Hippo信号通路及其在消化系统肿瘤中的作用研究进展

Emerging roles of Hippo signaling pathway in gastrointestinal cancers and its molecular mechanisms

Hippo信号通路在进化上高度保守,哺乳动物细胞中该信号通路的核心成员包括MST1/2激酶、LATS1/2激酶和效应蛋白YAP/TAZ。虽然YAP/TAZ及其下游相关研究相对较多,但Hippo信号通路的上游调控因子并不明确,是目前该通路研究的热点方向之一。另外,Hippo信号通路可与Wnt和Notch等其他信号通路发生交叉对话,并在控制器官大小、维持组织稳态、促进组织修复再生等过程中扮演重要角色。Hippo信号通路异常可能会导致多种肿瘤的发生,尤其是肝癌、结直肠癌和胃癌等消化系统肿瘤,其成员在消化系统肿瘤中的异常表达与肿瘤细胞的增殖、凋亡、侵袭和迁移等过程密切相关。Hippo信号通路对肝脏的修复再生至关重要,其失活会导致原发性肝癌的发生,YAP在肝癌中的促肿瘤作用机制主要依赖于TEAD介导的基因转录。Hippo信号通路对于维持肠道稳态也很重要,其失调会导致结直肠癌的发生及复发。在原发性和转移性胃癌中,YAP/TAZ的表达显著上调,但具体分子调控机制并不清楚。本文总结了近年来Hippo信号通路的发现、上游调控因子及其在消化系统肿瘤发生发展过程中的作用和分子调控机制,并对未来的研究方向进行初步探讨。

Hippo signaling pathway is highly conservative in evolution.MST1/2,LATS1/2,and the effector protein YAP/TAZ are the core members of this signaling pathway in mammalian cells.There have been many studies on YAP/TAZ and its downstream,however,the upstream regulatory factors of the Hippo signaling pathway remain unclear,and become one of the hot research directions of this pathway at present.In addition,Hippo signaling pathway can cross-talk with other signaling pathways such as Wnt and Notch signaling pathways,and plays an important role in controlling organ size,maintaining tissue homeostasis,and promoting tissue repair and regeneration.Abnormal Hippo signaling pathway may lead to the occurrence of a variety of tumors,especially gastrointestinal cancers such as liver cancer,colorectal cancer and gastric cancer.The abnormal expression of its members in gastrointestinal cancers is related to cancer cell proliferation,apoptosis,invasion and migration.Hippo signaling pathway is vital for liver repair and regeneration.Its inactivation will lead to the occurrence of primary liver cancer.The mechanism of YAP in liver cancer mainly depends on TEAD-mediated gene transcription.Hippo signaling pathway is also important for maintaining intestinal homeostasis,and its imbalance can lead to the occurrence and recurrence of colorectal cancer.In primary and metastatic gastric cancer,the expression of YAP/TAZ is significantly up-regulated,but the specific molecular mechanism is unclear.This article summarizes the recent progress on Hippo signaling pathway and its upstream regulatory factors,its roles in the development of gastrointestinal cancers and related molecular mechanisms;and also discusses the future research directions of Hippo signaling pathway.