Hypoxia-induced epithelial-mesenchymal transition is regulated by phosphorylation of GSK3-β via PI3 K/Akt signaling in oral squamous cell carcinoma

Publication date: December 2016
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 122, Issue 6
Author(s): Takeshi Kaneko, Hironari Dehari, Takanori Sasaki, Tomohiro Igarashi, Kazuhiro Ogi, Jun-ya Okamoto, Mayumi Kawata, Jun-ichi Kobayashi, Akihiro Miyazaki, Kenji Nakamori, Hiroyoshi Hiratsuka
ObjectiveEpithelial–mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis induced by hypoxia. Here, we examined whether phosphorylation of GSK3-β via phosphoinositide 3-kinase (PI3 K)/Akt signaling is involved in enhancing the hypoxia-induced EMT in oral squamous cell carcinoma (OSCC).Study DesignExperiments were performed in OSCC cell lines (HSC-2, HSC-3, HSC-4, SAS, and HO-1-U-1) under normoxic or hypoxic conditions. The EMT was assessed by Matrigel invasion assays and wound healing assays. OSCC cell lines (HSC-2 and HSC-4) overexpressing hypoxia-inducible factor (HIF)-1α were established to examine the effects of HIF-1α on EMT-related factors. Immunohistochemical staining was performed to examine phosphorylation of GSK3-β in 33 cases of tongue squamous cell carcinoma.ResultsUnder hypoxic conditions, OSCC cell lines exhibited HIF-1α expression and showed evidence of the EMT. In cells overexpressing HIF-1α, the levels of phospho-Akt and phospho-GSK3-β were increased, resulting in induction of the EMT. Inhibition of GSK3-β phosphorylation suppressed these effects. Moreover, the intensity of pGSK3-β staining was significantly increased with cN stage and cTNM stage in patients with tongue squamous cell carcinoma.ConclusionsOur data showed that the hypoxia-induced EMT in OSCC was enhanced by GSK3-β phosphorylation, suggesting that GSK3-β may be important in the invasion and metastasis of OSCC.



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