EPB41L3

Gene Summary

Gene:EPB41L3; erythrocyte membrane protein band 4.1 like 3
Aliases: 4.1B, DAL1, DAL-1
Location:18p11.31
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:band 4.1-like protein 3
Source:NCBIAccessed: 11 March, 2017

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 (1992-2017)
Graph generated 11 March 2017 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.

  • Immunohistochemistry
  • RTPCR
  • Genotype
  • Adolescents
  • Loss of Heterozygosity
  • Promoter Regions
  • Immunoglobulins
  • Chromosome 18
  • Tumor Suppressor Gene
  • Epigenetics
  • DNA Methylation
  • Microfilament Proteins
  • Neurofibromin 2
  • Down-Regulation
  • Cervical Cancer
  • Cohort Studies
  • Human papillomavirus 16
  • Cervical Intraepithelial Neoplasia
  • Cancer Gene Expression Regulation
  • Meningioma
  • Papillomavirus Infections
  • Sensitivity and Specificity
  • Risk Factors
  • Non-Small Cell Lung Cancer
  • Staging
  • Adenocarcinoma
  • Western Blotting
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Breast Cancer
  • Single-Stranded Conformational Polymorphism
  • Polymerase Chain Reaction
  • Membrane Proteins
  • Oligonucleotide Array Sequence Analysis
  • Lung Cancer
  • Base Sequence
  • Squamous Cell Carcinoma
  • Cancer DNA
  • Gene Expression Profiling
  • Xenograft Models
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: EPB41L3 (cancer-related)

Lorincz AT
Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention.
Acta Cytol. 2016; 60(6):501-512 [PubMed] Related Publications
Epigenetics is the study of heritable and non-heritable genetic coding that is additive to information contained within classical DNA base pair sequences. Differential methylation has a fundamental role in the development and outcome of malignancies, chronic and degenerative diseases and aging. DNA methylation can be measured accurately and easily via various molecular methods and has become a key technology for research and healthcare delivery, with immediate roles in the elucidation of disease natural history, diagnostics and drug discovery. This review focuses on cancers of the lower genital tract, for which the most epigenetic information exists. DNA methylation has been proposed as a triage for women infected with human papillomavirus (HPV) and may eventually directly complement or replace HPV screening as a one-step molecular diagnostic and prognostic test. Methylation of human genes is strongly associated with cervical intraepithelial neoplasia (CIN) and cancer. Of the more than 100 human methylation biomarker genes tested so far in cervical tissue, close to 20 have been reported in different studies, and approximately 10 have been repeatedly shown to have elevated methylation in cervical cancers and high-grade CIN (CIN2 and CIN3), most prominently CADM1, EPB41L3, FAM19A4, MAL, miR-124, PAX1 and SOX1. Obtaining consistent performance data from the literature is quite difficult because most methylation studies used a variety of different assay methodologies and had incomplete and/or biased clinical specimen sets, varying assay thresholds and disparate target gene regions. There have been relatively few validation studies of DNA methylation biomarkers in large population-based screening studies, but an encouraging development more recently is the execution of well-designed studies to test the true performance of the markers in real-world settings. Methylation of HPV genes, especially HPV16, HPV18, HPV31, HPV33 and HPV45, in disease progression has been a major focus of research. Elevated methylation of the HPV16 L1 and L2 open reading frames, in particular, is associated with CIN2, CIN3 and invasive cancer. Essentially all cancers have high levels of methylation for human genes and for driver HPV types, which suggests that quantitative methylation tests may have utility in predicting CIN2 and CIN3 that are likely to progress. It is still early in the process of development of methylation biomarkers, but already they are showing strong promise as a universal and systematic approach to molecular triage, applicable to all cancers, not just cancer of the cervix. DNA methylation testing is better than HPV genotyping triage and is competitive with or complementary to other approaches such as cytology and p16 staining. Genome-wide studies are underway to systematically expand methylation classifier panels and find the best combinations of biomarkers. Methylation testing is likely to show big improvements in performance in the next 5 years.

Martín-Sánchez E, Pernaut-Leza E, Mendaza S, et al.
Gene promoter hypermethylation is found in sentinel lymph nodes of breast cancer patients, in samples identified as positive by one-step nucleic acid amplification of cytokeratin 19 mRNA.
Virchows Arch. 2016; 469(1):51-9 [PubMed] Related Publications
We analysed the promoter methylation status of five genes, involved in adhesion (EPB41L3, TSLC-1), apoptosis (RASSF1, RASSF2) or angiogenesis (TSP-1), in intraoperative sentinel lymph node (SLN) biopsy samples from patients with breast cancer, that had been processed by the one-step nucleic acid amplification (OSNA) technique. SLN resection is performed to estimate the risk of tumour cells in the clinically negative axilla, to avoid unnecessary axillary lymph node dissection. OSNA is currently one of the eligible molecular methods for detecting tumour cells in SLNs. It is based on the quantitative evaluation of cytokeratin 19 mRNA which allows distinguishing between macrometastasis, micrometastasis and isolated tumour cells, on the basis of the quantity of tumour cells present. There have been no prior studies on the question whether or not samples processed by OSNA can be used for further molecular studies, including epigenetic abnormalities which are some of the most important molecular alterations in breast cancer. Genomic DNA was extracted from samples obtained from 50 patients diagnosed with primary breast cancer. The content of tumour cells in SLNs was evaluated by OSNA, and the promoter methylation status of the selected genes was analysed by methylation-specific PCR. All were found to be hypermethylated to a variable degree, and RASSF1 hypermethylation was significantly associated with macrometastasis, micrometastasis and isolated tumour cells (p = 0.002). We show that samples used for OSNA are suitable for molecular studies, including gene promoter methylation. These samples provide a new source of material for the identification of additional biomarkers.

Boers A, Wang R, van Leeuwen RW, et al.
Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.
Clin Epigenetics. 2016; 8:29 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive.
RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear.
CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

Wang H, Xu M, Cui X, et al.
Aberrant expression of the candidate tumor suppressor gene DAL-1 due to hypermethylation in gastric cancer.
Sci Rep. 2016; 6:21755 [PubMed] Free Access to Full Article Related Publications
By allelotyping for loss of heterozygosity (LOH), we previously identified a deletion region that harbors the candidate tumor suppressor gene DAL-1 at 18p11.3 in sporadic gastric cancers (GCs). The expression and function of DAL-1 in GCs remained unclear. Here, we demonstrated that the absence of or notable decreases in the expression of DAL-1 mRNA and protein was highly correlated with CpG hypermethylation of the DAL-1 promoter in primary GC tissues and in GC cell lines. Furthermore, abnormal DAL-1 subcellular localization was also observed in GC cells. Exogenous DAL-1 effectively inhibited cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT); exogenous DAL-1 also promoted apoptosis in GC AGS cells. When endogenous DAL-1 was knocked down in GC HGC-27 cells, the cells appeared highly aggressive. Taken together, these findings provide solid evidence that aberrant expression of DAL-1 by hypermethylation in the promoter region results in tumor suppressor gene behavior that plays important roles in the malignancy of GCs. Understanding the role of it played in the molecular pathogenesis of GC, DAL-1 might be a potential biomarker for molecular diagnosis and evaluation of the GC.

Zeng R, Huang JP, Li XF, et al.
Epb41l3 suppresses esophageal squamous cell carcinoma invasion and inhibits MMP2 and MMP9 expression.
Cell Biochem Funct. 2016; 34(3):133-41 [PubMed] Related Publications
EPB41L3 may play a role as a metastasis suppressor by supporting regular arrangements of actin stress fibres and alleviating the increase in cell motility associated with enhanced metastatic potential. Downregulation of epb41l3 has been observed in many cancers, but the role of this gene in esophageal squamous cell carcinoma (ESCC) remains unclear. Our study aimed to determine the effect of epb41l3 on ESCC cell migration and invasion. We investigated epb41l3 protein expression in tumour and non-tumour tissues by immunohistochemical staining. Expression in the non-neoplastic human esophageal cell line Het-1a and four ESCC cell lines - Kyse150, Kyse510, Kyse450 and Caes17 - was assessed by quantitative Polymerase Chain Reaction (qPCR) and Western blotting. Furthermore, an EPB41L3 overexpression plasmid and EPB41L3-specific small interfering RNA were used to upregulate EPB41L3 expression in Kyse150 cells and to downregulate EPB41L3 expression in Kyse450 cells, respectively. Cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The expression levels of p-AKT, matrix metalloproteinase (MMP)2 and MMP9 were evaluated. Expression of epb41l3 was significantly lower in tumour tissues than in non-tumour tissues and in ESCC cell lines compared with the Het-1a cell line. Kyse450 and Caes17 cells exhibited higher expression of epb41l3 than Kyse150 and Kyse510 cells. Overexpressing epb41l3 decreased Kyse150 cell migration and invasion, whereas EPB41L3-specific small interfering RNA silencing increased these functions in Kyse450 cells. Furthermore, overexpressing epb41l3 led to downregulation of MMP2 and MMP9 in Kyse150 and Kyse510 cells. Our findings reveal that EPB41L3 suppresses tumour cell invasion and inhibits MMP2 and MMP9 expression in ESCC cells.

Xu H, Ma J, Wu J, et al.
Gene expression profiling analysis of lung adenocarcinoma.
Braz J Med Biol Res. 2016; 49(3) [PubMed] Free Access to Full Article Related Publications
The present study screened potential genes related to lung adenocarcinoma, with the aim of further understanding disease pathogenesis. The GSE2514 dataset including 20 lung adenocarcinoma and 19 adjacent normal tissue samples from 10 patients with lung adenocarcinoma aged 45-73 years was downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) between the two groups were screened using the t-test. Potential gene functions were predicted using functional and pathway enrichment analysis, and protein-protein interaction (PPI) networks obtained from the STRING database were constructed with Cytoscape. Module analysis of PPI networks was performed through MCODE in Cytoscape. In total, 535 upregulated and 465 downregulated DEGs were identified. These included ATP5D, UQCRC2, UQCR11 and genes encoding nicotinamide adenine dinucleotide (NADH), which are mainly associated with mitochondrial ATP synthesis coupled electron transport, and which were enriched in the oxidative phosphorylation pathway. Other DEGs were associated with DNA replication (PRIM1, MCM3, and RNASEH2A), cell surface receptor-linked signal transduction and the enzyme-linked receptor protein signaling pathway (MAPK1, STAT3, RAF1, and JAK1), and regulation of the cytoskeleton and phosphatidylinositol signaling system (PIP5K1B, PIP5K1C, and PIP4K2B). Our findings suggest that DEGs encoding subunits of NADH, PRIM1, MCM3, MAPK1, STAT3, RAF1, and JAK1 might be associated with the development of lung adenocarcinoma.

Lorincz AT, Brentnall AR, Scibior-Bentkowska D, et al.
Validation of a DNA methylation HPV triage classifier in a screening sample.
Int J Cancer. 2016; 138(11):2745-51 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomavirus (hrHPV) DNA tests have excellent sensitivity for detection of cervical intraepithelial neoplasia 2 or higher (CIN2+). A drawback of hrHPV screening, however, is modest specificity. Therefore, hrHPV-positive women might need triage to reduce adverse events and costs associated with unnecessary colposcopy. We compared the performance of HPV16/18 genotyping with a predefined DNA methylation triage test (S5) based on target regions of the human gene EPB41L3, and viral late gene regions of HPV16, HPV18, HPV31 and HPV33. Assays were run using exfoliated cervical specimens from 710 women attending routine screening, of whom 38 were diagnosed with CIN2+ within a year after triage to colposcopy based on cytology and 341 were hrHPV positive. Sensitivity and specificity of the investigated triage methods were compared by McNemar's test. At the predefined cutoff, S5 showed better sensitivity than HPV16/18 genotyping (74% vs 54%, P = 0.04) in identifying CIN2+ in hrHPV-positive women, and similar specificity (65% vs 71%, P = 0.07). When the S5 cutoff was altered to allow equal sensitivity to that of genotyping, a significantly higher specificity of 91% was reached (P < 0.0001). Thus, a DNA methylation test for the triage of hrHPV-positive women on original screening specimens might be a valid approach with better performance than genotyping.

Brentnall AR, Vasiljevic N, Scibior-Bentkowska D, et al.
HPV33 DNA methylation measurement improves cervical pre-cancer risk estimation of an HPV16, HPV18, HPV31 and \textit{EPB41L3} methylation classifier.
Cancer Biomark. 2015; 15(5):669-75 [PubMed] Related Publications
BACKGROUND: Persistent infection %by with high risk human papillomavirus (hrHPV) types causes cervical cancer but most women who test positive are at very low risk of neoplasia. Strategies are needed which can retain high sensitivity of hrHPV testing but reduce the number of false-positives. We showed previously that a combination DNA methylation triage assay for HPV types 16, 18 and 31 and human gene EPB41L3 was useful to identify high grade cervical lesions.
OBJECTIVE: Assess whether measurement of DNA methylation in HPV type 33 can improve the previous classifier.
METHODS: A London colposcopy referral group of 1493 women of whom 556 (37%) had histologically-confirmed CIN (cervical intraepithelial neoplasia) 2 or 3 that included 114 HPV33 positive women with methylation measured for three L2 CpGs 5557, 5560 and 5566. Discrimination performance was assessed for the new classifier S5, built by adding HPV33 to the earlier classifier.
RESULTS: HPV33 methylation measurement improved prediction among HPV33 positive women. Receiver operating characteristic analyses showed an area under the curve (AUC) for HPV33 methylation of 0.68 (95% CI 0.57-0.78). The earlier risk score was significantly improved by HPV33 methytlation (AUC = 0.82 vs 0.80; P < 0.001). For 90% sensitivity the specificity for CIN2/3 was 49% (95% CI 46-52%).
CONCLUSIONS: Measurement of HPV33 DNA methylation contributes independent diagnostic information to EPB41L3 and HPV16, HPV18 and HPV31, and is superior to genotyping. Other HPV and human methylation target regions might be useful to further improve S5.

Yu F, Yang H, Zhang Z, et al.
DAL-1/4.1B contributes to epithelial-mesenchymal transition via regulation of transforming growth factor-β in lung cancer cell lines.
Mol Med Rep. 2015; 12(4):6072-8 [PubMed] Related Publications
The present study aimed to investigate the effects of the tumor suppressor gene differentially expressed in adenocarcinoma of the lung 1 (DAL‑1)/4.1B on early‑stage adenocarcinoma of the lung. The role of DAL‑1/4.1B in the epithelial‑mesenchymal transition (EMT), which is implicated in cancer metastasis, was examined using DAL‑1 knockdown and overexpression, followed by polymerase chain reaction and western blot analysis of EMT markers, as well as cell counting and cell migration/invasion assays. The results showed that DAL‑1/4.1B has a role in transforming growth factor (TGF)‑β‑induced EMT in non‑small cell lung cancer cells. Silencing of DAL‑1/4.1B with inhibitory RNAs altered the expression of numerous EMT markers, including E‑cadherin and β‑catenin, whereas overexpression of DAL‑1/4.1B had the opposite effect. In addition, DAL‑1/4.1B expression was induced following TGF‑β treatment at the protein and mRNA level. DAL‑1/4.1B deficiency impaired TGF‑β‑induced EMT and increased cell migration and invasion. These results suggested that DAL‑1/4.1B contributed to the EMT and may be important for tumor metastasis in lung cancer. Together with the results of a previous study by our group, the present study suggested that DAL‑1/4.1B acts as a tumor suppressor in the early transformation process in lung cancer, while in later stages, it functions as an oncogene affecting the biological features of human lung carcinoma cells. The results of the present study provided evidence for the feasibility of utilizing DAL‑1/4.1B as a target for lung cancer gene therapy.

Li L, Li S, Cai T, et al.
The targeted inhibitory effects of human amniotic fluid stem cells carrying CXCR4 promoter and DAL-1 on non-small cell lung carcinoma growth.
Gene Ther. 2016; 23(2):214-22 [PubMed] Related Publications
The differentially expressed in adenocarcinoma of the lung-1 (DAL-1) protein has been demonstrated to be suppressive to various types of tumors including lung cancer. This study aimed to determine the targeted effects of human amniotic fluid stem cells (hAFS cells) carrying CXCR4 promoter driven conditionally replicable adenovirus vector overexpressing DAL-1 (Ad-CXCR4-DAL-1) on non-small cell lung carcinoma (NSCLC) growth. The apoptotic effects of virus vectors were assessed using flow cytometry, and the cytotoxicity analyzed by CCK-8 assay. In vivo imaging system was used to determine the homing capability of hAFS cells. A549 cell xenograft mouse model was created to assess the in vivo effect of DAL-1 overexpression on NSCLC growth. We found that infection of Ad-CXCR4-DAL-1 increased the apoptosis of A549 NSCLC cells but not 16HBE normal human bronchial epithelial cells. Ad-CXCR4-DAL-1 administered via intratumoral injection led to significant reduced growth and greater necrosis of A549 xenograft tumors comparing to null vector treated animals. When infused via tail vein, hAFS cells carrying Ad-CXCR4-DAL-1 homed to lung cancer xenografts, caused virus replication and DAL-1 overexpression, and led to significant lower growth and greater necrosis of A549 cell xenografts comparing to non-treatment control. In conclusion, hAFS cells are capable of carrying Ad-CXCR4-DAL-1 vectors, specifically targeting to lung cancer, and causing oncolytic effects when administered in vivo.

Blanco-Luquin I, Guarch R, Ojer A, et al.
Differential role of gene hypermethylation in adenocarcinomas, squamous cell carcinomas and cervical intraepithelial lesions of the uterine cervix.
Pathol Int. 2015; 65(9):476-85 [PubMed] Related Publications
Cervical cancer is the third most common cancer in women worldwide. The hypermethylation of P16, TSLC-1 and TSP-1 genes was analyzed in squamous cell carcinomas (SCC), cervical intraepithelial lesions (CIN) and adenocarcinomas (ADC) of the uterine cervix (total 181 lesions). Additionally human papillomavirus (HPV) type, EPB41L3, RASSF1 and RASSF2 hypermethylation were tested in ADC and the results were compared with those obtained previously by our group in SCC. P16, TSLC-1 and TSP-1 hypermethylation was more frequent in SCCs than in CINs. These percentages and the corresponding ones for EPB41L3, RASSF1 and RASSF2 genes were also higher in SCCs than in ADCs, except for P16. The presence of HPV in ADCs was lower than reported previously in SCC and CIN. Patients with RASSF1A hypermethylation showed significantly longer disease-free survival (P = 0.015) and overall survival periods (P = 0.009) in ADC patients. To our knowledge, this is the first description of the EPB41L3 and RASSF2 hypermethylation in ADCs. These results suggest that the involvement of DNA hypermethylation in cervical cancer varies depending on the histological type, which might contribute to explaining the different prognosis of patients with these types of tumors.

Liang H, Yan X, Pan Y, et al.
MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3.
Mol Cancer. 2015; 14:58 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with hematogenous metastatic lung cancer displayed significantly increased platelet count and aggregation compared to lung cancer patients without hematogenous metastasis. The mechanism underlying the correlation between the lung cancer hematogenous metastasis and platelet activation remains unknown.
RESULTS: In the present study, we explored the role of microRNA-223 (miR-223) derived from platelets in modulating lung cancer cell invasion. Our results demonstrated that platelets from NSCLC patients contain higher level of miR-223 than that from healthy subjects. The concentration of miR-223 in the platelet-secreted microvesicles (P-MVs) from NSCLC patients was also increased compared to that from healthy subjects. Incubation of human lung cancer A549 cells with P-MVs resulted in rapid delivery of miR-223 into A549 cells, in which platelet miR-223 targeted EPB41L3 and thus promoted A549 cell invasion. The effect of P-MVs on reducing EPB41L3 in A549 cells but promoting tumor cell invasion could be largely abolished by depletion of miR-223 via transfection with miR-223 antagomir. The role of EPB41L3 in inhibiting A549 cell invasion was further validated by directly downregulating EPB41L3 via transfecting cells with EPB41L3 siRNA or miR-223 mimic.
CONCLUSIONS: Our study demonstrates for the first time that platelet-secreted miR-223 via P-MVs can promote lung cancer cell invasion via targeting tumor suppressor EPB41L3.

Perez-Janices N, Blanco-Luquin I, Tuñón MT, et al.
EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas.
Oncotarget. 2015; 6(1):368-80 [PubMed] Free Access to Full Article Related Publications
Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3, RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients' clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1) and bisulfite-sequencing (for RASSF2). EPB41L3, RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2'-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3, RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse (p = 0.047) and better (p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas (p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance.

Vasiljević N, Ahmad AS, Carter PD, et al.
DNA methylation of PITX2 predicts poor survival in men with prostate cancer.
Biomark Med. 2014; 8(9):1143-50 [PubMed] Related Publications
AIM: We investigated if methylation of candidate genes can be useful for predicting prostate cancer (PCa) specific death.
PATIENTS & METHODS: Methylation of PITX2, WNT5a, SPARC, EPB41L3 and TPM4 was investigated in a 1:2 case-control cohort comprising 45 men with cancer of Gleason score ≤ 7 who died (cases), and 90 men who were alive or died of other causes with survival time longer than the cases (controls). A univariate conditional logistic regression model was fitted by maximizing the likelihood of DNA methylation of each gene versus the primary end point.
RESULTS: A 10% increase in methylation of PITX2 was associated with PCa related death with OR 1.56 (95% CI: 1.17-2.08; p = 0.005).
CONCLUSION: Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.

Louvanto K, Franco EL, Ramanakumar AV, et al.
Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16.
Int J Cancer. 2015; 136(6):E638-45 [PubMed] Related Publications
Methylation of human papillomavirus (HPV) and host genes may predict cervical cancer risk. We examined the methylation status of selected sites in HPV16 and human genes in DNA extracted from exfoliated cervical cell samples of 244 women harboring HPV16-positive cancer or cervical intraepithelial neoplasia (CIN) or negative for intraepithelial lesions or malignancy (NILM). We quantified the methylation of CpG sites in the HPV16 L1 gene (CpG 6367 and 6389) and in the human genes EPB41L3 (CpG 438, 427, 425) and LMX1 (CpG 260, 262, 266, 274) following bisulfite treatment and pyrosequencing. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic utility of methylation level for the different sites and for a joint predictor score. Methylation in all sites significantly increased with lesion severity (p < 0.0001). Area under the curve (AUC) was highest among the CIN2/3 vs. cancer ranging from 0.786 to 0.853 among the different sites. Site-specific methylation levels strongly discriminated CIN2/3 from NILM/CIN1 and cancer from CIN2/3 (range of odds ratios [OR]: 3.69-12.76, range of lower 95% confidence bounds: 1.03-4.01). When methylation levels were mutually adjusted for each other EPB41L3 was the only independent predictor of CIN2/3 vs. NILM/CIN1 contrasts (OR = 9.94, 95%CI: 2.46-40.27). High methylation levels of viral and host genes are common among precancerous and cancer lesions and can serve as independent risk biomarkers. Methylation of host genes LMX1 and EPB41L3 and of the viral HPV16 L1 sites has the potential to distinguish among precancerous lesions and to distinguish the latter from invasive disease.

Li X, Zhou F, Jiang C, et al.
Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis.
PLoS One. 2014; 9(7):e103162 [PubMed] Free Access to Full Article Related Publications
DNA methylation is a critical epigenetic mechanism involved in key cellular processes. Its deregulation has been linked to many human cancers including esophageal squamous cell carcinoma (ESCC). This study was designed to explore the whole methylation status of ESCC and to identify potential plasma biomarkers for early diagnosis. We used Infinium Methylation 450k array to analyze ESCC tissues (n = 4), paired normal surrounding tissues (n = 4) and normal mucosa from healthy individuals (n = 4), and combined these with gene expression data from the GEO database. One hundred and sixty eight genes had differentially methylated CpG sites in their promoter region and a gene expression pattern inverse to the direction of change in DNA methylation. These genes were involved in several cancer-related pathways. Three genes were validated in additional 42 ESCC tissues and paired normal surrounding tissues. The methylation frequency of EPB41L3, GPX3, and COL14A1 were higher in tumor tissues than in normal surrounding tissues (P < 0.017). The higher methylation frequency of EPB41l3 was correlated with large tumor size (P = 0.044) and advanced pT tumor stage (P = 0.001). The higher methylation frequency of GPX3 and COL14A1 were correlated with advanced pN tumor stage (P = 0.001 and P < 0.001). The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals. Diagnostic sensitivity was increased when methylation of any of the 3 genes were counted (64.3% sensitivity and 100% specificity). These differentially methylated genes in plasma may be used as biomarkers for early diagnosis of ESCC.

Brentnall AR, Vasiljević N, Scibior-Bentkowska D, et al.
A DNA methylation classifier of cervical precancer based on human papillomavirus and human genes.
Int J Cancer. 2014; 135(6):1425-32 [PubMed] Free Access to Full Article Related Publications
Testing for high-risk (hr) types of human papillomavirus (HPV) is highly sensitive as a screening test of high-grade cervical intraepithelial neoplastic (CIN2/3) disease, the precursor of cervical cancer. However, it has a relatively low specificity. Our objective was to develop a prediction rule with a higher specificity, using combinations of human and HPV DNA methylation. Exfoliated cervical specimens from colposcopy-referral cohorts in London were analyzed for DNA methylation levels by pyrosequencing in the L1 and L2 regions of HPV16, HPV18, HPV31 and human genes EPB41L3, DPYS and MAL. Samples from 1,493 hrHPV-positive women were assessed and of these 556 were found to have CIN2/3 at biopsy; 556 tested positive for HPV16 (323 CIN2/3), 201 for HPV18 (73 CIN2/3) and 202 for HPV31 (98 CIN2/3). The prediction rule included EPB41L3 and HPV and had area under curve 0.80 (95% CI 0.78-0.82). For 90% sensitivity, specificity was 36% (33-40) and positive predictive value (PPV) was 46% (43-48). By HPV type, 90% sensitivity corresponded to the following specificities and PPV, respectively: HPV16, 38% (32-45) and 67% (63-71); HPV18, 53% (45-62) and 52% (45-59); HPV31, 39% (31-49) and 58% (51-65); HPV16, 18 or 31, 44% (40-49) and 62% (59-65) and other hrHPV 17% (14-21) and 21% (18-24). We conclude that a methylation assay in hrHPV-positive women might improve PPV with minimal sensitivity loss.

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.

Guerrero-Setas D, Pérez-Janices N, Blanco-Fernandez L, et al.
RASSF2 hypermethylation is present and related to shorter survival in squamous cervical cancer.
Mod Pathol. 2013; 26(8):1111-22 [PubMed] Related Publications
Ras association (RalGDS/AF-6) domain family member 2 (RASSF2) is a gene involved in the progression of several human cancers, including breast, colorectal and lung cancer. The aims of this study were to determine the hypermethylation of the gene in squamous cervical cancer and precursor lesions, along with that of RASSF1 and the recently described EPB41L3, and to analyze the potential prognostic role of these genes. Methylation-specific PCR and bisulfite sequencing were used to analyze the methylation status of RASSF2 and EPB41L3 gene in 60 squamous cervical cancer, 76 cervical intraepithelial neoplasias grade III, 16 grade II, 14 grade I and 13 cases of normal tissue adjacent to cervical intraepithelial neoplasia. RASSF2 expression was evaluated by immunohistochemistry and the re-expression of RASSF2 and EPB41L3 was analyzed by quantitative reverse-transcription PCR in HeLa, SiHa, C33A and A431 cell lines treated with 5-aza-2'-deoxycytidine and/or trichostatin. RASSF1 hypermethylation and human papillomavirus type were also analyzed in all the cases by methylation-specific PCR and reverse line blot, respectively. RASSF2 hypermethylation was predominant in squamous cervical cancer (60.9%) compared with cervical intraepithelial neoplasias (4.2%) and was associated with a lower level of RASSF2 expression and vascular invasion in squamous cervical cancer. EPB41L3 and RASSF1 hypermethylations were also more frequent in cancer than in precursor lesions. Patients with RASSF2 hypermethylation had shorter survival time, independent of tumor stage (hazard ratio: 6.0; 95% confidence interval: 1.5-24.5). Finally, the expressions of RASSF2 and EPB41L3 were restored in several cell lines treated with 5-aza-2'-deoxycytidine. Taken together, our results suggest that RASSF2 potentially functions as a new tumor-suppressor gene that is inactivated through hypermethylation in cervical cancer and is related to the bad prognosis of these patients.

Ji Y, Xie M, Lan H, et al.
PRR11 is a novel gene implicated in cell cycle progression and lung cancer.
Int J Biochem Cell Biol. 2013; 45(3):645-56 [PubMed] Related Publications
Identification and functional analysis of novel potential cancer-associated genes is of great importance for developing diagnostic, preventive and therapeutic strategies for cancer treatment and management. In the present study, we isolated and identified a novel gene, proline-rich protein 11 (PRR11), implicated in both cell cycle progression and lung cancer. Our results showed that PRR11 was periodically expressed in a cell cycle-dependent manner, and RNAi-mediated silencing of PRR11 caused significant S phase arrest as well as growth retardation in HeLa cells. Moreover, PRR11 was overexpressed at both mRNA and protein levels in lung cancer tissues as compared with normal lung tissues. Large scale in silico analysis of clinical microarray datasets also indicated that high expression of PRR11 was significantly associated with poor prognosis in lung cancer patients. RNAi-mediated silencing of PRR11 caused S phase arrest, suppressed cellular proliferation, colony formation ability in lung cancer cells and inhibited tumorigenic potential in nude mice. Knockdown of PRR11 also inhibited cell migration and invasion ability in lung cancer cells. Furthermore, microarray analysis revealed that PRR11 knockdown caused the dysregulation of multiple critical pathways and various important genes involved in cell cycle, tumorigenesis and metastasis (e.g. CCNA1, RRM1, MAP4K4 and EPB41L3). Taken together, our results strongly demonstrated that this newly identified gene, PRR11, had a critical role in both cell cycle progression and tumorigenesis, and might serve as a novel potential target in the diagnosis and/or treatment of human lung cancer.

Zhang Y, Xu R, Li G, et al.
Loss of expression of the differentially expressed in adenocarcinoma of the lung (DAL-1) protein is associated with metastasis of non-small cell lung carcinoma cells.
Tumour Biol. 2012; 33(6):1915-25 [PubMed] Related Publications
The differentially expressed in adenocarcinoma of the lung-1 (DAL-1) protein is a member of the membrane-associated cytoskeleton protein 4.1 family. This protein was previously found to be downregulated or lost in more than half of primary non-small cell lung cancers (NSCLC). In this study, the relationship between DAL-1 expression and NSCLC metastasis was examined. DAL-1 mRNA and protein levels were measured in NSCLC cell lines and in tumor cells isolated from the pleural fluid of NSCLC patients clinically diagnosed with distant metastases to the bone or brain. The results revealed that DAL-1 expression was observed in two (GLC-82 and NCI-H460) out of seven metastatic NSCLC cell lines examined. DAL-1 expression was not observed in the cells isolated from the pleural fluid in nine out of ten patients. Overexpression of DAL-1 in A549 cells, a cell line lacking endogenous DAL-1, inhibited cell migration and invasion by approximately 38 and 48 %, respectively. In contrast, DAL-1 knockdown in NCI-H460 cells enhanced the migration and invasion potential of this cell line 4.6- and 3-fold, respectively. Furthermore, DAL-1 promoter methylation was observed in six of nine pleural fluid NSCLC cell isolates and in two cell lines (A549 and H1299), as evidenced by a lack of endogenous DAL-1. Demethylation in A549 cells successfully restored DAL-1 mRNA and protein expression levels, resulting in a parallel remarkable inhibition of migration and invasion. These results indicated that DAL-1 was pivotal in triggering NSCLC migration and invasion and that loss of DAL-1 expression was due to the epigenetic methylation.

Eijsink JJ, Lendvai Á, Deregowski V, et al.
A four-gene methylation marker panel as triage test in high-risk human papillomavirus positive patients.
Int J Cancer. 2012; 130(8):1861-9 [PubMed] Related Publications
Cervical neoplasia-specific biomarkers, e.g. DNA methylation markers, with high sensitivity and specificity are urgently needed to improve current population-based screening on (pre)malignant cervical neoplasia. We aimed to identify new cervical neoplasia-specific DNA methylation markers and to design and validate a methylation marker panel for triage of high-risk human papillomavirus (hr-HPV) positive patients. First, high-throughput quantitative methylation-specific PCRs (QMSP) on a novel OpenArray™ platform, representing 424 primers of 213 cancer specific methylated genes, were performed on frozen tissue samples from 84 cervical cancer patients and 106 normal cervices. Second, the top 20 discriminating methylation markers were validated by LightCycler® MSP on frozen tissue from 27 cervical cancer patients and 20 normal cervices and ROCs and test characteristics were assessed. Three new methylation markers were identified (JAM3, EPB41L3 and TERT), which were subsequently combined with C13ORF18 in our four-gene methylation panel. In a third step, our methylation panel detected in cervical scrapings 94% (70/74) of cervical cancers, while in a fourth step 82% (32/39) cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and 65% (44/68) CIN2+ were detected, with 21% positive cases for ≤CIN1 (16/75). Finally, hypothetical scenario analysis showed that primary hr-HPV testing combined with our four-gene methylation panel as a triage test resulted in a higher identification of CIN3 and cervical cancers and a higher percentage of correct referrals compared to hr-HPV testing in combination with conventional cytology. In conclusion, our four-gene methylation panel might provide an alternative triage test after primary hr-HPV testing.

Li X, Zhang Y, Zhang H, et al.
miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3.
Mol Cancer Res. 2011; 9(7):824-33 [PubMed] Related Publications
Traditional research modes aim to find cancer-specific single therapeutic target. Recently, emerging evidence suggested that some micro-RNAs (miRNA) can function as oncogenes or tumor suppressors. miRNAs are single-stranded, small noncoding RNA genes that can regulate hundreds of downstream target genes. In this study, we evaluated the miRNA expression patterns in gastric carcinoma and the specific role of miR-223 in gastric cancer metastasis. miRNA expression signature was first analyzed by real-time PCR on 10 paired gastric carcinomas and confirmed in another 20 paired gastric carcinoma tissues. With the 2-fold expression difference as a cutoff level, we identified 22 differential expressed mature miRNAs. Sixteen miRNAs were upregulated in gastric carcinoma, including miR-223, miR-21, miR-23b, miR-222, miR-25, miR-23a, miR-221, miR-107, miR-103, miR-99a, miR-100, miR-125b, miR-92, miR-146a, miR-214 and miR-191, and six miRNAs were downregulated in gastric carcinoma, including let-7a, miR-126, miR-210, miR-181b, miR-197, and miR-30aa-5p. After examining these miRNAs in several human gastric originated cell lines, we found that miR-223 is overexpressed only in metastatic gastric cancer cells and stimulated nonmetastatic gastric cancer cells migration and invasion. Mechanistically, miR-223, induced by the transcription factor Twist, posttranscriptionally downregulates EPB41L3 expression by directly targeting its 3'-untranslated regions. Significantly, overexpression of miR-223 in primary gastric carcinomas is associated with poor metastasis-free survival. These findings indicate a new regulatory mode, namely, specific miRNA, which is activated by its upstream transcription factor, could suppress its direct targets and lead to tumor invasion and metastasis.

Nymark P, Guled M, Borze I, et al.
Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos- and histology-related changes in lung cancer.
Genes Chromosomes Cancer. 2011; 50(8):585-97 [PubMed] Related Publications
Lung cancer has the highest mortality rate of all of the cancers in the world and asbestos-related lung cancer is one of the leading occupational cancers. The identification of asbestos-related molecular changes has long been a topic of increasing research interest. The aim of this study was to identify novel asbestos-related molecular correlates by integrating miRNA expression profiling with previously obtained profiling data (aCGH and mRNA expression) from the same patient material. miRNA profiling was performed on 26 tumor and corresponding normal lung tissue samples from highly asbestos-exposed and non-exposed patients, and on eight control lung tissue samples. Data analyses on miRNA expression, and integration of miRNA and previously obtained mRNA data were performed using Chipster. A separate analysis was used to integrate miRNA and previously obtained aCGH data. Both known and new lung cancer-associated miRNAs and target genes with inverse correlation were discovered. Furthermore, DNA copy number alterations (e.g., gain at 12p13.31) were correlated with the deregulated miRNAs. Specifically, thirteen novel asbestos-related miRNAs (over-expressed: miR-148b, miR-374a, miR-24-1*, Let-7d, Let-7e, miR-199b-5p, miR-331-3p, and miR-96 and under-expressed: miR-939, miR-671-5p, miR-605, miR-1224-5p and miR-202) and inversely correlated target genes (e.g., GADD45A, LTBP1, FOSB, NCALD, CACNA2D2, MTSS1, EPB41L3) were identified. In addition, over-expression of the well known squamous cell carcinoma-associated miR-205 was linked to down-regulation of the DOK4 gene. The miRNAs/genes presented here may represent interesting targets for further investigation and could eventually have potential diagnostic implications.

Nagata M, Sakurai-Yageta M, Yamada D, et al.
Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma.
Int J Cancer. 2012; 130(6):1329-37 [PubMed] Related Publications
Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin-binding protein, 4.1B/DAL-1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin-superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM-family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786-O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B.

Pham MH, Zada G, Mosich GM, et al.
Molecular genetics of meningiomas: a systematic review of the current literature and potential basis for future treatment paradigms.
Neurosurg Focus. 2011; 30(5):E7 [PubMed] Related Publications
Although a majority of meningiomas are benign neoplasms, those occurring at the cranial base may be challenging tumors to treat because of extensive tissue invasion, an inability to achieve gross-total microscopic resection, and local tumor recurrence and/or progression. A more comprehensive understanding of the genetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide novel targets for grading assessments and individualizing molecular therapies for skull base meningiomas. The authors performed a review of the current literature to identify genes that have been associated with the formation and/or progression of meningiomas. Mutations in the NF2 gene have been most commonly implicated in the formation of the majority of meningiomas. Inactivation of other tumor suppressor genes, including DAL-1 and various tissue inhibitors of matrix metalloproteinases, upregulation of several oncogenes including c-sis and STAT3, and signaling dysregulation of pathways such as the Wnt pathway, have each been found to play important, and perhaps, complementary roles in meningioma development, progression, and recurrence. Identification of these genetic factors using genome-wide association studies and high-throughput genomics may provide data for future individualized treatment strategies.

Takahashi Y, Iwai M, Kawai T, et al.
Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer.
Breast Cancer. 2012; 19(3):242-52 [PubMed] Related Publications
BACKGROUND: The tumor suppressor genes CADM1/TSLC1 and DAL-1/4.1B are frequently inactivated by promoter methylation in non-small cell lung cancer. The proteins they encode, CADM1 and 4.1B, form a complex in human epithelial cells and are involved in cell-cell adhesion.
METHODS: Expression of CADM1 and 4.1B proteins was examined by immunohistochemistry in 67 primary breast cancer and adjacent noncancerous tissues. CADM1 and 4.1B messenger RNA (mRNA) was detected by reverse-transcription polymerase chain reaction (RT-PCR). The methylation status of the CADM1 and 4.1B promoters was determined quantitatively by bisulfite treatment followed by pyrosequencing.
RESULTS: CADM1 and 4.1B protein signals were detected along the cell membrane in normal mammary epithelia. By contrast, 47 (70%) and 49 (73%) of 67 primary breast cancers showed aberrant CADM1 and 4.1B staining, respectively. Aberrant CADM1 staining was more frequently observed in pT2 and pT3 tumors and for stages II and III (P = 0.045 and P = 0.020, respectively), while aberrant 4.1B staining was more often observed in tumors with lymph node metastasis, for pT2 and pT3 tumors, and for stages II and III (P = 0.0058, P = 0.0098, and P = 0.0007, respectively). Furthermore, aberrant CADM1 and 4.1B expression was preferentially observed in invasive relative to noninvasive lesions from the same specimen (P = 0.036 and P = 0.0009, respectively). Finally, hypermethylation of CADM1 and 4.1B genes was detected in 46% and 42% of primary breast cancers, respectively.
CONCLUSIONS: Our findings suggest that aberrant CADM1 and 4.1B expression is involved in progression of breast cancer, especially in invasion into the stroma and metastasis.

Alexiou GA, Markoula S, Gogou P, Kyritsis AP
Genetic and molecular alterations in meningiomas.
Clin Neurol Neurosurg. 2011; 113(4):261-7 [PubMed] Related Publications
Meningiomas are the most common benign intracranial tumors in adults arising from the dura matter. The etiology of meningiomas is mostly unknown, although several risk factors have been described, such as ionizing radiation, head injury, hormones and genetic factors. According to WHO they are classified into 3 grades, grade I, grade II and grade III. Meningiomas express various hormonal and growth factor receptors, such as progesterone, estrogen, somatostatin, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptors, which may be related to their biological behavior and response to treatment. Chromosomal abnormalities linked to meningiomas involve chromosomes 22, 1p, 9p, 10p, 11, 14q, 15, 17, and 18q. In addition, genes that may be involved in the formation of meningiomas include NF2, DAL-1, p14 (ARF), p53, MDM2, Rb, p16 and c-myc. It is likely that detailed molecular information will aid in establishing a molecular grading of these tumors and predict response to treatment and survival.

Schulz WA, Ingenwerth M, Djuidje CE, et al.
Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation.
BMC Cancer. 2010; 10:505 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network.
METHODS: Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as "cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry.
RESULTS: EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively.
CONCLUSIONS: Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.

Mawrin C, Perry A
Pathological classification and molecular genetics of meningiomas.
J Neurooncol. 2010; 99(3):379-91 [PubMed] Related Publications
Meningiomas are extremely common adult brain tumors originating from meningeal coverings of the brain and spinal cord. While most are slowly growing Word Health organization (WHO) grade I tumors, rare variants (clear cell, chordoid, papillary, and rhabdoid), as well as brain invasive (WHO grade II), atypical (WHO grade II), and anaplastic (WHO grade III) meningiomas are considerably more aggressive. This review summarizes the histopathological and genetic features of meningiomas, including differential diagnosis, pitfalls, and grading challenges. Early stages of meningioma tumorigenesis are closely linked to inactivation of one or more members of the 4.1 superfamily, including the neurofibromatosis type 2 (NF2) and 4.1B (DAL-1) genes, which interact with the 14-3-3 protein family. Other chromosome 22q genes implicated include BAM22, BCR (breakpoint cluster region), and TIMP-1, the last of which is implicated in higher-grade meningiomas. Atypical meningiomas also commonly show chromosomal losses of 1p, 6q, 10, 14q, and 18q, as well as multiple chromosomal gains. While most relevant genes remain unknown, two chromosome 14q candidates (MEG3 and NDRG2) have recently been identified. In addition to alterations of CDKN2A, p14(ARF), and CDKN2B tumor suppressor genes on 9p21, a contribution of the wingless (wnt) pathway with alterations of the E-cadherin and beta-catenin proteins, as well as alterations of the hedgehog signaling pathway have been implicated in anaplastic meningiomas. The integration of histopathological appearance, complex genetic/genomic data, and outcome will likely result in the identification of clinically distinct meningioma subgroups, which in turn can facilitate the development of targeted therapeutic strategies.

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