HIF-1α-induced RIT1 promotes liver cancer growth and metastasis and its deficiency increases sensitivity to sorafenib
HIF-1α-induced RIT1 promotes liver cancer growth and metastasis and its deficiency increases sensitivity to sorafenib
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HIF-1α诱导的RIT1促进肝癌生长和转移，其缺乏增加对索拉非尼的敏感性
DOI：
10.1016/j.canlet.2019.06.016
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Song, Zhen;Liu, Tengfei;Li, Hong
Ras样无CAAX-1（RIT 1）属于小GTP酶的RAS超家族，其在肿瘤进展中起关键作用。然而，RIT 1在肝细胞癌（HCC）中的作用知之甚少。我们发现RIT 1的表达与肝内转移的存在和HCC的组织学分级呈正相关，RIT 1的高表达表明HCC患者的总生存期较短。体外和体内研究表明，RIT 1作为癌基因发挥作用，因为RIT 1的过表达增强HCC细胞增殖和侵袭行为，而沉默RIT 1表达抑制恶性行为。此外，RIT 1缺乏增加了对索拉非尼治疗的药物敏感性。我们进一步证明了低氧诱导因子1（HIF-1 α）直接转录上调RIT 1，并且其稳定性与肝癌组织中RIT 1的表达呈正相关。RIT 1的敲低可减弱缺氧诱导的侵袭和迁移。总的来说，我们的数据突出了HIF-1 α/RIT 1轴在驱动HCC进展和索拉非尼耐药中的重要性。
Ras-like-without-CAAX-1 (RIT1) belongs to the RAS superfamily of small GTPases, which plays critical roles in tumor progression. However, little is known about the roles of RIT1 in hepatocellular carcinoma (HCC). Here we found that RIT1 expression was positively associated with the presence of intrahepatic metastasis and the histological grade of HCC and higher RIT1 expression indicated shorter overall survival in HCC patients. In vitro and in vivo studies revealed that RIT1 functioned as an oncogene, as overexpression of RIT1 enhanced HCC cell proliferation and aggressive behavior, whereas silencing RIT1 expression repressed the malignant behaviors. Furthermore, RIT1 deficiency increased drug sensitivity to sorafenib treatment. We further demonstrated that hypoxia-inducible factor l (HIF-1 alpha) directly transcriptionally upregulated RIT1, and its stableness was positively correlated with RIT1 expression in HCC tissues. Knockdown of RIT1 attenuated the invasion and migration induced by hypoxia. Collectively, our data highlight the significance of HIF-1 alpha/RIT1 axis in driving HCC progression and sorafenib resistance.