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.
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.
Oncogene. 2014 Jun 12;33(24):3109-18. doi: 10.1038/onc.2013.282. Epub 2013 Jul 29.
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.
3p12-22 的缺失在多种癌症类型中很常见，表明该区域存在关键的肿瘤抑制基因（TSGs）。我们研究了位于 3p22.3 CMTM 基因簇的新型候选 TSG，CMTM7，研究其肿瘤抑制功能和相关机制。三个 CMTM 基因，CMTM6、7 和 8，在人类正常成人组织和正常上皮细胞系中广泛表达。只有 CMTM7 在食管和鼻咽细胞系中经常被沉默或下调，但在其他癌细胞系中不常见。CMTM7 蛋白的组织微阵列免疫染色显示其在食管、胃、胰腺、肝、肺和宫颈肿瘤组织中的下调或缺失。启动子 CpG 甲基化和杂合性丢失都被发现导致 CMTM7 下调。CMTM7 在癌细胞中的异位表达抑制裸鼠中的细胞增殖、迁移和肿瘤形成，但在永生化正常细胞中不常见，提示 CMTM7 具有肿瘤抑制作用。CMTM7 的肿瘤抑制功能与其在 G1/S 细胞周期阻滞中的作用有关，通过上调 p27 并下调细胞周期蛋白依赖性激酶 2（CDK2）和 6（CDK6）。此外，CMTM7 可以促进表皮生长因子受体（EGFR）内化，进一步抑制 AKT 信号通路。因此，我们的研究结果表明，CMTM7 是一种新型的 3p22 肿瘤抑制基因，可调节肿瘤发生过程中的 G1/S 转换和 EGFR/AKT 信号通路。
