Downregulation of RAGE Inhibits Cell Proliferation and Induces Apoptosis via Regulation of PI3K/AKT Pathway in Cervical Squamous Cell Carcinoma

Ruyi Li; Yizuo Song; Lulu Zhou; Weibo Li; Xueqiong Zhu

doi:10.2147/OTT.S240378

Downregulation of RAGE Inhibits Cell Proliferation and Induces Apoptosis via Regulation of PI3K/AKT Pathway in Cervical Squamous Cell Carcinoma

Onco Targets Ther. 2020 Mar 20:13:2385-2397. doi: 10.2147/OTT.S240378. eCollection 2020.

Authors

Ruyi Li¹, Yizuo Song¹, Lulu Zhou¹, Weibo Li¹, Xueqiong Zhu¹

Affiliation

¹ Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.

Abstract

Aim: The receptor for advanced glycation endproducts (RAGE) expression has been reported to be implicated with cancer development. In this study, the role of RAGE in the regulation of cervical squamous cancer cell proliferation, apoptosis and the mechanism of RAGE involved in the biological behaviors were explored.

Methods: The RAGE expression was overexpressed or downregulated by lentivirus transfection. The effect of RAGE expression on cell proliferation was explored by CCK-8, MTT, and BrdU assay, and the effect of RAGE on tumor development was confirmed by the xenograft mouse model along with the immunohistochemistry stain of proliferating cell nuclear antigen (PCNA). Apoptosis was investigated by flow cytometry and TUNEL assay. Western blotting was performed to investigate the expression of possible proteins, including Bax, Bcl-2, PI3K, p-PI3K, AKT, and p-AKT.

Results: Overexpression of RAGE promoted proliferation of cervical squamous cancer cell and increased PCNA expression. In the meantime, RAGE overexpression inhibited cell apoptosis along with a decrease of Bax/Bcl-2 ratio, and induction of PI3K/AKT activation. The in vivo results showed that overexpression of RAGE enhanced tumor growth. Conversely, knockdown of RAGE exhibited opposed effects on cervical cancer cells and xenograft mouse model. Furthermore, RAGE inhibitor FPS-ZM1 effectively inhibited SiHa cell viability and PCNA expression, and increased cell apoptosis and Bax/Bcl-2 ratio. Moreover, PI3K inhibitor LY294002 effectively inhibited activation of PI3K and AKT, and further repressed RAGE overexpression-induced cell proliferation and apoptosis inhibition.

Conclusion: RAGE promotes the growth ability of cervical squamous cell carcinoma by inducing PCNA expression and inhibiting cell apoptosis via inactivation of the PI3K/AKT pathway.

Keywords: PI3K/AKT; RAGE; apoptosis; cervical squamous cancer; proliferation.

Grants and funding

This research was financially supported through grants from the Wenzhou Science and Technology Projects (Y20170126), Medical Science and Technology Project of Zhejiang Province (2019RC212) and Science and Technology Innovation Team of Wenzhou city-Gynecological Oncology (C20170004). Sponsors of the study had no involvement in the collection, analysis, and interpretation of data or the writing of the manuscript.