miR-193a-5p Promotes Pancreatic Cancer Cell Migration and Invasion Through SRSF6-Mediated Alternative Splicing of OGDHL and ECM1

Background: Recent studies have shown miRNAs indirectly regulated alternative splicing (AS) by targeting splicing factors and caused shifts in splicing patterns of target genes. However, the role of miRNA-regulating splicing factors in pancreatic cancer (PC) progression remain unknown. Therefore, we sought to investigate the role of miR-193a-5p targeting serine/arginine-rich splicing factor 6 (SRSF6) in PC. Methods: Expression levels of and prognostic information for miR-193a-5p and SRSF6 were examined based on the TCGA database, clinical samples and PC cell lines. The functional roles of miR-193a-5p targeting SRSF6 were investigated in PC cells and xenograft mouse model. The AS targets of SRSF6 in PC cells were determined using gel shift and minigene reporter assays. Findings: The expression of miR-193a-5p was upregulated in PC tissues and cell lines, whereas the expression of SRSF6 was downregulated. miR-193a-5p could promote PC cell metastasis by targeting SRSF6. Mechanistically, we demonstrated that SRSF6 downregulation could promote PC cell migration and invasion through regulating oxoglutarate dehydrogenase-like (OGDHL) and extracellular matrix protein 1 (ECM1) AS. Interpretation: miR-193a-5p-SRSF6-OGDHL/ECM1 axis may become useful prognostic biomarkers and provide effective targets for anti-metastasis therapies for PC. Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81702941 and No. 81570696), Priority Academic Program Development of Jiangsu Higher Education Institutions, and Qing Lan Project. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Written informed consent was provided by patients for tissue collection. The ethical approval was granted from Committees for Ethical Review in China Pharmaceutical University (Nanjing, China). The study is compliant with all relevant ethical regulations for human research participants. All animal experiments were approved by the Ethics Committee of China Pharmaceutical University (Permit No. 2162326).