YAP Promotes Cell Proliferation and Epithelium-Derived Cytokine Expression via NF-κB Pathway in Nasal Polyps

Abstract

Background

Hippo-Yes-associated protein (YAP) pathway plays an important role in epithelial cell proliferation and inflammation development in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the underlying mechanisms remain unclear.

Objective

This study intends to investigate the role of YAP and the nuclear factor kappa-B (NF-κB) pathway in cell proliferation and the expression of epithelium-derived cytokines in nasal polyps (NP).

Methods

The expression levels of YAP, TEA domain family member 1 (TEAD1), Ki-67, and NF-κB as well as interleukin (IL-) 33, IL-25 and thymic stromal lymphopoietin (TSLP) in sinonasal mucosa, primary nasal epithelial cells (NPECs), and human nasal epithelial RPMI 2650 cells were detected. NPECs were cultured and treated with verteporfin (VP), YAP shRNA or BAY 11–7082.

Results

The hippo pathway effector YAP, Ki-67, p65 NF-κB, and cyclin D1 were significantly increased in NP compared with control mucosa, which was accompanied by overexpression of IL-33, IL-25, and TSLP. Pharmaceutical inhibition of YAP by VP suppressed cell proliferation of RPMI 2650 cells by blocking cell cycle progression at G0/G1 without inducing obvious cell apoptosis. Furthermore, lentiviral transfection-mediated knockdown of hippo pathway activity reduced the expression of IL-33, IL-25, TSLP as well as p65 NF-κB in RPMI 2650 cells. Downregulation of NF-κB pathway with BAY 11–7082 in NPECs could decrease the mRNA level of TSLP, IL-33 and IL-25 accordingly.

Conclusion

Inhibition of hippo pathway suppressed nasal epithelial cell proliferation and declined the expression of epithelium-derived cytokines via the NF-κB pathway in NPECs.

Keywords:

• NF-κB signalling pathway
• yes-associated protein
• cell cycle progression
• cell proliferation
• nasal polyps

Ethics Approval and Informed Consent

All patients were informed of the purposes and procedures of the study and provided written informed consent. This study was approved by the Ethics Committee for Human Study at the Third Affiliated Hospital of Sun Yat-sen University (China).

Consent for Publication

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Acknowledgments

The authors would like to thank all the patients for their participation in this study, as well as the funding, and The Third Affiliated Hospital, Sun Yat-sen University.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82000957 and 81870704), the Science and Technology Planning Project of Guangdong Province (2014A020212057) and The Third Affiliated Hospital of Sun Yat-Sen University, Clinical Research Program (No. QHJH201901).