OPCML

Gene Summary

Gene:OPCML; opioid binding protein/cell adhesion molecule-like
Aliases: OPCM, OBCAM, IGLON1
Location:11q25
Summary:This gene encodes a member of the IgLON subfamily in the immunoglobulin protein superfamily. The encoded protein is localized in the plasma membrane and may have an accessory role in opioid receptor function. This gene has an ortholog in rat and bovine. The opioid binding-cell adhesion molecule encoded by the rat gene binds opioid alkaloids in the presence of acidic lipids, exhibits selectivity for mu ligands and acts as a GPI-anchored protein. Since the encoded protein is highly conserved in species during evolution, it may have a fundamental role in mammalian systems. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:opioid-binding protein/cell adhesion molecule
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (7)

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.

  • RTPCR
  • Azacitidine
  • Chromosome 11
  • Bladder Cancer
  • Cancer DNA
  • GPI-Linked Proteins
  • Loss of Heterozygosity
  • Carcinoma
  • Transfection
  • Signal Transduction
  • Cell Adhesion Molecules
  • Sensitivity and Specificity
  • DNA Methylation
  • Case-Control Studies
  • DNA Sequence Analysis
  • Nerve Tissue Proteins
  • Cancer Gene Expression Regulation
  • Staging
  • Ovarian Cancer
  • Tumor Suppressor Gene
  • Lung Cancer
  • Tumor Necrosis Factor Decoy Receptors
  • Trisomy
  • Twist Transcription Factor
  • Gene Expression Profiling
  • Survival Rate
  • Enzyme Inhibitors
  • Tumor Markers
  • Promoter Regions
  • Polymerase Chain Reaction
  • Messenger RNA
  • Tumor Suppressor Proteins
  • Lymphatic Metastasis
  • Phenotype
  • Cervical Cancer
  • Epigenetics
  • Alternative Splicing
  • Polymorphism
  • CpG Islands
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: OPCML (cancer-related)

Zhou F, Ma M, Tao G, et al.
Detection of circulating methylated opioid binding protein/cell adhesion molecule-like gene as a biomarker for ovarian carcinoma.
Clin Lab. 2014; 60(5):759-65 [PubMed] Related Publications
BACKGROUND: Hypermethylation of the opioid binding protein/cell adhesion molecule-like (OPCML) gene is frequently observed in ovarian carcinoma. We evaluated the detection of circulating hypermethylated OPCML for detecting ovarian carcinoma and assessing its prognosis.
METHODS: We studied 85 tissue samples including 45 ovarian cancer tissues and 40 normal ovarian tissues and blood samples from 45 ovarian cancer patients and 20 healthy individuals. Bisulfite sequencing and methylation-sensitive restriction enzyme-PCR (MSRE-PCR) were used to detect the frequency of OPCML hypermethylation.
RESULTS: We detected that the frequency of OPCML hypermethylation for tissue and serum samples in ovarian carcinoma were 86.7% (39/45) and 80.0% (36/45), respectively, but none was detected in ovarian tissue and serum of healthy individuals. The frequency of OPCML hypermethylation in endometrioid carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, clear cell carcinoma, and undifferentiated carcinoma were 80.0%, 85.5%, 50.0%, 80.0%, and 100%, respectively (p > 0.05). The frequencies of OPCML hypermethylation in patients were also different in terms of tumor differentiation degree. We detected hypermethylated OPCML in the sera of 50% of well differentiated, 62.5% of moderately differentiated, 93.1% of poorly differentiated tumors (p < 0.05). The frequency of OPCML hypermethylation at FIGO stage I was 42.9%, stage II was 66.7%, stage III was 85.7%, stage IV was 100% (p < 0.05).
CONCLUSIONS: Detection OPCML methylation in the serum is useful for ovarian carcinoma diagnosis.

Zhou F, Tao G, Chen X, et al.
Methylation of OPCML promoter in ovarian cancer tissues predicts poor patient survival.
Clin Chem Lab Med. 2014; 52(5):735-42 [PubMed] Related Publications
BACKGROUND: Ovarian cancer is a lethal gynecological malignancy largely due to the lack of biomarkers for early detection and treatment options. Opioid binding protein/cell adhesion molecule-like gene (OPCML) has a tumor-suppressor function in ovarian cancer, and epigenetic inactivation of OPCML induces oncogenic transformation of human ovarian surface epithelial cells.
METHODS: This study investigated OPCML promoter methylation levels in ovarian cancer tissues. A total of 30 normal ovarian, 85 benign ovarian tumor, and 102 ovarian cancer tissues were subjected to quantitative methylation-specific PCR analysis of OPCML methylation. Four ovarian cancer cell lines were cultured and treated with the DNA demethylation agent 5-aza-2'-deoxycytidine (5-AZA) for restoring OPCML expression.
RESULTS: The data showed that 80 of 102 (78.4%) ovarian cancer tissues and 28 of 85 (32.9%) benign ovarian tumors had a methylated OPCML gene promoter. In contrast, there was no OPCML gene promoter methylation in any of the 30 normal ovarian samples. OPCML promoter methylation was significantly associated with an older age of the patients (p=0.022), an advanced pathological stage of ovarian cancer (p=0.023), and poor overall survival of ovarian cancer patients (p<0.001). Multivariate analysis data showed that pathological stage, age, and OPCML promoter methylation were all independent factors to predict overall survival of patients. Furthermore, 5-AZA was able to restore expression of OPCML mRNA and protein in ovarian cancer cell lines.
CONCLUSIONS: These data indicate that detection of OPCML gene promoter methylation could be a useful biomarker for predicting the prognosis of ovarian cancer patients and disease progression.

Zhang Q, Hu G, Yang Q, et al.
A multiplex methylation-specific PCR assay for the detection of early-stage ovarian cancer using cell-free serum DNA.
Gynecol Oncol. 2013; 130(1):132-9 [PubMed] Related Publications
OBJECTIVE: Epithelial ovarian cancer (EOC) remains the most lethal disease among gynecological malignancies. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stage of the disease. As a result, there is an urgent need for improved detection methods. In this study, we established a multiplex methylation-specific PCR (MSP) assay to improve the early detection of ovarian cancer, via identification of the methylation status of cell-free serum DNA.
METHODS: After screening, we chose seven candidate genes (APC, RASSF1A, CDH1, RUNX3, TFPI2, SFRP5 and OPCML) with a high frequency of methylation to construct the multiplex-MSP assay. When methylation of at least one of the seven genes was observed, the multiplex-MSP assay was considered positive. We performed retrospective and screening studies to verify the specificity and sensitivity of the assay in the detection of EOC.
RESULTS: The methylation status of cell-free serum DNA was examined in the preoperative serum of 202 patients, including 87 EOC patients (stage I, n=41; stage II-IV, n=46), 53 patients with benign ovarian tumors and 62 healthy controls. As expected, the multiplex MSP assay achieved a sensitivity of 85.3% and a specificity of 90.5% in stageI EOC, strikingly higher rates compared with a single CA125, which produced a sensitivity of 56.1% at 64.15% specificity [P=0.0036].
CONCLUSION: A multiplex MSP assay that analyzes the methylation status of cell-free serum DNA is a suitable and reliable approach to improve the early detection of ovarian cancer, potentially benefiting a broad range of applications in clinical oncology.

Minhas HM, Pescosolido MF, Schwede M, et al.
An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma.
Am J Med Genet A. 2013; 161A(4):787-91 [PubMed] Free Access to Full Article Related Publications
We report on a pedigree with a pair of brothers each with minor anomalies, developmental delay, and autistic-symptoms who share an unbalanced translocation (not detectable by karyotype). The unbalanced translocation involves a 7.1 Mb loss of the terminal portion of 10q, and a 4.2 Mb gain of 11q. One of the brothers also developed a cerebellar juvenile pilocytic astrocytoma. The father was found to be a balanced carrier and the couple had a previous miscarriage. We demonstrate that the breakpoint for the triplicated region from chromosome 11 is adjacent to two IgLON genes, namely Neurotrimin (NTM) and Opioid Binding Protein/Cell Adhesion Molecule-like (OPCML). These genes are highly similar neural cell adhesion molecules that have been implicated in synaptogenesis and oncogenesis, respectively. The children also have a 10q deletion and are compared to other children with the 10q deletion syndrome which generally does not involve autism spectrum disorders (ASDs) or cancer. Together these data support a role for NTM and OPCML in developmental delay and potentially in cancer susceptibility.

Chen W, Xiang J, Chen DF, et al.
Screening for differentially methylated genes among human colorectal cancer tissues and normal mucosa by microarray chip.
Mol Biol Rep. 2013; 40(5):3457-64 [PubMed] Related Publications
UNLABELLED: High density DNA methylation microarrays were used to study the differences of gene methylation level in six pairs of colorectal cancer (CRC) and adjacent normal mucosa. We analyzed the profile of methylated genes by NimbleGen Microarray and the biologic functions by NIH-NAVID. In addition, preliminary validation studies were done in six pairs of samples by MSP (methylation-specific PCR). A total of 4,644 genes had a difference in methylation levels. Among them 2,296 were hypermethylated (log2ratio > 1), 2,348 genes were hypomethylated (log2ratio < -1), in which 293 hypermethylated and 313 hypomethylated genes were unmapped according to the NIH-NAVID. All these genes were randomly distributed on all the chromosomes. However, chromosome 1 contained the most of the hypermethylated genes (232 genes), followed by chromosome 19 (149 genes), chromosome 11 (144 genes), chromosome 2 (141 genes), chromosomes 3 (127 genes). Through the analysis of the statistics, There were 2 hypermethylated/3 hypomethylated genes involved in six pairs of samples simultaneously, followed by 10/14 in five samples, 34/37 in four samples, 101/113 in three samples, 341/377 in two samples, 1,808/1,804 in one sample. According to gene ontology analysis, some physiological processes play important roles in the cell division and the development of tumor, such as apoptosis, DNA repair, immune, cell cycle, cell cycle checkpoint, cell adhesion and invasion etc. Through Preliminary validation, there were two genes (St3gal6, Opcml) in thirty top-ranking genes shown hypermethylated in six pairs of CRC and adjacent normal mucosa.
CONCLUSIONS: High density DNA methylation microarrays is an effective method for screening aberrantly methylated genes in CRC. The methylated genes should be further studied for diagnostic or prognostic markers for CRC.

McKie AB, Vaughan S, Zanini E, et al.
The OPCML tumor suppressor functions as a cell surface repressor-adaptor, negatively regulating receptor tyrosine kinases in epithelial ovarian cancer.
Cancer Discov. 2012; 2(2):156-71 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo. Here, we further show the clinical relevance of OPCML and demonstrate that OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4. OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition. Exogenous recombinant OPCML domain 1-3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism. These findings demonstrate a novel mechanism of OPCML-mediated tumor suppression and provide a proof-of-concept for recombinant OPCML protein therapy in epithelial ovarian cancers.
SIGNIFICANCE: The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1–associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation. Recombinant OPCML domain 1-3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy.

Zhou F, Cao X, Liu M, et al.
A study of the methylation status of opioid binding protein/cell adhesion molecule-like gene in ovarian cancer using nested methylation-specific polymerase chain reaction detection.
Clin Lab. 2011; 57(5-6):421-4 [PubMed] Related Publications
BACKGROUND: The goal was to improve the methylation-specific PCR (MSP) method and investigate the methylation status of the OPCML gene in carcinoma tissues from ovarian cancer patients.
METHODS: MSP and nested MSP methods were used to examine the methylation status of the OPCML gene promoter in ovarian cancer, borderline tumor, and normal ovary tissues.
RESULTS: Methylation of the OPCML gene was detected in 58.3% (14/24) and 83.3% (20/24) of the specimens from ovarian cancer patients using MSP and nested MSP methods, respectively. No methylation was observed in normal ovarian tissues using either method.
CONCLUSIONS: The modified nested MSP method showed better sensitivity. The methylation of the OPCML gene was significantly higher in ovarian cancer than in normal tissue. The detection of OPCML gene methylation could serve as one of the molecular markers for the diagnosis of ovarian cancer.

Duarte-Pereira S, Paiva F, Costa VL, et al.
Prognostic value of opioid binding protein/cell adhesion molecule-like promoter methylation in bladder carcinoma.
Eur J Cancer. 2011; 47(7):1106-14 [PubMed] Related Publications
The OPCML gene (opioid binding protein/cell adhesion molecule-like), a putative tumour suppressor gene, is frequently inactivated in carcinomas, namely through aberrant promoter methylation. Herein, we aimed to determine whether OPCML altered expression mediated by epigenetic mechanisms was implicated in bladder carcinogenesis and to assess its potential as a bladder cancer epi-marker. OPCML promoter methylation levels from 91 samples of bladder urothelial carcinoma, 25 normal bladder tissues and bladder cancer cell lines were assessed by quantitative methylation-specific polymerase chain reaction, and correlated with OPCML mRNA expression, determined by quantitative reverse-transcription polymerase chain reaction. To prove the epigenetic regulation of OPCML, five bladder cancer cell lines were exposed to 5-aza-2'deoxycytidine (5-aza-dC), a specific DNA methyltransferase inhibitor and trichostatin A (TSA), a histone deacetylase inhibitor. In bladder tumours, the overall frequency of methylation was 60% and methylation levels were significantly higher when compared with normal mucosa (P=0.0001). No correlation was found between methylation levels and clinicopathological parameters. Interestingly, OPCML promoter methylation was associated with worse disease-specific survival (P=0.022) in univariate analysis. Furthermore, a significant inverse correlation between OPCML promoter methylation and mRNA expression levels was found, although a significant re-expression was only achieved when 5-aza-dC and TSA were used simultaneously. The high frequency of OPCML promoter methylation in urothelial carcinomas suggests an important role for this epigenetic alteration in bladder carcinogenesis, highlighting its potential as an epigenetic biomarker for bladder urothelial carcinoma with prognostic significance.

Zhang Y, Wang R, Song H, et al.
Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.
Cancer Lett. 2011; 303(1):21-8 [PubMed] Related Publications
Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARβ and p16(INK4A)) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues (P≤0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14(ARF), MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequentin cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues (P<0.001), and CIMP+ was associated with advanced stage (P=0.017), lymphatic metastasis (P=0.001) and adverse 2-year progression-free survival (P=0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified.

Li B, Liu W, Wang L, et al.
CpG island methylator phenotype associated with tumor recurrence in tumor-node-metastasis stage I hepatocellular carcinoma.
Ann Surg Oncol. 2010; 17(7):1917-26 [PubMed] Related Publications
BACKGROUND: CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.
METHODS: We investigated the methylation status of ten TSGs and CIMP in 115 samples of HCC and 48 samples of corresponding nonneoplastic liver tissues using a methylation-specific polymerase chain reaction.
RESULTS: The methylation frequencies of the ten genes examined in HCC were 40.0% for p14 ( ARF ), 60.9% for p15 ( INK4b ), 70.4% for p16 ( INK4a ), 34.8% for p73, 70.4% for GSTP1, 64.3% for MGMT, 13.0% for hMLH1, 59.1% for RARbeta, 82.6% for SOCS-1, and 80.9% for OPCML. CIMP+ (with six or more methylated genes) was detected in 68 (59.1%) of 115 HCCs and none of 48 nonneoplastic liver tissues. On stratified univariate analysis, patients with tumor-node-metastasis (TNM) stage I HCC with CIMP+ had significantly shorter overall survival (OS) (P = 0.002) and recurrence-free survival (RFS) (P = 0.042) than those with CIMP-. Furthermore, multivariate analysis revealed CIMP+ as an independent prognostic factor for both OS [hazard ratio (HR), 12.266; P = 0.015] and RFS (HR, 2.275; P = 0.032) in TNM stage I patients.
CONCLUSIONS: CIMP+ may specifically define a subgroup of patients with unfavorable outcome in TNM stage I HCC. Examination of CIMP status may be useful for stratifying prognosis of patients with early-stage HCC and identifying patients who are at higher risk for recurrence.

Cui Y, Ying Y, van Hasselt A, et al.
OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.
PLoS One. 2008; 3(8):e2990 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction.
METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing.
CONCLUSIONS/SIGNIFICANCE: Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.

Anglim PP, Galler JS, Koss MN, et al.
Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer.
Mol Cancer. 2008; 7:62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is the leading cause of cancer death in men and women in the United States and Western Europe. Over 160,000 Americans die of this disease every year. The five-year survival rate is 15% - significantly lower than that of other major cancers. Early detection is a key factor in increasing lung cancer patient survival. DNA hypermethylation is recognized as an important mechanism for tumor suppressor gene inactivation in cancer and could yield powerful biomarkers for early detection of lung cancer. Here we focused on developing DNA methylation markers for squamous cell carcinoma of the lung. Using the sensitive, high-throughput DNA methylation analysis technique MethyLight, we examined the methylation profile of 42 loci in a collection of 45 squamous cell lung cancer samples and adjacent non-tumor lung tissues from the same patients.
RESULTS: We identified 22 loci showing significantly higher DNA methylation levels in tumor tissue than adjacent non-tumor lung. Of these, eight showed highly significant hypermethylation in tumor tissue (p < 0.0001): GDNF, MTHFR, OPCML, TNFRSF25, TCF21, PAX8, PTPRN2 and PITX2. Used in combination on our specimen collection, this eight-locus panel showed 95.6% sensitivity and specificity.
CONCLUSION: We have identified 22 DNA methylation markers for squamous cell lung cancer, several of which have not previously been reported to be methylated in any type of human cancer. The top eight markers show great promise as a sensitive and specific DNA methylation marker panel for squamous cell lung cancer.

Ye F, Zhang SF, Xie X, Lu WG
OPCML gene promoter methylation and gene expression in tumor and stroma cells of invasive cervical carcinoma.
Cancer Invest. 2008; 26(6):569-74 [PubMed] Related Publications
To investigate the CpG island methylation and the mRNA expression of OPCML gene in patients with cervical carcinoma, we collected tumor and stroma cells from 36 invasive cervical carcinoma samples and 16 normal cervical tissues as well as Hela cells. Methylation specific PCR was used to detect promoter CpG island methylation status, and fluorescence quantitative RT-PCR was used to detection of OPCML gene expression. Our data showed that OPCML gene promoter methylation may play an important role in the carcinogenesis of cervical carcinoma and OPCML gene may be a cervical carcinoma-associated candidate TSG (tumor suppressor gene).

Margetts CD, Morris M, Astuti D, et al.
Evaluation of a functional epigenetic approach to identify promoter region methylation in phaeochromocytoma and neuroblastoma.
Endocr Relat Cancer. 2008; 15(3):777-86 [PubMed] Free Access to Full Article Related Publications
The molecular genetics of inherited phaeochromocytoma have received considerable attention, but the somatic genetic and epigenetic events that characterise tumourigenesis in sporadic phaeochromocytomas are less well defined. Previously, we found considerable overlap between patterns of promoter region tumour suppressor gene (TSG) hypermethylation in two neural crest tumours, neuroblastoma and phaeochromocytoma. In order to identify candidate biomarkers and epigenetically inactivated TSGs in phaeochromocytoma and neuroblastoma, we characterised changes in gene expression in three neuroblastoma cell lines after treatment with the demethylating agent 5-azacytidine. Promoter region methylation status was then determined for 28 genes that demonstrated increased expression after demethylation. Three genes HSP47, homeobox A9 (HOXA9) and opioid binding protein (OPCML) were methylated in >10% of phaeochromocytomas (52, 17 and 12% respectively). Two of the genes, epithelial membrane protein 3 (EMP3) and HSP47, demonstrated significantly more frequent methylation in neuroblastoma than phaeochromocytoma. These findings extend epigenotype of phaeochromocytoma and identify candidate genes implicated in sporadic phaeochromocytoma tumourigenesis.

Reed JE, Dunn JR, du Plessis DG, et al.
Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours.
Neuropathol Appl Neurobiol. 2007; 33(1):77-85 [PubMed] Related Publications
The four GPI-anchored cell adhesion molecules that exemplify the IgLON family are most highly expressed in the nervous system and associate to form up to six different heterodimeric 'Diglons' that can modify cell adhesion and inhibit axon migration. Recently, two members, OPCML and LSAMP, were identified as putative tumour suppressor genes in ovarian and renal carcinomas respectively. In this study, we investigated OPCML expression in nonneoplastic brain tissue and 35 brain tumours (18 glioblastoma multiformes, five anaplastic gliomas, five meningiomas, six metastases and one medulloblastoma) and four glioma cell lines using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). OPCML was highly expressed in cerebellum, less so in cerebral cortex, frontal lobe and meninges and was significantly reduced or absent in 83% of brain tumours and all cell lines compared with nonneoplastic whole brain. Two OPCML splice variants have been identified in humans, termed alpha1 and alpha2, but the latter has not been demonstrated in human neural tissues. Using PCR with specific primers, nonneoplastic brain and 3/6 of tested brain tumours expressed both splice variants, whereas the remaining brain tumours only expressed the alpha2 variant. Hypermethylation of the alpha1 OPCML promoter, associated with down-regulation of expression in ovarian tumours, did not correlate with expression levels in the subset of brain tumours tested, implying transcription of OPCML from an alternative promoter or a different mechanism of down-regulation. This study demonstrates that OPCML down-regulation occurs in the majority of brain tumours tested, warranting further investigation of OPCML and other IgLONs in the development and progression of brain tumours.

Czekierdowski A, Czekierdowska S, Szymanski M, et al.
Opioid-binding protein/cell adhesion molecule-like (OPCML) gene and promoter methylation status in women with ovarian cancer.
Neuro Endocrinol Lett. 2006; 27(5):609-13 [PubMed] Related Publications
OBJECTIVE: The expression profile of the OPMCL gene was studied to find out if there was any evidence of a CpG island methylator phenotype and if there was an association of CpG island methylation with the gene downregulation in women with ovarian cancer.
MATERIAL AND METHODS: Expression of OPCML in 43 ovarian cancer tumor samples and in 4 normal ovaries was determined by RT-PCR. Methylation status of OPCML promoter region was studied with methylation-specific PCR (MSP) method. Possible associations with selected clinicopathologic variables: FIGO stage, histological grade, patient's age and menopausal status were tested.
RESULTS: In all normal ovarian samples OPCML mRNA was present, but it was not detectable in 24 of 43 ovarian cancer cases. We have not found the relationship between age and menopausal status with the presence of RTPCR product of OPCML. Hypermethylation of OPCML was not correlated to FIGO stage, however, in 80% of cases with methylated OPCML early clinical stage was also present. Tumor grading and histological type had no significant influence on the presence of hypermethylation of OPCML gene. In 20 of 43 cases of ovarian cancer methylated product of MSP amplification was present. In a group of OPCMLmRNA-negative tumors there were 75% of cases with hypermethylated exon of OPCML and the correlation between these variables was statistically significant (chi2 =17.7; p=0,00003). No promoter hypermethylation of the studied gene was found in normal ovaries.
CONCLUSIONS: Reduced OPCMPL gene expression in ovarian cancer in comparison to normal ovaries could be related to the hypermethylation of promoter region. This epigenetic alteration may be the reason of gene silencing and the loss of suppressor function.

Wang L, Zhu JS, Song MQ, et al.
Comparison of gene expression profiles between primary tumor and metastatic lesions in gastric cancer patients using laser microdissection and cDNA microarray.
World J Gastroenterol. 2006; 12(43):6949-54 [PubMed] Free Access to Full Article Related Publications
AIM: To study the differential gene expression profiles of target cells in primary gastric cancer and its metastatic lymph nodes using laser microdissection (LMD) in combination with cDNA microarray.
METHODS: Normal gastric tissue samples from 30 healthy individuals, 36 cancer tissue samples from primary gastric carcinoma and lymph node metastasis tissue samples from 58 patients during gastric cancer resection were obtained using LMD in combination with cDNA microarray independently. After P27-based amplification, aRNA from 36 of 58 patients (group 1) with lymph node metastasis and metastatic tissue specimens from the remaining 22 patients (group 2) were applied to cDNA microarray. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical assay verified the results of microarray in group 2 and further identified genes differentially expressed in the progression of gastric cancer.
RESULTS: The expression of 10 genes was up-regulated while the expression of 15 genes was down-regulated in 22 gastric carcinoma samples compared with that of genes in the normal controls. The results were confirmed at the level of mRNA and protein, and suggested that four genes (OPCML, RNASE1, YES1 and ACK1) could play a key role in the tumorigenesis and metastasis of gastric cancer. The expression pattern of 3 genes (OPCML, RNASE1 and YES1) was similar to tumor suppressor genes. For example, the expression level of these genes was the highest in normal gastric epithelium, which was decreased in primary carcinoma, and further decreased in metastatic lymph nodes. On the contrary, the expression pattern of gene ACK1 was similar to that of oncogene. Four genes were further identified as differentially expressed genes in the majority of the cases in the progression of gastric cancer.
CONCLUSION: LMD in combination with cDNA microarray provides a unique support foe the identification of early expression profiles of differential genes and the expression pattern of 3 genes (OPCML, RNASE1 and YES1) associated with the progression of gastric cancer. Further study is needed to reveal the molecular mechanism of lymph node metastasis in patients with gastric cancer.

Mei FC, Young TW, Liu J, Cheng X
RAS-mediated epigenetic inactivation of OPCML in oncogenic transformation of human ovarian surface epithelial cells.
FASEB J. 2006; 20(3):497-9 [PubMed] Related Publications
Opioid binding protein/cell adhesion molecule-like gene (OPCML), a recently identified tumor-suppressor, is frequently inactivated by allele loss and CpG island promoter methylation in epithelial ovarian cancer. Since elevated activation of the RAS signaling pathway, including overexpression of HER-2/neu and mutations of RAS and BRAF, is common in human ovarian carcinoma, we examined the cellular effect of oncogenic RAS on the expression status of OPCML in a genetically defined human ovarian cancer model. Our study revealed that RAS(V12)-mediated oncogenic transformation was accompanied by a concomitant loss of OPCML expression. Methylation-sensitive PCR analysis showed that the OPCML promoter was hypermethylated in RAS-transformed human ovarian epithelial cells (T29H) and that treatment with the DNA methyltransferase inhibitor 5'-aza-2'-deoxycytidine promoted demethylation of the OPCML promoter and restored OPCML expression in T29H cells. Furthermore, suppression of oncogenic RAS activity by stable siRNA specific for HRAS(V12) led to the demethylation and re-expression of OPCML in T29H cells, demonstrating that oncogenic RAS activity is directly responsible for the observed OPCML promoter hypermethylation and epigenetic gene silencing of OPCML. Taken together, our study suggests that elevation of the RAS signaling pathway may play an important role in epigenetic inactivation of OPCML in human epithelial ovarian cancer.

Teodoridis JM, Hall J, Marsh S, et al.
CpG island methylation of DNA damage response genes in advanced ovarian cancer.
Cancer Res. 2005; 65(19):8961-7 [PubMed] Related Publications
We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position -149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.

Ntougkos E, Rush R, Scott D, et al.
The IgLON family in epithelial ovarian cancer: expression profiles and clinicopathologic correlates.
Clin Cancer Res. 2005; 11(16):5764-8 [PubMed] Related Publications
PURPOSE: The IgLON family of cell adhesion molecules, comprising OPCML, HNT, LSAMP, and NEGR1, has recently been linked to cancer, through two of its members being proposed as tumor suppressors. We examined the expression profile of the family in human sporadic epithelial ovarian cancer and the normal ovary.
EXPERIMENTAL DESIGN: We determined the expression level of each IgLON in a panel comprising 57 tumor and 11 normal ovarian samples by quantitative real-time reverse transcription-PCR. The results were statistically tested for associations with clinicopathologic variables.
RESULTS: OPCML, LSAMP and NEGR1 exhibited reduced expression in the tumor samples relative to the normal samples, whereas HNT expression was elevated. Statistically significant changes were specific to histologic type. The expression levels of individual IgLONs were correlated, the most significant finding being a positive correlation between LSAMP and NEGR1. LSAMP expression was also negatively correlated with overall survival and was found to be a negative predictor of outcome.
CONCLUSIONS: The expression of the IgLON family is altered in sporadic epithelial ovarian tumors in comparison to the normal ovary. In our small but representative cohort of patients, we have found significant correlations and associations in expression and clinicopathology that suggest a wider role of the family in ovarian cancer.

Sellar GC, Watt KP, Rabiasz GJ, et al.
OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.
Nat Genet. 2003; 34(3):337-43 [PubMed] Related Publications
Epithelial ovarian cancer (EOC), the leading cause of death from gynecological malignancy, is a poorly understood disease. The typically advanced presentation of EOC with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases are hallmarks of the disease. These features relate to the biology of the disease, which is a principal determinant of outcome. EOC arises as a result of genetic alterations sustained by the ovarian surface epithelium (OSE; ref. 3). The causes of these changes are unknown but are manifest by activation of oncogenes and inactivation of tumor-suppressor genes (TSGs). Our analysis of loss of heterozygosity at 11q25 identified OPCML (also called OBCAM), a member of the IgLON family of immunoglobulin (Ig) domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecules, as a candidate TSG in EOC. OPCML is frequently somatically inactivated in EOC by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with TSG properties both in vitro and in vivo. A somatic missense mutation from an individual with EOC shows clear evidence of loss of function. These findings suggest that OPCML is an excellent candidate for the 11q25 ovarian cancer TSG. This is the first description to our knowledge of the involvement of the IgLON family in cancer.

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