MicroRNA hsa-miR-623 directly suppresses MMP1 and attenuates IL-8-induced metastasis in pancreatic cancer
MicroRNA hsa-miR-623 directly suppresses MMP1 and attenuates IL-8-induced metastasis in pancreatic cancer
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MicroRNA hsa-miR-623 直接抑制 MMP1 并减弱 IL-8 诱导的胰腺癌转移
DOI：
10.3892/ijo.2019.4803
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Zeng, Linjuan
中科院分区：
文献类型：
--
作者：
Chen, Yutong;Peng, Siqi;Zeng, Linjuan
基质金属蛋白酶-1（MMP-1）参与胰腺癌的转移，其表达受内源性microRNAs（miRs/miRNAs）和外源性炎症因子的调控。潜在调节MMP 1表达的miRNA是否也可以减弱其诱导剂对胰腺癌的促转移作用尚未完全阐明。本研究采用计算机模拟和生物信息学分析、荧光素酶报告基因分析和RNA电泳迁移率变动分析（EMSA）等系统分析方法研究了miRNAs与MMP 1 mRNA之间的相互作用。此外，通过伤口愈合试验、Transwell试验和异种移植裸鼠模型来研究候选miRNAs发挥的抗肿瘤活性。结果，hsa-miR-623被筛选为与MMP 1转录物相互作用的候选miRNA，并且在人胰腺癌组织样品中观察到hsa-miR-623和MMP 1的表达之间的负相关性。EMSA证实hsa-miR-623能够直接结合MMP 1转录物的3 '-非翻译区内的同源靶标。此外，hsa-miR-623模拟物转染PANC-1和BXPC-3细胞后，在mRNA和蛋白水平上显著抑制MMP 1的表达，并减弱IL-8诱导的MMP 1表达。hsa-miR-623还通过抑制ERK磷酸化的潜在机制减少PANC-1和BXPC-3细胞中IL-8诱导的上皮-间充质转化。因此，hsa-miR-623在体外抑制胰腺癌细胞的迁移和侵袭以及在体内抑制转移。本研究的结果表明，hsa-miR-623代表了预防胰腺癌转移的新的辅助治疗靶点。
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.