Activation of PI3 kinase/Akt/HIF-1α pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma

Int J Oncol. 2012 Feb;40(2):461-8. doi: 10.3892/ijo.2011.1197. Epub 2011 Sep 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / physiopathology
  • Cell Hypoxia
  • Cell Movement
  • Cell Survival
  • Chromones / administration & dosage
  • Cisplatin / administration & dosage
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition*
  • Gene Expression
  • Genes, MDR
  • Hep G2 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Indazoles / administration & dosage
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / physiopathology
  • Male
  • Mice
  • Mice, Nude
  • Morpholines / administration & dosage
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction*
  • Xenograft Model Antitumor Assays


  • Chromones
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Morpholines
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Cisplatin