Objective
Epithelial–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 Design
Experiments 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.
Results
Under 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.
Conclusions
Our 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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Article info
Publication history
Published online: June 22, 2016
Accepted:
June 5,
2016
Received in revised form:
June 3,
2016
Received:
October 20,
2015
Footnotes
This work was supported by JSPS KAKENHI (grant numbers 22390388 and 24659901).
Identification
Copyright
© 2016 Elsevier Inc. All rights reserved.
