Xu Dong, Qu Liujing, Hu Jia, Li Ge, Lv Ping, Ma Dalong, Guo Mingzhou, Chen Yingyu
Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, China; Peking University Center for Human Disease Genomics, Peking University, Beijing, China.
J Cell Mol Med. 2014 Aug;18(8):1655-66. doi: 10.1111/jcmm.12352. Epub 2014 Jun 28.
Inactivation of tumour suppressor genes by promoter methylation plays an important role in the initiation and progression of gastric cancer (GC). Transmembrane 106A gene (TMEM106A) encodes a novel protein of previously unknown function. This study analysed the biological functions, epigenetic changes and the clinical significance of TMEM106A in GC. Data from experiments indicate that TMEM106A is a type II membrane protein, which is localized to mitochondria and the plasma membrane. TMEM106A was down-regulated or silenced by promoter region hypermethylation in GC cell lines, but expressed in normal gastric tissues. Overexpression of TMEM106A suppressed cell growth and induced apoptosis in GC cell lines, and retarded the growth of xenografts in nude mice. These effects were associated with the activation of caspase-2, caspase-9, and caspase-3, cleavage of BID and inactivation of poly (ADP-ribose) polymerase (PARP). In primary GC samples, loss or reduction of TMEM106A expression was associated with promoter region hypermethylation. TMEM106A was methylated in 88.6% (93/105) of primary GC and 18.1% (2/11) in cancer adjacent normal tissue samples. Further analysis suggested that TMEM106A methylation in primary GCs was significantly correlated with smoking and tumour metastasis. In conclusion, TMEM106A is frequently methylated in human GC. The expression of TMEM106A is regulated by promoter hypermethylation. TMEM106A is a novel functional tumour suppressor in gastric carcinogenesis.
启动子甲基化导致的肿瘤抑制基因失活在胃癌（GC）的发生和发展中起重要作用。跨膜蛋白106A基因（TMEM106A）编码一种功能未知的新型蛋白质。本研究分析了TMEM106A在GC中的生物学功能、表观遗传学变化及临床意义。实验数据表明，TMEM106A是一种II型膜蛋白，定位于线粒体和质膜。在GC细胞系中，TMEM106A因启动子区域高甲基化而下调或沉默，但在正常胃组织中表达。TMEM106A的过表达抑制了GC细胞系的细胞生长并诱导细胞凋亡，还延缓了裸鼠体内异种移植瘤的生长。这些效应与半胱天冬酶-2、半胱天冬酶-9和半胱天冬酶-3的激活、BID的切割以及聚（ADP-核糖）聚合酶（PARP）的失活有关。在原发性GC样本中，TMEM106A表达缺失或降低与启动子区域高甲基化有关。在原发性GC样本中，88.6%（93/105）存在TMEM106A甲基化，在癌旁正常组织样本中为18.1%（2/11）。进一步分析表明，原发性GC中TMEM106A甲基化与吸烟和肿瘤转移显著相关。总之，TMEM106A在人类GC中频繁发生甲基化。TMEM106A的表达受启动子高甲基化调控。TMEM106A是胃癌发生过程中一种新型的功能性肿瘤抑制因子。
