RAP1在肝细胞癌中的表达及其功能机制研究

The Expression and Function Mechanisms of RAP1 in Hepatocellular Carcinoma

RAS相关蛋白1(RAS-associated protein 1,RAP1)是属于RAS家族的一种小分子G蛋白,被报道与多种癌症有关。然而,RAP1在肝细胞癌(hepatocellular carcinoma,HCC)中的作用及机制尚不清楚。TCGA和GTEx联合分析显示,HCC组织中RAP1A和RAP1B的mRNA水平显著高于正常肝组织。免疫组织化学技术和蛋白质免疫印迹(Western blot,WB)分析均证实,HCC患者癌组织中的RAP1蛋白水平高于其癌旁正常组织。体外研究表明,与对照细胞相比,下调RAP1表达可以减弱HCC细胞的增殖、迁移和侵袭能力。从机制上说,下调RAP1表达可以促进线粒体氧化磷酸化,抑制糖酵解,并激活p38 MAPK通路,而抑制p38 MAPK通路可以抑制HCC线粒体功能,提示RAP1可以通过抑制p38 MAPK通路促使细胞代谢从氧化磷酸化转为糖酵解,从而促进HCC进程。尽管还需要进一步的研究来阐明RAP1是如何调节p38 MAPK通路及其下游能量代谢重编程的,但该研究结果为HCC的治疗提供了新的潜在靶点。

RAP1(RAS-associated protein 1)is one of small GTPases belonging to RAS family,which has long been associated with the development of varies of cancers.However,the causal role of RAP1 in HCC(hepatocellular carcinoma)and its mechanism were not known.The conjoint analysis of TCGA and GTEx showed that the mRNA levels of RAP1A and RAP1B in HCC tissues were significantly higher than those in normal liver tissues.Both immunohistochemistry and WB(Western blot)analysis confirmed that the RAP1 level in tumor tissues was higher than that in paired adjacent normal tissues from HCC patients.In vitro study showed that,RAP1 depletion in HCC cells resulted in delayed cell proliferation,decreased cell migration and invasion when compared with control cells.Mechanistically,RAP1 depletion boosts mitochondrial oxidative phosphorylation,inhibits glycolysis,and activates p38 MAPK pathway.Whereas p38 MAPK inhibition suppresses HCC mitochondrial function.These findings suggest that RAP1 can promote HCC progression by converting the cell metabolism from oxidative phosphorylation to glycolysis via inhibition of p38 MAPK pathway.Although further studies are required to clarify how RAP1 regulates p38 MAPK pathway and its downstream energy metabolic reprogramming,these findings provide a new therapeutic target for the treatment of HCC.