Downregulation of TET2 Contributes to Nasal Polypogenesis Through Hypoxia-Inducible Factor 1-Mediated Epithelial-to-Mesenchymal Transition

Objectives. Hypoxia-inducible factor 1 alpha (HIF1 alpha) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to mediate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1 alpha can regulate the expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1 alpha mediation in nasal epithelial cells is still poorly understood. Methods. Nasal tissue samples were collected from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. The expression of HIF1 alpha and TET2 was detected using Western blotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with CoCl2 to mimic hypoxia. Vitamin C (VC), a TET2 non-specific activator, and small interfering RNA (siRNA) transfection of TET2 were used to further determine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream consequences of TET2 in hypoxic hNECs. Results. TET2 levels were lower in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS. However, HIF1 alpha exhibited the opposite pattern and was negatively correlated with TET2 expression. CoCl2-simulated hypoxia led to EMT and increased HIF1 alpha in hNECs in vitro, with simultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1 alpha expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl2-simulated hNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression and ROS generation. Conclusion. TET2 was negatively correlated with HIF1 alpha and EMT in vivo. TET2 was downregulated by HIF1 alpha, resulting in the EMT in CoCl2-hypoxic hNECs via regulation of oxidative stress in vitro. Hence, TET2 might provide a new therapeutic approach for CRSwNP.