Potential regulatory mechanisms of hsa_circ_0131457/miR-636/SFRP2 inhibition of tumor progression in pancreatic ductus adenocarcinoma

Abstract

Abstract Background: Circular RNAs (circRNAs), a novel class of non-coding RNAs, have been found to act as miRNA sponges that competitively inhibit the binding of miRNA to target mRNA. However, studies on circRNA in pancreatic ductal adenocarcinoma are still lacking and need to be further explored. Methods: The expression level of SOX4 in pancreatic cancer cells and tissues was detected by qRT-PCR and immunohistochemistry, and the correlation between the expression level of SOX4 in pancreatic cancer tissues and clinicopathological features was analyzed by Pearson Chi-square test. Kaplan-meier method was used to analyze the survival curve of pancreatic cancer patients. The circRNA regulating SOX4 was predicted by bioinformatics and verified in pancreatic cancer cells and tissues. The miRNA and target genes were predicted by bioinformatics, and the circRNA-miRNA-mRNA regulatory network was constructed. Then, the expression of SFRP2 in pancreatic cancer cells and tissues was detected by qRT-PCR and immunohistochemistry, and the correlation between clinicopathological features and prognosis was analyzed. Finally, the biological function of SFRP2 was analyzed by bioinformatics to construct a prognostic model for pancreatic cancer. Result: The expression level of SOX4 was significantly up-regulated in various tumor tissues including pancreatic ductal adenocarcinoma. Further analysis showed that up-regulated SOX4 expression was correlated with tumor size and T stage of patients and resulted in poor prognosis of patients. Bioinformatics analysis revealed that SOX4 was a key protein in the Wnt/β-catenin pathway. QRT-PCR was used to detect tissue samples and cells of 9 pancreatic cancer patients, and the expression of 4 circRNA was down-regulated, among which hsa_circ_0131457 was the most significant. A total of 10 miRNA were selected for the prediction of miRNA that bind to hsa_circ_0131457, and the optimal matching value was miR-636. The mRNA targeted to miR-636 was predicted, SFRP2 with the most obvious differential expression was screened out, and the hsa_circ_0131457-miR-636-SFRP2 network regulation map was constructed. Analysis and verification of the target gene SFRP2 showed that the expression of SFRP2 was significantly down-regulated in pancreatic cancer tissues and cells, which was related to preoperative direct bilirubin, tumor size, T stage and tumor differentiation degree. In addition, downregulation of SFRP2 expression in cancer tissues predicted poor prognostic survival in pancreatic cancer patients. Functional analysis of SFRP2 revealed that SFRP2 is a key protein in the Wnt/β-catenin pathway and may be involved in epithelial-mesenchymal transition (EMT). Conclusion: hsa_circ_0131457 and target gene SFRP2 were found to be low expressed in pancreatic cancer, and SFRP2 had an inhibitory effect on the progression of pancreatic cancer. Therefore, the potential regulatory mechanism of hsa_circ_0131457/miR-636/SFRP2 inhibiting the invasion and metastasis of pancreatic cancer was inferred.