title: Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma.
abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P<0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.
authors.affiliation: Department of General Surgery, The Second People's Hospital of Yueqing, Yueqing 325608, China.
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Zhao
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Li
authors.forename: Jianxin
authors.initials: J
authors.lastname: Zhuo
authors.forename: Liuxin
authors.initials: L
authors.lastname: Cai
mesh_terms: D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins; C117386:DIRAS3 protein, human; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins