mTOR信号通路与肾上腺肿瘤发生发展的关系进展

Recent Advances on The Roles of m TOR Signal Pathway in The Pathogenesis and Progression of Adrenal Tumors

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)是一种丝/苏氨酸蛋白激酶,是细胞内调控生长、增殖的中心信号分子,与肿瘤发生、发展关系密切.近年发现,m TOR信号通路在肾上腺肿瘤的发生发展中扮演重要角色.许多研究证实,PI3K/Akt/m TOR信号通路的关键蛋白Akt、m TOR、S6K1、4EB-P1的磷酸化水平在肾上腺皮质癌(adrenocortical carcinoma,ACC)和嗜铬细胞瘤(pheochromocytomas,PCC)中均明显高于正常肾上腺组织,且可能与肾上腺肿瘤的恶性转化相关.胰岛素样生长因子2基因的杂合性缺失、PTEN的生殖系突变、微小RNA表达异常均可激活PI3K/Akt/m TOR信号通路,使得血管内皮生长因子、细胞周期蛋白等分子过表达,从而产生抑凋亡、促增殖、促血管形成等效应,使组织呈现出肿瘤特征,并促进肿瘤的侵袭和转移.目前,细胞和动物模型研究已证实m TOR抑制剂对ACC与PCC有良好的疗效,且联合其他抗癌药物治疗效果更佳,这给肾上腺肿瘤患者的治疗带来了新的希望.本文总结了近年来m TOR信号通路与肾上腺肿瘤发生、发展的关系进展,希望为肾上腺肿瘤的机制研究及临床治疗提供实验室依据.

The mammalian target of rapamycin（mTOR） is a serine/threonine kinase that regulates cell growth and proliferation, which plays a significant role in the pathogenesis and progression of tumors, including adrenal tumors. Numerous studies have shown that the phosphorylation levels of Akt, mTOR, S6K1 and 4EB-P1, are obviously higher in adrenocortical carcinoma（ACC） and pheochromocytomas（PCC） than in normal adrenal glands, which suggest that PI3K/Akt/mTOR signal pathway is active in adrenal tumors and probably associated with the malignant biological properties. This pathway in adrenal gland can be activated by several factors, including the loss of heterozygosity of IGF2 gene, the germline mutation in PTEN gene and the abnormal expression of microRNA, resulting in the increasing expression of VEGF and cyclin D1, which will promote proliferation, apoptosis resistance, invasion and metastasis of tumors. At present, the treatment of ACC and PCC with mTOR inhibitors has shown satisfactory effect in vitro and in vivo. What＇s more, a combination of mTOR inhibitors and other anti-cancer drugs provide superior effectiveness, giving new hopes to patients suffering from adrenal tumors. This review summarizes recent advances in understanding the roles of mTOR signal pathway in the pathogenesis and progression of adrenal tumors.