抑癌基因ARHI研究进展

Advances in the Research of Tumor Suppressor Gene ARHI

ARHI(aplasia ras homologue member I)/NOEY2是1999年新发现的一个母源性抑癌印迹基因,位于人染色体1p31,编码一个相对分子量为26kD的小GTP结合蛋白。ARHI属ras/rap超家族成员,与该家族成员有50%～60%的同源性并且两者具有相似的GTP/GDP结合域,但与该家族其它成员不同,ARHI发挥抑癌基因作用,是该家族第一个被报道的肿瘤抑制基因。ARHI基因编码的蛋白在人类多种组织表达,而该基因在人卵巢癌、乳腺癌、胰腺癌、肝癌等多种肿瘤中表达下调或缺失,提示其与上述肿瘤的发生、发展密切相关。ARHI可能通过作用于cyclin D1,使其不能与CDK结合形成活性激酶,从而使细胞停止于G_1期来参与细胞周期调控;可能通过依赖caspase和calpain两条途径参与信号通路传导诱发细胞凋亡;另外,该基因可通过抑制STAT3的激活而发挥抑癌基因功能,也可以调节自体吞噬和肿瘤细胞休眠。目前研究显示,ARHI基因的表达缺失主要通过遗传事件和表观遗传学机制发生,包括DNA甲基化异常、杂合性丢失,乙酰化组蛋白的低水平表达及基因突变有关,但有待进一步深入研究。可以预见,ARHI基因的深入研究必将为早期肿瘤的基因诊治提供新的思路和理论依据。

ARHI （aplasia ras homologue member I）/NOEY2 is a novel maternally imprinted tumor suppressor gene discovered in 1999. It is located in human chromosome Ip3 i. The ARHI gene encodes a 26 kDa small GTP-binding protein. It is a member of ras/ rap superfamily, which has 50%-60% homology and share similar GTP/GDP-binding domains with the ras/rap superfamily. Unlike other members, however, it acts as a tumor suppressor gene and is the first reported tumor suppressor gene in the ras/rap family. The ARHI gene encodes protein that is widely expressed in most types of human tissues, but it often reduced or absent in human ovarian, breast, pancreas, and liver cancer, and other tumors, which suggests that it is closely related to the occurrence and development of tumors. Affecting cyclin DI, ARHI is a negative regulator of the cell cycle and blocks the cell growth at the GI phase. ARHI induces cell apoptosis through the caspase and calpain cell signal transduction pathway. In addition, the ARHI gene functions as a tumor suppressor gene by inhibiting the activation of STAT3. It also regulates autophagy and tumor dormancy. Studies have shown that the loss of ARHI expression can occur through genetic events and epigenetic mechanisms, including DNA aberrant methylation, loss of heterozygosity, low-level expression of acetylation histone, and gene mutation. This issue needs further research. Further studies on the ARHI gene will provide new ideas and theories for the early diagnosis and treatment of tumors