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Open Full Page research article McKie et al. ReseaRch aRticle the OPcMl tumor suppressor Functions as a cell surface repressor –adaptor, Negatively regulating receptor tyrosine Kinases in epithelial Ovarian cancer Arthur B. McKie1, Sebastian Vaughan1, Elisa Zanini1, Imoh S. Okon1, Louay Louis1, Camila de Sousa1, Mark I. Greene4, Qiang Wang4, Roshan Agarwal1, Dmitry Shaposhnikov1, Joshua L. C. Wong1, Hatice Gungor1, Szymon Janczar1, Mona El-Bahrawy2, Eric W-F. Lam1, Naomi E. Chayen3, and Hani Gabra1 abstRact Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid bind- ing 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 inhi- bition. Exogenous recombinant OPCML domain 1–3 protein inhibited the cell growth of epithelial ovarian can- cers 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 tyro- sine 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 polyubiq- uitination and proteasomal degradation. Recombinant OPCML domain 1-3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy. Cancer Discovery; 2(2); 156–71. ©2012 AACR. authors’ affiliations: 1Ovarian Cancer Action Research Centre, Division of corresponding authors: Arthur B. McKie and Hani Gabra, Ovarian Cancer Cancer, 2Department of Histopathology, Centre for Pathology, Imperial Action Research Centre, Department of Surgery and Cancer, Imperial College College London Hammersmith Campus, and 3Section of Biomolecular London, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44–208– Medicine, Division of Surgery, Imperial College London, London, United 383–5828; Fax: 44–208–383–5830; E-mail: [email protected]; and Kingdom; 4Department of Pathology and Laboratory Medicine, University of Hani Gabra, [email protected] Pennsylvania School of Medicine, Philadelphia, Pennsylvania doi: 10.1158/2159-8290.CD-11-0256 Note: Supplementary data for this article are available at Cancer Discovery Online (http://www.cancerdiscovery.aacrjournals.org). © 2012 American Association for Cancer Research. 156 | CANCER DISCOVERY FEBRUARY 2012 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2012 American Association for Cancer Research. The BATTLE Trial: Personalizing Therapy for Lung Cancer research article intRoduction Ovarian cancer is the leading cause of death OPCML is a glycosyl phospha- from gynecologic malignancy (1). The molecular basis of tidylinositol (GPI)-anchored cell adhesion-like ovarian carcinogenesis is poorly understood but frequently molecule and a member of the IgLON family, denoting the involves lesions affecting p53 (2); BRCA1 and 2 (3); the immunoglobulin domain protein family that includes limbic phosphoinositide 3-kinase pathway, including dysregulation system-associated membrane protein (20, 21), OPCML, neurotr- of AKT (4); growth factor signaling pathways, including the imin (22), and more recently neuronal growth regulator 1 (23). epidermal growth factor (EGF) and fibroblast growth The IgLONs are medium-sized proteins (~55 kDa) compris- factor (FGF) pathways (5–9); and neoangiogenesis (10). ing 3 conserved extracellular I-type immunoglobulin domains We previously identified that opioid binding protein cell that share common molecular recognition properties enabling adhesion molecule (OPCML) was inactivated by LOH and homo- and heterodimerization between family members (24). epigenetic silencing in more than 80% of human epithelial GPI-anchored proteins are trafficked to the plasma membrane ovarian cancers (11). We demonstrated that OPCML expres- and often are associated with detergent-insoluble fractions sion inhibited ovarian cancer cell growth, enhanced inter- termed “lipid rafts” that mainly consist of sphingolipids and cellular attachment, and abrogated both subcutaneous and cholesterol (25). Lipid raft domains have also been shown to in- intraperitoneal tumorigenicity in vivo (11). In recent publica- fluence the distribution and signaling of many receptors from tions, others have also confirmed OPCML to be frequently tyrosine kinases to integrins (26–28), although there is still epigenetically inactivated in epithelial ovarian cancers (12– some debate about the definition and existence of physiologi- 14), brain tumors (15), non–small cell lung carcinoma (16), cally relevant lipid rafts (29). bladder cancer (17), cholangiocarcinoma (18), primary na- Here, we describe the mechanism underlying the in vitro sopharyngeal, esophageal, gastric, hepatocellular, colorectal, and in vivo tumor-suppression phenotype previously de- breast, and cervical cancers, as well as lymphomas (19), indi- scribed for OPCML (11). Our results reveal that OPCML cating that OPCML has broad tumor suppressor activity in negatively regulates a specific spectrum of receptor tyrosine common cancers. In many tumor types, OPCML was ubiq- kinases (RTK) through physical interactions with their extra- uitously nonexpressed. In several of these studies, investiga- cellular domains and promotion of their proteasomal degra- tors demonstrated a significant correlation between OPCML dation via trafficking redistribution, which in turn leads to hypermethylation and loss of expression in cancer cell lines altered RTK signaling. We also demonstrate that exogenous (11, 17, 19) and primary tumors (12, 14, 18), and OPCML recombinant OPCML is a potent RTK suppressor in most methylation and loss of expression were associated with poor ovarian cancer cell lines tested and provide a proof-of-con- survival for the patient (17). cept of its therapeutic potential in vivo. FEBRUARY 2012 CANCER DISCOVERY | 157 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2012 American Association for Cancer Research. research article McKie et al. Results OPCML transfection in SKOV-3 (Fig. 1A), or transient, poly- clonal OPCML transfection in PEO1 ovarian cancer cells In Silico analysis of Publicly available (Fig. 1B; ref. 31). Microarray Datasets confirms the clinical These same RTKs were found to be reciprocally upregulated relevance of OPcMl when physiologic OPCML was knocked down by transient With several investigators demonstrating a correlation transfection with an siRNA pool in OSE-C2 (Fig. 1C; ref. 32). between OPCML methylation and loss of OPCML expres- Endogenous protein expression of OPCML and a variety of RTKs sion in cancer cell lines and primary tumors, we used the is shown in Figure 1. The first (left) lanes for SKOV3, PEO1, and online database of the Cancer Genome Atlas (TCGA) OSE-C2 (Fig. 1A–C) demonstrate that OPCML does not read- HumanMethylation27 (Illumina) assay to confirm the ily coexpress with the specific spectrum of RTKs identified previ- frequency of OPCML methylation in human cancer. We ously while not affecting unassociated RTKs. Deconvolution of found that 678 of 1537 (44%) of cancer patients with avail- the siRNA duplexes in this pool demonstrated their specificity able methylation data (representing breast, ovarian, brain, (Supplementary Fig. S4). Conversely, a group of other RTKs were leukemia, colon, renal, lung, and endometrial cancers) had unaltered by either OPCML overexpression or siRNA knockdown, OPCML-methylated tumors (with site-specific methylation including EPHA10, FGFR2, FGFR4, EGFR, HER3, VEGFR1, and rates ranging from 31% for breast cancer to 73% for colonic VEGFR3 (Fig. 1 and summarized in Supplementary Table S1). We adenocarcinoma; Supplementary Fig. S1). The ovarian cancer confirmed by quantification of immunofluorescence microscopy TCGA dataset (30) also indicated loss of OPCML expression (IFM) that the expression of OPCML dramatically reduced the in 92% of serous high-grade ovarian cancers, suggesting that levels of EPHA2, FGFR1, and HER2 but not the levels of FGFR2 mechanisms other than somatic methylation (such as LOH) or EGFR in BKS-2.1 cells compared with SKOBS-V1.2 (Fig. may also result in loss of OPCML expression. We then used 1D and E; Supplementary Fig. S5). Expression of the OPCML- the KMPlotter online ovarian and breast cancer meta-analysis regulated RTKs EphA2 and FGFR1 was analyzed in SKOV-3 and demonstrated that high OPCML expression (defined as (OPCML–) and BKS-2.1 (OPCML+) cells stimulated with EGF above median expression for breast cancer and above lowest and FGF1. No
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