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J Cell Physiol. 2017 Jul;232(7):1907-1913. doi: 10.1002/jcp.25744. Epub 2017 Feb 16.

MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells.

Author information

1
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy.
2
Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy.
3
Sbarro Institute for Cancer Research and Molecular Medicine & Center for Biotechnology, Temple University, Philadelphia, Pennsylvania.

Abstract

Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR-125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017.

PMID:
27982429
DOI:
10.1002/jcp.25744
[Indexed for MEDLINE]

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