title: Activation of PI3 kinase/Akt/HIF-1α pathway contributes to hypoxia-induced             epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma.
abstract: Hypoxia is known to promote malignant progression and to induce chemoresistance             in cancer. However, the exact mechanisms driving hypoxia induced malignance remain             elusive. We found that with exposure to hypoxic condition, hepatocellular carcinoma             (HCC) cells experienced epithelial-mesenchymal transition (EMT), with increased             cell migration and invasion, and exhibited high resistance to chemotherapy. We             demonstrated that hypoxia-induced EMT and chemoresistance were accompanied by             increased HIF-1α expression and activation of Akt. HIF-1α could be blocked by             PI3K inhibitor LY294002, indicating HIF-1α activation was regulated by PI3K/Akt             pathway. Furthermore, we showed that inhibition of PI3K/Akt and HIF-1α enhanced             the therapeutic efficacy of hypoxic chemotherapy in the HCC xenograft model. Our             findings indicate that the activation of PI3K/Akt/HIF-1α pathway plays a critical             role in mediating hypoxia-induced EMT and drug resistance leading to unfavorable             treatment outcome. Our study provides novel insights into the malignant progression             triggered by hypoxic microenvironment in HCC cells.
authors.affiliation: Department of Oncology, First Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiao
authors.forename: Ke-Jun
authors.initials: KJ
authors.lastname: Nan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D015687:Cell Hypoxia; D002465:Cell Movement; D002470:Cell Survival; D002867:Chromones / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D019450:Genes, MDR; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007191:Indazoles / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D009025:Morpholines; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin