Downregulation of TET2 Contributes to Nasal Polypogenesis Through Hypoxia-Inducible Factor 1α-Mediated Epithelial-to-Mesenchymal Transition
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Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to me-diate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulatethe expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1αmediation 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 HIF1α and TET2 was detected using Westernblotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohisto-chemistry. 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 de-termine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measuredto 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-cadherinbut negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negativelycorrelated with TET2 expression. CoCl2-simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro, withsimultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibitedEMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl2-simulatedhNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression andROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo. TET2 was downregulated by HIF1α, resulting inthe EMT in CoCl2-hypoxic hNECs via regulation of oxidative stress in vitro. Hence, TET2 might provide a new thera-peutic approach for CRSwNP.
Abstract
Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to me-diate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulatethe expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1αmediation 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 HIF1α and TET2 was detected using Westernblotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohisto-chemistry. 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 de-termine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measuredto 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-cadherinbut negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negativelycorrelated with TET2 expression. CoCl2-simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro, withsimultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibitedEMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl2-simulatedhNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression andROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo. TET2 was downregulated by HIF1α, resulting inthe EMT in CoCl2-hypoxic hNECs via regulation of oxidative stress in vitro. Hence, TET2 might provide a new thera-peutic approach for CRSwNP.
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