ATLL patients was highly correlated with the DNA copy number of HTLV-1 in lymphocytes. In particular, we identified the soluble form of CADM1/TSLC1 in the peripheral blood of HTLV-1 carriers and ATLL patients. Therefore, measurements of soluble CADM1/TSLC1 serum levels and the detection of CD4+CADM1+ cells in the blood, when combined with standard diagnostic methods, would be useful for identifying and monitoring disease progression in HTLV-1 carriers. Such tests would provide increased accuracy and may aid in early diagnosis and in determining the effects of ATLL treatments.

Li QJ, Zhou L, Yang F, et al.
MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells.
Tumour Biol. 2012; 33(5):1455-65 [PubMed] Related Publications
MicroRNA-10b (miR-10b) was recently reported to be dysregulated in some types of cancer and to play a role in invasion and metastasis. However, effects and potential mechanisms of action of miR-10b in the metastasis of hepatocellular carcinoma (HCC) have not been explored. In this study, we confirmed that miR-10b is highly expressed in metastatic HCC tissues and in metastatic HCC cell lines by qRT-PCR. Moreover, patients with higher miR-10b expression had significantly poorer overall survival, and high miR-10b expression was an independent predictor of poor prognosis. Inhibition of miR-10b reduced cell migration and invasion in MHCC97H cells, whereas over-expression of miR-10b in HepG2 cells increased cell migration and invasion. Bioinformatics and luciferase reporter assays revealed that miR-10b binds the 3'-UTR of CADM1 mRNA and represses its translation. Western blot and qRT-PCR showed that CADM1 is inhibited by miR-10b over-expression. Silencing of CADM1 resulted in substantially increased cell motility and invasion similar to that observed with over-expression of miR-10b in HepG2 cells. These results suggest that miR-10b may positively regulate the invasion and metastasis of HCC through targeting CADM1.

Samakoglu S, Deevi DS, Li H, et al.
Preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for the treatment of NSCLC.
Cancer Genomics Proteomics. 2012 Mar-Apr; 9(2):77-92 [PubMed] Related Publications
BACKGROUND: Although the addition of epidermal growth factor receptor (EGFR) antibodies to various platinum-based chemotherapy regimens for non-small cell lung cancer (NSCLC) is being actively pursued in the clinic, rationale for the prioritization of specific regimens is lacking.
MATERIALS AND METHODS: We evaluated the antitumor effects of necitumumab, a recombinant human IgG1 antibody targeting EGFR, in combination with cisplatin plus gemcitabine, pemetrexed, or paclitaxel in a panel of 9 subcutaneous tumor models of NSCLC established in nu/nu athymic mice.
RESULTS: Necitumumab in combination with cisplatin/gemcitabine was particularly effective, although interestingly, the mechanisms underlying these benefits were model dependent. For example, increased tumor cell apoptosis contributed towards combination efficacy in the A549 model, in association with increased expression of hsa-miR-29b and reduced expression of antiapoptotic genes including DNA methyltransferase DNMT3B, commonly up-regulated in patients with NSCLC. Such inverse effects of combination therapy on DNMT3B and hsa-miR-29b expression were found in multiple models. Importantly, in the A549 model, hsa-miR-29b down-regulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as Cell adhesion molecule 1 (CADM1), Ras associated (RalGDS/AF-6) domain family member 1 (RASSF1), and Fragile histidine triad gene (FHIT), increasing their expression.
CONCLUSION: These results offer a preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for patients with NSCLC, and provide potential molecular biomarkers for tailoring therapy.

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