Downregulation of TET2 contributes to nasal polypogenesis through HIF1α-mediated epithelial-to-mesenchymal transition.

OBJECTIVES: Hypoxia-inducible factor (HIF) 1α and Ten-eleven translocation 2 (TET2) have been reported to mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Besides, expression and function of TET2 can be regulated by HIF1α. However, the precise mechanism of how TET2 regulated EMT through HIF1α-induced EMT in nasal epithelial cell is still poorly understood.

METHODS: Nasal tissue samples were collected from patients with CRSwNP, CRSsNP and controls. The expression of HIF1α and TET2 were detected using westernblotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with Cobalt dichloride (CoCl2) to mimic hypoxia environment. In addition, TET2 non-specific activator vitamin C and small interfering RNA (siRNA) transfection of TET2 was used to further determine the role TET2 played through hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream of TET2 in hypoxia hNECs.

RESULTS: In our study, we found that TET2 was decreased in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS but HIF1α was on the contrary. Moreover, HIF1α was negatively correlated with TET2 expression. CoCl2-simulated hypoxia led to EMT and HIF1α increase in hNECs in vitro, but downregulated TET2 expression at the same time. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1α expression. Futhermore, siRNA knockdown of TET2 still contributed to the EMT process in CoCl2-simulated hNECs even with the addition of VC. Finally, TET2 regulated EMT in hypoxia hNECs through Nrf2 expression and ROS generation.

CONCLUSION: TET2 was negatively correlated with HIF1α and EMT in vivo. Moreover, TET2 was down-regulated by HIF1α, resulting in EMT in CoCl2-hypoxia hNECs via regulation of oxidative stress in vitro. Hence, TET2 might provide a new therapeutic approach for CRSwNP.