Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

OPCML (opioid binding protein/cell adhesion molecule-like) Artur Czekierdowski, Sylwia Czekierdowska Ist Dept.of Gynecologic Oncology and Gynecology, Medical University in Lublin, Poland (AC, SC)

Published in Atlas Database: January 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/OPCMLID44423ch11q25.html DOI: 10.4267/2042/44641 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology

being a truncated C2 domain, and a GPI anchor. Identity Protein is extensively glycosylated with six potential Other names: OBCAM; OPCM N-linked sites. HGNC (Hugo): OPCML Expression Location: 11q25 OPCML is highly expressed in the nervous system and Note: OPCML belongs to the IgLON family of involved in cell adhesion and cell-cell recognition. immunoglobulin domain containing During the first postnatal week, protein is prominent glycosylphosphatidylinositol (GPI)-anchored cell within cerebral cortex, developing hippocampus, adhesion molecules, which includes OPCML, LSAMP, pyriform cortex, and the mitral cell layer of the NEGR1 and HNT. The protein is localized in the olfactory bulb. At later ages, OPCML is expressed plasma membrane and may have an accessory role in prominently within all regions of Ammon's horn and in opioid receptor function. the mitral cell layer of the olfactory bulb and the pyriform cortex. OPCML is localized preferentially to DNA/RNA dendrites compared with somata and terminals of hypothalamic vasopressin-secreting magnocellular Note neurons. This localization indicates that protein is one OPCML comprises 7 exons, spans approximately 600 of the dendrite-associated cell adhesion molecules. It is kb and is transcribed from telomere to centromere. synthesized within the somata, attached to vasopressin Sequence analysis of the OPCML promoter revealed a neurosecretory granules via the GC-rich region spanning 900 bp approximate 500 bp glycosylphosphatidylinositol anchor, and transported to upstream of the translational start site. the dendrites. Moreover, the subcellular localization of OPCML is changed in an activity-dependent manner. Protein Recently published data suggested that OPCML-v1 was widely expressed in all normal adult and fetal tissues Description except for placenta and peripheral blood mononuclear OPCML consisted of one half beta-sheets and one cells, though at varying levels (highly expressed in fourth alpha-helices. Hydropathy analysis suggested brain, kidney, spleen, stomach, trachea, testis, cervix, that hydrophobic and hydrophilic regions were evenly ovary and prostate, and weakly in lung, breast, and distributed along the sequence, but the NH2- and bone marrow). Compared to v1, OPCML-v2 displayed COOH-termini were hydrophobic. Hydrophobic a more tissue-specific expression pattern in adult moments and Fourier-transform amphipathic analyses tissues, with expression absent or barely detectable in further suggest that residues 23-30 and 83-93 were kidney, spleen, pancreas, breast, testis, lung, colon, amphipathic beta-sheets. Structural elements include liver, testis and bone marrow. In contrast to its three, with the first and expression in adult tissues, OPCML-v2 was expressed third being full C2 domains and the middle domain at moderate to high levels in all fetal tissues except for placenta.

Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12) 956 OPCML (opioid binding protein/cell adhesion molecule-like) Czekierdowski A, Czekierdowska S

Function Ectopic expression of OPCML in tumor cell lines with endogenous silencing led to strong inhibition of cell OPCML was originally isolated as a potential micro- colony formation, dramatic anchorage-dependent and - type opiate receptor. Subsequent studies have shown independent growth inhibition demonstrating that that the physiologic opiate receptors belong to the G- OPCML acts as a broad tumor suppressor. The role of protein-coupled receptor family, however, they do not OPCML in DNA damage repair, apoptosis and cell promote direct binding of opioids when transfected into cycle arrest with respect to stress response remains to heterologous cells. IgLONs have been suggested to be further investigated. play an important role in cell adhesion and cell-cell recognition, through both homo- and heterophilic Homology interactions within the family. Recently, it has been Two alternative splice transcripts of OPCML, variant 1 proposed that IgLONs function mainly as heterodimers (v1) and variant 2 (v2), were previously identified in called Diglons. OPCML may contribute to the diversity human, which differ only in their 59 exons but encode at the surface of different populations of neurons during an identical mature protein. Among the four IgLON development. Some latest evidences also suggest that family members, OPCML shares the highest homology OPCML is a synaptic cell adhesion molecule to HNT that lies approximately 80 kb centromeric to concerning synaptogenesis and its surface localization OPCML in the opposite orientation. Notably, the is dynamically regulated in response to neuronal coding region in exon 1 of OPCML-v1 and HNT is activity. Recently, it has been shown that IgLONs are identical, and so is the exon 2 except for only several expressed outside the nervous system, and OPCML bases. The first Ig domains of these two proteins share might act as a tumor suppressor. As a cell adhesion 92% identity, while the second and third Ig domains molecule, OPCML comprises several protein-protein share 70% and 66% identity, respectively. This raises interaction domains, commonly found in cell surface- the possibility that OPCML and HNT may originate adhesion and receptor molecules. Through these from the same antecestor by gene conversion during domains, OPCML may bind directly to growth evolution. promoting or inhibitory molecules and modulate their functions in tumor cells. New findings suggested that OPCML is an excellent Implicated in candidate for tumor suppressor gene (TSG). OPCML is Epithelial ovarian cancer (EOC) frequently somatically inactivated in cancer by allele loss and by CpG island methylation. OPCML has Oncogenesis functional characteristics consistent with TSG OPCML is frequently somatically inactivated in EOC properties both in vitro and in vivo. It has been found by allele loss and by CpG island methylation (Sellar et existence somatic missense mutation in individual with al., 2003). epithelial ovarian cancer and it shows clear evidence of Hypermethylation of OPCML was not correlated to loss of function. Another data showed that OPCML FIGO stage, however, in 80% of cases with methylated gene promoter methylation may play an important role OPCML early clinical stage was also present. Tumor in the carcinogenesis of cervical and lung carcinoma. grading and histological type had no significant OPCML probably functions as a tumor suppressor influence on the presence of hypermethylation of through interacting with other IgLONs to form OPCML gene. In a group of OPCMLmRNA-negative heterodimeric complex involved in signal transduction. tumors there were 75% of cases with hypermethylated Among the IgLON family, OPCML was the first exon of OPCML and the correlation between these member reported to possess tumor suppressor functions variables was statistically significant. No promoter in epithelial ovarian cancer, being frequently silenced hypermethylation of the studied gene was found in genetically and epigenetically at the early step of normal ovaries (Czekierdowski et al., 2006). ovarian carcinogenesis. This inactivation is due to its Methylation-sensitive PCR analysis showed that the promoter methylation, which further impairs its OPCML promoter was hypermethylated in RAS- response to environmental stresses. Loss of OPCML transformed human ovarian epithelial cells (T29H) and reduces the intercellular adhesion and heterodimeric that treatment with the DNA methyltransferase complex formation and thus impairs the corresponding inhibitor 5'-aza-2'-deoxycytidine promoted signaling pathways, thereby promoting the progress of demethylation of the OPCML promoter and restored carcinogenesis. Latest evidences of Cui et al (2008) OPCML expression in T29H cells. Suppression of suggested that OPCML is frequently inactivated oncogenic RAS activity by stable siRNA specific for epigenetically in multiple tumor cell line including HRAS(V12) led to the demethylation and re-expression nasopharyngeal, esophageal, lung, gastric, of OPCML in T29H cells, demonstrating that hepatocellular, colorectal, breast, cervical and prostate oncogenic RAS activity is directly responsible for the carcinomas. Authors showed that OPCML is a stress- observed OPCML promoter hypermethylation and responsive and p53-regulated gene, with the response epigenetic gene silencing of OPCML. RAS signaling abrogated when the promoter becomes methylated. pathway may play an important role in epigenetic

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inactivation of OPCML in human epithelial ovarian nonneoplastic whole brain. Two OPCML splice cancer (Mei et al., 2006). variants have been identified in humans, termed alpha1 Expression of OPCML mRNA in ovarian epithelial and alpha2, but the latter has not been demonstrated in carcinoma was significantly lower than those of normal human neural tissues. Hypermethylation of the alpha1 and benign tumors. Methylations were detected in OPCML promoter, associated did not correlate with 44.4% of cancer cells promoter, while 0% in normal expression levels in the subset of brain tumours tested, ovarian tissue and benign ovarian tumors. The ratio of implying transcription of OPCML from an alternative methylation of ovarian epithelial carcinoma was promoter or a different mechanism of down-regulation significantly higher than those of normal and benign (Reed et al., 2007). tumors (Zhang et al., 2006). Phaeochromocytoma The relationship between gene expression and promoter methylation was significantly correlated (OPCML Oncogenesis expression in ovarian serous carcinomas was OPCML was methylated in 12% of significantly higher than in ovarian adenomas and phaeochromocytomas (Margetts et al., 2008). normal tissues. CpG island methylation and LOH are probably two mechanisms of OPCML inactivation. References LOH at D11S4085 was also correlated with loss of Wu CS, Hasegawa J, Smith AP, Loh HH, Lee NM, Yang JT. OPCML expression. The LOH rate at D11S4085 in Opioid-binding protein (OBCAM) is rich in beta-sheets. J carcinomas was significantly higher than that for Protein Chem. 1990 Feb;9(1):3-7 adenomas and normal tissues. Abnormal methylation of Lane CM, Elde R, Loh HH, Lee NM. Regulation of an opioid- OPCML was found in 53.4% of the carcinomas, while binding protein in NG108-15 cells parallels regulation of delta- in none of the adenomas or normal tissues (Chen et al., opioid receptors. Proc Natl Acad Sci U S A. 1992 Dec 2007). 1;89(23):11234-8 Shark KB, Lee NM. Cloning, sequencing and localization to Invasive cervical carcinoma chromosome 11 of a cDNA encoding a human opioid-binding Oncogenesis cell adhesion molecule (OBCAM). Gene. 1995 Apr OPCML gene promoter methylation may play an 3;155(2):213-7 important role in the carcinogenesis of cervical Hachisuka A, Yamazaki T, Sawada J, Terao T. carcinoma and OPCML gene may be a cervical Characterization and tissue distribution of opioid-binding cell adhesion molecule (OBCAM) using monoclonal antibodies. carcinoma-associated candidate tumor suppressor gene Neurochem Int. 1996 Apr;28(4):373-9 (Ye et al., 2008). Miyata S, Matsumoto N, Taguchi K, Akagi A, Iino T, Funatsu N, Squamous cell lung carcinoma Maekawa S. Biochemical and ultrastructural analyses of IgLON cell adhesion molecules, Kilon and OBCAM in the rat brain. Oncogenesis Neuroscience. 2003;117(3):645-58 OPCML hypermethylation did not differ significantly Miyata S, Taguchi K, Maekawa S. Dendrite-associated opioid- based on gender, race, age or tumor stage, indicating binding cell adhesion molecule localizes at neurosecretory their wide applicability as potential lung granules in the hypothalamic magnocellular neurons. adenocarcinoma markers (Tsou et al., 2007). Neuroscience. 2003;122(1):169-81 Gastric cancer Sellar GC, Watt KP, Rabiasz GJ, Stronach EA, Li L, Miller EP, Massie CE, Miller J, Contreras-Moreira B, Scott D, Brown I, Oncogenesis Williams AR, Bates PA, Smyth JF, Gabra H. OPCML at 11q25 OPCML could play a key role in the tumorigenesis and is epigenetically inactivated and has tumor-suppressor function metastasis of gastric cancer. The expression level of in epithelial ovarian cancer. Nat Genet. 2003 Jul;34(3):337-43 this gene was the highest in normal gastric epithelium, Reed J, McNamee C, Rackstraw S, Jenkins J, Moss D. which was decreased in primary carcinoma, and further Diglons are heterodimeric proteins composed of IgLON subunits, and Diglon-CO inhibits neurite outgrowth from decreased in metastatic lymph nodes (Wang et al., cerebellar granule cells. J Cell Sci. 2004 Aug 1;117(Pt 2007). 17):3961-73 Hepatocellular carcinoma Czekierdowski A, Czekierdowska S, Szymanski M, Wielgos M, Kaminski P, Kotarski J. Opioid-binding protein/cell adhesion Oncogenesis molecule-like (OPCML) gene and promoter methylation status Hypermethylation rates of OPCML was higher in HCC in women with ovarian cancer. Neuro Endocrinol Lett. 2006 than in pericancer tissues (70.0% vs. 64.6%). Promoter Oct;27(5):609-13 methylation of OPCML gene may play an important Li P, Prasad SS, Mitchell DE, Hachisuka A, Sawada JI, Al- role in hepatocarcinogenesis (Liu et al., 2006). Housseini AM, Gu Q. Postnatal expression profile of OBCAM implies its involvement in visual cortex development and Gliomas plasticity. Cereb Cortex. 2006 Feb;16(2):291-9 Oncogenesis Liu WJ, Wang L, Wang JP, Li JQ, Zhang CQ, Zheng L, Yuan OPCML was significantly reduced or absent in 83% of YF. [Correlations of CpG island methylator phenotype and brain tumours and all cell lines compared with OPCML gene methylation to carcinogenesis of hepatocellular carcinoma]. Ai Zheng. 2006 Jun;25(6):696-700

Atlas Genet Cytogenet Oncol Haematol. 2009; 13(12) 958 OPCML (opioid binding protein/cell adhesion molecule-like) Czekierdowski A, Czekierdowska S

Mei FC, Young TW, Liu J, Cheng X. RAS-mediated epigenetic molecule OBCAM; synaptogenesis and dynamic inactivation of OPCML in oncogenic transformation of human internalization. Brain Res. 2007 Aug 24;1165:5-14 ovarian surface epithelial cells. FASEB J. 2006 Mar;20(3):497- 9 Cui Y, Ying Y, van Hasselt A, Ng KM, Yu J, Zhang Q, Jin J, Liu D, Rhim JS, Rha SY, Loyo M, Chan AT, Srivastava G, Tsao Wang L, Zhu JS, Song MQ, Chen GQ, Chen JL. Comparison GS, Sellar GC, Sung JJ, Sidransky D, Tao Q. OPCML is a of gene expression profiles between primary tumor and broad tumor suppressor for multiple carcinomas and metastatic lesions in gastric cancer patients using laser lymphomas with frequently epigenetic inactivation. PLoS One. microdissection and cDNA microarray. World J Gastroenterol. 2008 Aug 20;3(8):e2990 2006 Nov 21;12(43):6949-54 Margetts CD, Morris M, Astuti D, Gentle DC, Cascon A, Zhang J, Ye F, Chen HZ, Ye DF, Lu WG, Xie X. [Deletion of McRonald FE, Catchpoole D, Robledo M, Neumann HP, Latif OPCML gene and promoter methylation in ovarian epithelial F, Maher ER. Evaluation of a functional epigenetic approach to carcinoma]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2006 identify promoter region methylation in phaeochromocytoma Apr;28(2):173-7 and neuroblastoma. Endocr Relat Cancer. 2008 Sep;15(3):777-86 Reed JE, Dunn JR, du Plessis DG, Shaw EJ, Reeves P, Ye F, Zhang SF, Xie X, Lu WG. OPCML gene promoter Gee AL, Warnke PC, Sellar GC, Moss DJ, Walker C. methylation and gene expression in tumor and stroma cells of Expression of cellular adhesion molecule 'OPCML' is down- invasive cervical carcinoma. Cancer Invest. 2008 regulated in gliomas and other brain tumours. Neuropathol Jul;26(6):569-74 Appl Neurobiol. 2007 Feb;33(1):77-85 Tsou JA, Galler JS, Siegmund KD, Laird PW, Turla S, Cozen This article should be referenced as such: W, Hagen JA, Koss MN, Laird-Offringa IA. Identification of a Czekierdowski A, Czekierdowska S. OPCML (opioid binding panel of sensitive and specific DNA methylation markers for protein/cell adhesion molecule-like). Atlas Genet Cytogenet lung adenocarcinoma. Mol Cancer. 2007 Oct 29;6:70 Oncol Haematol. 2009; 13(12):956-959. Yamada M, Hashimoto T, Hayashi N, Higuchi M, Murakami A, Nakashima T, Maekawa S, Miyata S. Synaptic adhesion

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