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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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6561617 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Chen Yutong Y Peng Siqi S Cen Hong H Lin Yujing Y Huang Chumei C Chen Yinting Y Shan Hong H Su Yonghui Y Zeng Linjuan L

International journal of oncology 20190517 1

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 ...[more]

PMID: 31115512

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Project description:PurposeHepatocellular carcinoma (HCC), a worldwide leading cause of morbidity and mortality, is the most frequent primary liver tumor. Most HCC patients are diagnosed with advanced liver cancer, resulting in a very low 5-year survival rate. Thus, there is an urgent need for the development of targeted therapies. In this study, we aimed to investigate the effect and mechanism of the miR-20a/EZH1 axis on the proliferation and metastasis of HCC and the inhibitory effect of the EZH1/EZH2 inhibitor UNC1999 on HCC.Materials and methodsThe expression of miR-20a in human HCC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). The expressions of proteins were analyzed with immunohistochemistry and Western blotting. Luciferase assay was used to verify whether miR-20a targets EZH1 or EZH2. The effect of miR-20a on HCC progression was studied in vivo and in vitro. The tumor inhibitory effect of UNC1999 was confirmed in vivo. CCK8 assay, wound healing assay, cell migration and invasion assay were used to evaluate the synergistic effect of UNC1999 with sorafenib. RNA sequencing (RNA-seq) was performed to screen the differentially expressed genes in the Huh7 and SMMC7721 cell lines after UNC1999, sorafenib, and combination treatments.ResultsIn this study, miR-20a showed a lower expression in both HCC tissues and cell lines. MiR-20a inhibited the proliferation and migration of SMMC7721 and Huh7 cells. The results of the luciferase assay and Western blot analysis revealed that miR-20a directly targeted EZH1, a histone methyltransferase. We demonstrated that miR-20a negatively regulated the expression of EZH1 and inhibited the proliferation and metastasis of HCC by reducing H3K27 methylation. We found UNC1999 inhibited tumor cells proliferation and enhanced the inhibitory effect of sorafenib.ConclusionWe demonstrated that miR-20a suppresses the tumor proliferation and metastasis in HCC by directly targeting EZH1. UNC1999 can inhibit tumor proliferation in vivo and increase the sensitivity of hepatoma cell lines to sorafenib.

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

Publications

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

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