PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells.
Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. Although the exact mechanisms driving hypoxia-induced invasion and metastasis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating hepatocellular carcinoma cells under 1.0% O(2). After the hypoxia treatment, the cells exhibited some morphological changes including cell elongation, cytoskeletal rearrangement, and junctional disruption. Moreover, expression of the epithelia-specific marker E-cadherin was decreased and expression of the myofibroblast-specific marker vimentin was detected in the treated cells. Cell migration and ECM gel invasion were increased. These findings were consistent with events observed during EMT. Hypoxia-induced EMT is accompanied by increased phosphorylation, activation of Akt and the downstream signaling. Hypoxia-induced EMT was blocked by PI3K inhibitor LY294002. The results suggest that the PI3K/Akt-dependent signaling pathways serve to regulate hypoxia-induced EMT of hepatocellular carcinoma cells.
Yan
Wei
W
Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
Fu
Yu
Y
Tian
Dean
D
Liao
Jiazhi
J
Liu
Mei
M
Wang
Bo
B
Xia
Limin
L
Zhu
Qian
Q
Luo
Min
M
D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D015687:Cell Hypoxia; D002867:Chromones / Q000494:pharmacology; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one