Long non-coding RNA SLC25A21-AS1 inhibits the development of epithelial ovarian cancer by specifically inducing PTBP3 degradation

Sihui Li; Shizhen Shen; Wanzhong Ge; Yixuan Cen; Songfa Zhang; Xiaodong Cheng; Xinyu Wang; Xing Xie; Weiguo Lu

doi:10.1186/s40364-022-00432-x

Long non-coding RNA SLC25A21-AS1 inhibits the development of epithelial ovarian cancer by specifically inducing PTBP3 degradation

Biomark Res. 2023 Jan 30;11(1):12. doi: 10.1186/s40364-022-00432-x.

Authors

Sihui Li¹, Shizhen Shen¹, Wanzhong Ge^{2

3

4}, Yixuan Cen¹, Songfa Zhang⁵, Xiaodong Cheng^{1

5}, Xinyu Wang^{1

5}, Xing Xie^{1

5}, Weiguo Lu^{6

7

8}

Affiliations

¹ Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China.
² Cancer Center, Zhejiang University, Hangzhou, 310058, China.
³ Division of Human Reproduction and Developmental Genetics, Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
⁴ Institute of Genetics, Zhejiang University, Hangzhou, 310058, China.
⁵ Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China.
⁶ Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China. lbwg@zju.edu.cn.
⁷ Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China. lbwg@zju.edu.cn.
⁸ Cancer Center, Zhejiang University, Hangzhou, 310058, China. lbwg@zju.edu.cn.

Abstract

Background: Epithelial ovarian cancer (EOC) is a highly prevalent disease that rapidly metastasizes and has poor prognosis. Most women are in the middle or late stages when diagnosed and have low survival rates. Recently, long non-coding RNAs (lncRNAs) were recognized to play pivotal roles in the development of EOC.

Methods: The expression of SLC25A21 antisense RNA 1 (SLC25A21-AS1) and Polypyrimidine Tract Binding Protein 3 (PTBP3) in EOC cells was assessed via qPCR. The proliferation activity of these cells was detected by EdU and Cell counting kit-8 (CCK8) assays, while the death rate of apoptotic cells and the cell cycle were detected by flow cytometry. Detection of cell transfer rate by transwell assay. Protein expression was measured through western blotting. Interactions between SLC25A21-AS1 and PTBP3 were detected through RNA immunoprecipitation (RIP), IF-FISH co-localization experiments and electrophoretic mobility shift assay (EMSA). The in vivo importance of SLC25A21-AS1 as a tumor suppressor modulator was assessed using murine xenograft models.

Results: The lncRNA SLC25A21-AS1 has negligible expression in ovarian cancer tissues compared with that in normal ovarian tissues. A series of functional experiments revealed that the upregulation of SLC25A21-AS1 markedly blocked the proliferation and metastasis of EOC cells in vitro, while its downregulation had the opposite effect. Overexpression of SLC25A21-AS1 in a nude mouse model of EOC in vivo resulted in slower tumor growth and weakened metastatic potential. Moreover, SLC25A21-AS1 reduced the protein stability of PTBP3 and promoted its degradation. A series of subsequent experiments found that SLC25A21-AS1 inhibits EOC cell proliferation and metastasis by modulating PTBP3 through the ubiquitin-proteasome pathway and that the combination of SLC25A21-AS1 and PTBP3 provides the necessary conditions for the for the function to be realized.

Conclusions: Our research reveals the effect of SLC25A21-AS1 in EOC development and suggests SLC25A21-AS1 can serve as a prognostic target by promoting the degradation of PTBP3 to improve patient survival.

Keywords: PTBP3; SLC25A21-AS1; epithelial ovarian cancer; long noncoding RNAs; ubiquitination.