Int J Biol Sci 2021; 17(8):1909-1924. doi:10.7150/ijbs.57623

Research Paper

ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1

Feng-Nan Li1,2#, Qin-Yi Zhang1,2#, Ou Li1,2#, Shi-Lei Liu1,2, Zi-Yi Yang1,2, Li-Jia Pan1,2, Cheng Zhao1,2, Wei Gong1,2, Yi-Jun Shu1,2✉, Ping Dong1,2✉

1. Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.
2. Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai 200092, China.
#These authors contributed equally to this work.

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Citation:
Li FN, Zhang QY, Li O, Liu SL, Yang ZY, Pan LJ, Zhao C, Gong W, Shu YJ, Dong P. ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1. Int J Biol Sci 2021; 17(8):1909-1924. doi:10.7150/ijbs.57623. Available from https://www.ijbs.com/v17p1909.htm

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Abstract

Background: Estrogen-related receptor-α (ESRRA) is an orphan nuclear receptor, expressing at high level in exuberant metabolism organs and acting as transcription factor. High expression was found in many malignances but no research was done in gastric cancer (GC), where lipid metabolism disorder is common.

Methods: Kaplan-Meier plot was utilized to find the relationship between ESRRA expression and patients' prognoses. The expression level of ESRRA was measured by real-time PCR. The protein expression levels were tested with western-blot and immunohistochemistry. Cell cycle and apoptosis was identified with flow cytometry. RNA-seq, bioinformatics analysis, dual-luciferase assay and ChIP assay were used to predict and validate ESRRA's target gene and binding motif. Animal models were also introduced in our study.

Results: ESRRA expression is notably higher in GC cell lines and high ESRRA levels are correlated to poor prognoses. ESRRA silencing decreased GC cell viability, migration, and invasion capacities. Its downstream gene DSN1 was spotted by RNA-seq and confirmed by later bioinformatics analyses, dual-luciferase, and ChIP assays. Western-blot showed G2M arrest caused by ESRRA silencing was via CDC25C-CDK1-Cyclin B1 pathway.

Conclusion: ESRRA/DSN1/CDC25C-CDK1-Cyclin B1 is of great importance in GC development. ESRRA could be a potential target as well as prognostic marker in GC.

Keywords: gastric cancer, oncogene, estrogen-related receptor-α (ESRRA), DSN1 component of MIS12 kinetochore complex (DSN1), cell cycle, CDC25C-CDK1-Cyclin B1