SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis

Yang Yang; Xin Fan; Yukai Ren; Kai Wu; Xiangyu Tian; Fengbiao Wen; Donglei Liu; Yuxia Fan; Song Zhao

doi:10.1016/j.omtn.2020.10.027

SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis

Mol Ther Nucleic Acids. 2020 Oct 22:23:200-214. doi: 10.1016/j.omtn.2020.10.027. eCollection 2021 Mar 5.

Authors

Yang Yang¹, Xin Fan², Yukai Ren¹, Kai Wu¹, Xiangyu Tian³, Fengbiao Wen¹, Donglei Liu¹, Yuxia Fan⁴, Song Zhao¹

Affiliations

¹ Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
² Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
³ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
⁴ Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.

Abstract

Esophageal cancer (EC) is a highly aggressive disease, and its progression involves a complex gene regulation network. Transcription factor SOX2 is amplified in various cancers including EC. A pathway involving SOX2 regulation of microRNAs (miRNAs) and their target genes has been previously revealed. This study aims to delineate the ability of SOX2 to influence the EC progression, with the involvement of miR-30e/USP4/SMAD4/CK2 axis. SOX2 expression was first examined in the clinical tissue samples from 30 EC patients. Effects of SOX2 on proliferation, migration, and invasion alongside tumorigenicity of transfected cells were examined by means of gain- and loss-of-function experiments. EC tissues and cells exhibited high expression of SOX2, miR-30e, and CK2 and poor expression of USP4 and SMAD4. Mechanistically, SOX2 was positively correlated with miR-30e and upregulated the expression of miR-30e. miR-30e specifically targeted USP4, which induced deubiquitination of SMAD4 and promoted its expression. Meanwhile, SMAD4 was enriched in the CK2 promoter region and thus inhibited its expression. SOX2 stimulated EC cell proliferative, invasive, and migratory capacities in vitro and tumor growth in vivo by regulating the miR-30e/USP4/SMAD4/CK2 axis. Collectively, our work reveals a novel SOX2-mediated regulatory network in EC that may be a viable target for EC treatment.

Keywords: CK2; EMT; SMAD4; SOX2; USP4; esophageal cancer; invasion; microRNA-30e.