title: A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth.
abstract: Deletion of 3p12-22 is frequent in multiple cancer types, indicating the presence of critical tumor-suppressor genes (TSGs) at this region. We studied a novel candidate TSG, CMTM7, located at the 3p22.3 CMTM-gene cluster, for its tumor-suppressive functions and related mechanisms. The three CMTM genes, CMTM6, 7 and 8, are broadly expressed in human normal adult tissues and normal epithelial cell lines. Only CMTM7 is frequently silenced or downregulated in esophageal and nasopharyngeal cell lines, but uncommon in other carcinoma cell lines. Immunostaining of tissue microarrays for CMTM7 protein showed its downregulation or absence in esophageal, gastric, pancreatic, liver, lung and cervix tumor tissues. Promoter CpG methylation and loss of heterozygosity were both found contributing to CMTM7 downregulation. Ectopic expression of CMTM7 in carcinoma cells inhibits cell proliferation, motility and tumor formation in nude mice, but not in immortalized normal cells, suggesting a tumor inhibitory role of CMTM7. The tumor-suppressive function of CMTM7 is associated with its role in G1/S cell cycle arrest, through upregulating p27 and downregulating cyclin-dependent kinase 2 (CDK2) and 6 (CDK6). Moreover, CMTM7 could promote epidermal growth factor receptor (EGFR) internalization, and further suppress AKT signaling pathway. Thus, our findings suggest that CMTM7 is a novel 3p22 tumor suppressor regulating G1/S transition and EGFR/AKT signaling during tumor pathogenesis.
authors.affiliation: 1] Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China [2] Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: R
authors.initials: R
authors.lastname: Rong
authors.affiliation: Department of Pathology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: K
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China.
authors.forename: G
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Ma
authors.affiliation: Cancer Epigenetics Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: Q
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Department of Immunology, Center for Human Disease Genomics, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Han
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018925:Chemokines / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D062792:MARVEL Domain-Containing Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C552173:CMTM7 protein, human; D018925:Chemokines; D062792:MARVEL Domain-Containing Proteins; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors