Sep 28

SS 04 - GYN 1: Molecular and Precision Medicine for Gynecologic Cancers in Diverse Resource Settings

122 - Radiation-Induced CTD-2292M14.1 Enhances Cervical Cancer Radioresistance by Promoting P62 Ubiquitination

02:37pm - 02:44pm PT

Room 160

Presenter(s)

Jie Zhou, PhD, RT - Sichuan Cancer Hospital and Institute, Chengdu, Sichuan

J. Zhou¹, C. Yang², and S. Lu¹; ¹Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China, ²Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer,Sichuan Cancer Hospital &Institute,Sichuan Cancer Center ,School of Medicine,University of Electronic Science and Technology of China, Chengdu, China

Purpose/Objective(s):

Radioresistance is a significant obstacle in the treatment of advanced cervical cancer, however, the underlying molecular mechanism remains poorly understood, limiting the development of effective radiosensitization strategies. Long noncoding RNAs (lncRNAs) are emerging as crucial modulators of various biological processes including tumor progression and radiosensitivity. This study aims to explore novel lncRNAs that closely associated with cervical cancer radioresistance and reveal the molecular regulatory mechanisms.

Materials/Methods:

We analyzed differential lncRNA expression in cervical cancer tissues from radiosensitive and radioresistant patients using whole exome sequencing, followed by validation in 66 post-radiotherapy cervical cancer samples. In vitro and in vivo experiments were conducted using cervical cancer cell lines and their radioresistant (RR) subclones to assess the functional role of the identified lncRNA CTD-2292M14.1 in cervical cancer radioresistance. The molecular mechanisms of CTD-2292M14.1 in regulating cervical cancer radiosensitivity were investigated by proteome datasets, co-immunoprecipitation (Co-IP), and RNA pull-down coupled with mass spectrometry (MS).

Results:

We discovered CTD-2292M14.1, a novel lncRNA that is lowly expressed in cervical cancer patients, but becomes overexpressed when those patients developed radioresistance, accompanied by a worse prognosis. High CTD-2292M14.1 expression positively correlates with reduced radiosensitivity, as confirmed in radiation-resistant cervical cancer cell lines. We also found that the irradiation triggers the overexpression of CTD-2292M14. Overexpression of CTD-2292M14.1 significantly suppressed the effects of irradiation on DNA damage repair, cell proliferation, cell cycle, and cell apoptosis, leading to decreased radio-sensitivity in vitro and in vivo. In contrast, CTD-2292M14.1 knockdown reversed these effects. Mechanistically, CTD-2292M14.1 promotes the ubiquitination and degradation of the p62 protein, thereby enhancing autophagy, reducing radiation-induced ferroptosis, and conferring cervical cancer cells with radioresistant activity.

Conclusion:

Herein, we identified CTD-2292M14.1, which was upregulated by irradiation and confers radioresistant properties in cervical cancer cells by facilitating p62 protein degradation and promoting autophagy. Targeting the CTD-2292M14.1-p62 pathway may offer a promising therapeutic strategy to overcome cervical cancer radioresistance.