MicroRNA-155-5p promotes hepatocellular carcinoma progression by suppressing PTEN through the PI3K/Akt pathway

Summary

MicroRNA-155-5p (miR-155-5p) has been reported to play an oncogenic role in different human malignancies; however, its role in HCC progression is not clearly understood. In this study, we used real-time PCR in 20 rats with chemically-induced HCC, 28 human HCC tissues, and the matched paracarcinoma tissues, and HCC cell lines to determine the expression patterns of miR-155-5p and PTEN mRNA. Algorithm-based and experimental strategies, such as dual luciferase gene reporter assays, real-time PCR, and Western Blots were used to identify PTEN as a candidate miR-155-5p target. Gain- and loss-of-function experiments and administration of a PI3K/Akt pathway inhibitor (wortmannin) were utilized to identify the effects of miR-155-5p and PTEN in MTT assays, flow cytometric analysis, wound healing assays, and transwell assays. The results showed that miR-155-5p was highly over-expressed; however, PTEN was under-expressed in the HCC rat models, human HCC tissues, and cell lines. Also, miR-155-5p up-regulation and PTEN down-regulation were significantly associated with tumor-node-metastasis stage (p<0.05). Through in vitro experiments, we found that miR-155-5p promoted proliferation, invasion, and migration, but inhibited apoptosis in HCC by directly targeting the 3’-UTR of PTEN. Western Blots showed that miR-155-5p inactivated Bax and caspase9, but activated Bcl-2 to inhibit apoptosis, and it activated MMPs to promote migration and invasion via the PI3K/Akt pathway. Xenograft tumor model was used to demonstrate that miR-155-5p targets PTEN and activates the PI3K/Akt pathway in vivo as well. Our study highlighted the importance of miR-155-5p and PTEN associated with aggressive HCC both in vitro and in vivo.

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