MicroRNA hsa-miR-623 directly suppresses MMP1 and attenuates IL-8-induced metastasis in pancreatic cancer.

Abstract

Matrix metalloproteinase-1 (MMP1) participates in the metastasis of pancreatic cancer, and its expression can be regulated by endogenous microRNAs (miRs/miRNAs) and exogenous inflammatory factors. Whether miRNAs that potentially modulate MMP1 expression can also attenuate the pro-metastatic effects of its inducer on pancreatic cancer is yet to be completely elucidated. In the present study, a systematic analysis including in silico and bioinformatics analyses, a luciferase reporter assay and an RNA electrophoretic mobility shift assay (EMSA), were used to investigate the interaction between miRNAs and MMP1 mRNA. In addition, wound-healing assays, Transwell assays and xenograft nude mouse models were implemented to investigate the antitumor activities exerted by candidate miRNAs. As a result, hsa-miR-623 was screened as a candidate miRNA that interacts with the MMP1 transcript, and an inverse correlation between the expression of hsa-miR-623 and MMP1 was observed in human pancreatic cancer tissue samples. The EMSA confirmed that hsa-miR-623 was able to directly bind to its cognate target within the 3′-untranslated region of the MMP1 transcript. In addition, transfection of hsa-miR-623 mimics into PANC-1 and BXPC-3 cell lines markedly inhibited the expression of MMP1 at the mRNA and protein levels, and attenuated IL-8-induced MMP1 expression. hsa-miR-623 also decreased IL-8-induced epithelial-mesenchymal transition in PANC-1 and BXPC-3 cells via the underlying mechanism of inhibition of ERK phosphorylation. Consequently, hsa-miR-623 inhibited pancreatic cancer cell migration and invasion in vitro and metastasis in vivo. The results of the present study suggest that hsa-miR-623 represents a novel adjuvant therapeutic target to prevent metastasis in pancreatic cancer.