Activation of phosphatidylinositol 3-kinase/Akt signaling mediates sorafenib-induced invasion and metastasis in hepatocellular carcinoma

Oncol Rep. 2014 Oct;32(4):1465-72. doi: 10.3892/or.2014.3352. Epub 2014 Jul 23.


Sorafenib, an antiangiogenic agent, can promote tumor invasion and metastasis. The phosphatidylinositol 3-kinase (PI3K)/Akt/Snail-dependent pathway plays an important role in tumor invasion and metastasis. Yet, little is known concerning the role of the PI3K/Akt/Snail-dependent pathway in sorafenib‑induced invasion and metastasis of hepatic carcinoma (HCC). A human HCC orthotopic xenograft model was established, and sorafenib (30 mg/kg/day) was administered orally. Tumor growth and intrahepatic metastasis were assessed, and immunohistochemistry was applied to analyze the activation of the PI3K/Akt/Snail-dependent pathway. HCC cell lines were treated with sorafenib (1, 5 and 10 µM), and proliferation, migration and invasion were assessed. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the related gene expression of epithelial-mesenchymal transition (EMT) markers and the PI3K/Akt/Snail-dependent pathway. Sorafenib inhibited tumor growth and promoted intrahepatic invasion and metastasis of the orthotopic tumors grown from SMMC7721-GFP cells in vivo. Additionally, sorafenib promoted EMT and invasion and metastasis of HCC cells in vitro. Importantly, sorafenib enhanced PI3K and Akt activation and upregulation of the expression of transcription factor Snail, a critical EMT mediator. The upregulation of transcription factor Snail expression by sorafenib may be related to activation of the PI3K/AKT signaling pathway. The PI3K/Akt/Snail-dependent pathway may mediate the pro-invasive and pro-metastatic effects of sorafenib on HCC by inducing EMT.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Humans
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / metabolism*
  • Liver Neoplasms, Experimental / pathology
  • Mice
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis / genetics
  • Neoplasm Transplantation
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology*
  • Phosphatidylinositol 3-Kinases / drug effects*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / drug effects*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Snail Family Transcription Factors
  • Sorafenib
  • Transcription Factors / drug effects*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Angiogenesis Inhibitors
  • Phenylurea Compounds
  • Snail Family Transcription Factors
  • Transcription Factors
  • Niacinamide
  • Sorafenib
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt