Knockdown of hsa_circ_0074298 suppressed the progression of pancreatic cancer by targeting the miR-519/SMOC2 axis

Abstract

BACKGROUND: Pancreatic cancer (PC) is among the most malignant tumors in the digestive system because of its fast progression, metastasis, as well as its resistance to chemotherapy. Former studies found that circRNAs that were differentially expressed were correlated with progression and gemcitabine (GEM)-resistance in PC, and hsa_circ_0074298 aberrant expression played a role in PC progression, but the regulatory mechanism was unclear. METHODS: RT-qPCR was used to detect hsa_circ_0074298 expression in PC cell lines. CCK8, colony formation, and Transwell assays were used to evaluate the effect of hsa_circ_0074298 on PC cell migration and proliferation. Bioinformatics and luciferase reporter experiments were used to characterize the regulatory mechanism. Nude mouse xenografts were generated to examine the effect of hsa_circ_0074298 on tumor growth. RESULTS: The present study showed that hsa_circ_0074298 expression increased significantly in both PC cell lines and PC tissues. Downregulation of hsa_circ_0074298 caused a significant decrease in PC cell proliferation and in nude mouse xenograft growth. Hsa_circ_0074298 silencing also increased chemotherapy sensitivity to GEM. Bioinformatics analysis indicated that hsa_circ_0074298 was a miR-519 sponge and that the SMOC2 gene was a miR-519 target. MiR-519 downregulation or SMOC2 overexpression restored cell proliferation, migration, and chemoresistance after hsa_circ_0074298 silencing. The dual luciferase reporter assay showed that hsa_circ_0074298 interacted with miR-519, and miR-519 binding to the SMOC2 3′-UTR then suppressed posttranscriptional SMOC2 expression. CONCLUSIONS: Taken together, hsa_circ_0074298 functioned as a tumor promoter through a novel miR-519/SMOC2 axis, highlighting its possibility as a potential therapy for PC.