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CMTM3, Located at the Critical Tumor Suppressor Locus 16q22.1, Is Silenced by CpG Methylation in Carcinomas and Inhibits Tumor Cell Growth through Inducing Apoptosis

¹ Peking University Center for Human Disease Genomics, Department of Immunology, Health Science Center, Peking University, Beijing, China; ² Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong; ³ Department of General Surgery, General Hospital of People's Liberation Army, Beijing, China; ⁴ Department of Urology, Peking University First Hospital & Institute of Urology, Peking University; ⁵ Institute of Digestive Disease, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong; ⁶ Department of Pathology, University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong; and ⁷ Department of Medical Microbiology, Qingdao University Medical College, Qingdao, China

Requests for reprints: Qian Tao, Room 315, Cancer Center, PWH, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, Hong Kong. Phone: 852-2632-1340; Fax: 852-2648-8842; E-mail: qtao{at}clo.cuhk.edu.hk and Wenling Han, Peking University Center for Human Disease Genomics, 38 Xueyuan Road, Beijing 100191, China. Phone: 86-10-8280-5479; Fax: 86-10-8280-1149; E-mail: hanwl{at}bjmu.edu.cn.

Key Words: CMTM3 • methylation • tumor suppressor gene • apoptosis • 16q22

Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas. [Cancer Res 2009;69(12):5194–201]