| Description | OPCML consisted of one half beta-sheets and one fourth alpha-helices. Hydropathy analysis suggested that hydrophobic and hydrophilic regions were evenly distributed along the sequence, but the NH2- and COOH-termini were hydrophobic. Hydrophobic moments and Fourier-transform amphipathic analyses further suggest that residues 23-30 and 83-93 were amphipathic beta-sheets. Structural elements include three, with the first and third being full C2 domains and the middle domain being a truncated C2 domain, and a GPI anchor. Protein is extensively glycosylated with six potential N-linked sites. |
| Expression | OPCML is highly expressed in the nervous system and involved in cell adhesion and cell-cell recognition. During the first postnatal week, protein is prominent within cerebral cortex, developing hippocampus, pyriform cortex, and the mitral cell layer of the olfactory bulb. At later ages, OPCML is expressed prominently within all regions of Ammon's horn and in the mitral cell layer of the olfactory bulb and the pyriform cortex. OPCML is localized preferentially to dendrites compared with somata and terminals of hypothalamic vasopressin-secreting magnocellular neurons. This localization indicates that protein is one of the dendrite-associated cell adhesion molecules. It is synthesized within the somata, attached to vasopressin neurosecretory granules via the glycosylphosphatidylinositol anchor, and transported to the dendrites. Moreover, the subcellular localization of OPCML is changed in an activity-dependent manner.
Recently published data suggested that OPCML-v1 was widely expressed in all normal adult and fetal tissues except for placenta and peripheral blood mononuclear cells, though at varying levels (highly expressed in brain, kidney, spleen, stomach, trachea, testis, cervix, ovary and prostate, and weakly in lung, breast, and bone marrow). Compared to v1, OPCML-v2 displayed a more tissue-specific expression pattern in adult tissues, with expression absent or barely detectable in kidney, spleen, pancreas, breast, testis, lung, colon, liver, testis and bone marrow. In contrast to its expression in adult tissues, OPCML-v2 was expressed at moderate to high levels in all fetal tissues except for placenta. |
| Function | OPCML was originally isolated as a potential micro-type opiate receptor. Subsequent studies have shown that the physiologic opiate receptors belong to the G-protein-coupled receptor family, however, they do not promote direct binding of opioids when transfected into heterologous cells. IgLONs have been suggested to play an important role in cell adhesion and cell-cell recognition, through both homo- and heterophilic interactions within the family. Recently, it has been proposed that IgLONs function mainly as heterodimers called Diglons. OPCML may contribute to the diversity at the surface of different populations of neurons during development. Some latest evidences also suggest that OPCML is a synaptic cell adhesion molecule concerning synaptogenesis and its surface localization is dynamically regulated in response to neuronal activity. Recently, it has been shown that IgLONs are expressed outside the nervous system, and OPCML might act as a tumor suppressor. As a cell adhesion molecule, OPCML comprises several protein-protein interaction domains, commonly found in cell surface- adhesion and receptor molecules. Through these domains, OPCML may bind directly to growth promoting or inhibitory molecules and modulate their functions in tumor cells.
New findings suggested that OPCML is an excellent candidate for tumor suppressor gene (TSG). OPCML is frequently somatically inactivated in cancer by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with TSG properties both in vitro and in vivo. It has been found existence somatic missense mutation in individual with epithelial ovarian cancer and it shows clear evidence of loss of function. Another data showed that OPCML gene promoter methylation may play an important role in the carcinogenesis of cervical and lung carcinoma. OPCML probably functions as a tumor suppressor through interacting with other IgLONs to form heterodimeric complex involved in signal transduction. Among the IgLON family, OPCML was the first member reported to possess tumor suppressor functions in epithelial ovarian cancer, being frequently silenced genetically and epigenetically at the early step of ovarian carcinogenesis. This inactivation is due to its promoter methylation, which further impairs its response to environmental stresses. Loss of OPCML reduces the intercellular adhesion and heterodimeric complex formation and thus impairs the corresponding signaling pathways, thereby promoting the progress of carcinogenesis. Latest evidences of Cui et al (2008) suggested that OPCML is frequently inactivated epigenetically in multiple tumor cell line including nasopharyngeal, esophageal, lung, gastric, hepatocellular, colorectal, breast, cervical and prostate carcinomas. Authors showed that OPCML is a stress-responsive and p53-regulated gene, with the response abrogated when the promoter becomes methylated. Ectopic expression of OPCML in tumor cell lines with endogenous silencing led to strong inhibition of cell colony formation, dramatic anchorage-dependent and - independent growth inhibition demonstrating that OPCML acts as a broad tumor suppressor. The role of OPCML in DNA damage repair, apoptosis and cell cycle arrest with respect to stress response remains to be further investigated. |
| Homology | Two alternative splice transcripts of OPCML, variant 1 (v1) and variant 2 (v2), were previously identified in human, which differ only in their 59 exons but encode an identical mature protein. Among the four IgLON family members, OPCML shares the highest homology to HNT that lies approximately 80 kb centromeric to OPCML in the opposite orientation. Notably, the coding region in exon 1 of OPCML-v1 and HNT is identical, and so is the exon 2 except for only several bases. The first Ig domains of these two proteins share 92% identity, while the second and third Ig domains share 70% and 66% identity, respectively. This raises the possibility that OPCML and HNT may originate from the same antecestor by gene conversion during evolution. |
| Note | |
| | |
| Entity | Epithelial ovarian cancer (EOC) |
| Oncogenesis | OPCML is frequently somatically inactivated in EOC by allele loss and by CpG island methylation (Sellar et al., 2003).
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 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. No promoter hypermethylation of the studied gene was found in normal ovaries (Czekierdowski et al., 2006).
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. 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. RAS signaling pathway may play an important role in epigenetic inactivation of OPCML in human epithelial ovarian cancer (Mei et al., 2006).
Expression of OPCML mRNA in ovarian epithelial carcinoma was significantly lower than those of normal and benign tumors. Methylations were detected in 44.4% of cancer cells promoter, while 0% in normal ovarian tissue and benign ovarian tumors. The ratio of methylation of ovarian epithelial carcinoma was significantly higher than those of normal and benign tumors (Zhang et al., 2006).
The relationship between gene expression and promoter methylation was significantly correlated (OPCML expression in ovarian serous carcinomas was significantly higher than in ovarian adenomas and normal tissues. CpG island methylation and LOH are probably two mechanisms of OPCML inactivation. LOH at D11S4085 was also correlated with loss of OPCML expression. The LOH rate at D11S4085 in carcinomas was significantly higher than that for adenomas and normal tissues. Abnormal methylation of OPCML was found in 53.4% of the carcinomas, while in none of the adenomas or normal tissues (Chen et al., 2007). |
| | |
| | |
| Entity | Invasive cervical carcinoma |
| Oncogenesis | 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 tumor suppressor gene (Ye et al., 2008). |
| | |
| | |
| Entity | Squamous cell lung carcinoma |
| Oncogenesis | OPCML hypermethylation did not differ significantly based on gender, race, age or tumor stage, indicating their wide applicability as potential lung adenocarcinoma markers (Tsou et al., 2007). |
| | |
| | |
| Entity | Gastric cancer |
| Oncogenesis | OPCML could play a key role in the tumorigenesis and metastasis of gastric cancer. The expression level of these gene was the highest in normal gastric epithelium, which was decreased in primary carcinoma, and further decreased in metastatic lymph nodes (Wang et al., 2007). |
| | |
| | |
| Entity | Hepatocellular carcinoma |
| Oncogenesis | Hypermethylation rates of OPCML was higher in HCC than in pericancer tissues (70.0% vs. 64.6%). Promoter methylation of OPCML gene may play an important role in hepatocarcinogenesis (Liu et al., 2006). |
| | |
| | |
| Entity | Gliomas |
| Oncogenesis | OPCML 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. Hypermethylation of the alpha1 OPCML promoter, associated 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 (Reed et al., 2007). |
| | |
| | |
| Entity | Phaeochromocytoma |
| Oncogenesis | OPCML was methylated in 12% of phaeochromocytomas (Margetts et al., 2008). |
| | |
| OPCML Is a Broad Tumor Suppressor for Multiple Carcinomas and Lymphomas with Frequently Epigenetic Inactivation. |
| 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 GS, Sellar GC, Sung JJ, Sidransky D, Tao Q. |
| PLoS ONE. 2008 Aug 20;3(8):e2990. |
| PMID 18714356 |
| |
| Opioid-binding protein/cell adhesion molecule-like (OPCML) gene and promoter methylation status in women with ovarian cancer. |
| Czekierdowski A, Czekierdowska S, Szymanski M, Wielgos M, Kaminski P, Kotarski J. |
| Neuro Endocrinol Lett. 2006 Oct;27(5):609-13. |
| PMID 17159813 |
| |
| Characterization and tissue distribution of opioid-binding cell adhesion molecule (OBCAM) using monoclonal antibodies. |
| Hachisuka A, Yamazaki T, Sawada J, Terao T. |
| Neurochem Int. 1996 Apr;28(4):373-9. |
| PMID 8740443 |
| |
| Regulation of an opioid-binding protein in NG108-15 cells parallels regulation of delta-opioid receptors. |
| Lane CM, Elde R, Loh HH, Lee NM. |
| Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11234-8. |
| PMID 1333602 |
| |
| Postnatal expression profile of OBCAM implies its involvement in visual cortex development and plasticity. |
| Li P, Prasad SS, Mitchell DE, Hachisuka A, Sawada JI, Al-Housseini AM, Gu Q. |
| Cereb Cortex. 2006 Feb;16(2):291-9. Epub 2005 May 18. |
| PMID 15901654 |
| |
| Correlations of CpG island methylator phenotype and OPCML gene methylation to carcinogenesis of hepatocellular carcinoma. |
| Liu WJ, Wang L, Wang JP, Li JQ, Zhang CQ, Zheng L, Yuan YF. |
| Ai Zheng. 2006 Jun;25(6):696-700. |
| PMID 16764763 |
| |
| Evaluation of a functional epigenetic approach to identify promoter region methylation in phaeochromocytoma and neuroblastoma. |
| Margetts CD, Morris M, Astuti D, Gentle DC, Cascon A, McRonald FE, Catchpoole D, Robledo M, Neumann HP, Latif F, Maher ER. |
| Endocr Relat Cancer. 2008 Sep;15(3):777-86. Epub 2008 May 22. |
| PMID 18499731 |
| |
| RAS-mediated epigenetic inactivation of OPCML in oncogenic transformation of human ovarian surface epithelial cells. |
| Mei FC, Young TW, Liu J, Cheng X. |
| FASEB J. 2006 Mar;20(3):497-9. Epub 2005 Dec 29. |
| PMID 16384911 |
| |
| Biochemical and ultrastructural analyses of IgLON cell adhesion molecules, Kilon and OBCAM in the rat brain. |
| Miyata S, Matsumoto N, Taguchi K, Akagi A, Iino T, Funatsu N, Maekawa S. |
| Neuroscience. 2003;117(3):645-58. |
| PMID 12617969 |
| |
| Dendrite-associated opioid-binding cell adhesion molecule localizes at neurosecretory granules in the hypothalamic magnocellular neurons. |
| Miyata S, Taguchi K, Maekawa S. |
| Neuroscience. 2003;122(1):169-81. |
| PMID 14596858 |
| |
| Diglons are heterodimeric proteins composed of IgLON subunits, and Diglon-CO inhibits neurite outgrowth from cerebellar granule cells. |
| Reed J, McNamee C, Rackstraw S, Jenkins J, Moss D. |
| J Cell Sci. 2004 Aug 1;117(Pt 17):3961-73. Epub 2004 Jul 20. |
| PMID 15265982 |
| |
| Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours. |
| Reed JE, Dunn JR, du Plessis DG, Shaw EJ, Reeves P, Gee AL, Warnke PC, Sellar GC, Moss DJ, Walker C. |
| Neuropathol Appl Neurobiol. 2007 Feb;33(1):77-85. |
| PMID 17239010 |
| |
| OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer. |
| Sellar GC, Watt KP, Rabiasz GJ, Stronach EA, Li L, Miller EP, Massie CE, Miller J, Contreras-Moreira B, Scott D, Brown I, Williams AR, Bates PA, Smyth JF, Gabra H. |
| Nat Genet. 2003 Jul;34(3):337-43. |
| PMID 12819783 |
| |
| Cloning, sequencing and localization to chromosome 11 of a cDNA encoding a human opioid-binding cell adhesion molecule (OBCAM). |
| Shark KB, Lee NM. |
| Gene. 1995 Apr 3;155(2):213-7. |
| PMID 7721093 |
| |
| Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma. |
| Tsou JA, Galler JS, Siegmund KD, Laird PW, Turla S, Cozen W, Hagen JA, Koss MN, Laird-Offringa IA. |
| Mol Cancer. 2007 Oct 29;6:70. |
| PMID 17967182 |
| |
| Comparison of gene expression profiles between primary tumor and metastatic lesions in gastric cancer patients using laser microdissection and cDNA microarray. |
| Wang L, Zhu JS, Song MQ, Chen GQ, Chen JL. |
| World J Gastroenterol. 2006 Nov 21;12(43):6949-54. |
| PMID 17109515 |
| |
| Opioid-binding protein (OBCAM) is rich in beta-sheets. |
| Wu CS, Hasegawa J, Smith AP, Loh HH, Lee NM, Yang JT. |
| J Protein Chem. 1990 Feb;9(1):3-7. |
| PMID 2340074 |
| |
| Synaptic adhesion molecule OBCAM; synaptogenesis and dynamic internalization. |
| Yamada M, Hashimoto T, Hayashi N, Higuchi M, Murakami A, Nakashima T, Maekawa S, Miyata S. |
| Brain Res. 2007 Aug 24;1165:5-14. Epub 2007 Apr 27. |
| PMID 17658490 |
| |
| OPCML gene promoter methylation and gene expression in tumor and stroma cells of invasive cervical carcinoma. |
| Ye F, Zhang SF, Xie X, Lu WG. |
| Cancer Invest. 2008 Jul;26(6):569-74. |
| PMID 18584347 |
| |
| Deletion of OPCML gene and promoter methylation in ovarian epithelial carcinoma. |
| Zhang J, Ye F, Chen HZ, Ye DF, Lu WG, Xie X. |
| Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2006 Apr;28(2):173-7. |
| PMID 16733898 |
| |
