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MicroRNA‐125a‐5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells
Author(s) -
Potenza Nicoletta,
Mosca Nicola,
Zappavigna Silvia,
Castiello Filomena,
Panella Marta,
Ferri Carmela,
Vanacore Daniela,
Giordano Antonio,
Stiuso Paola,
Caraglia Michele,
Russo Aniello
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25744
Subject(s) - sorafenib , cell growth , cancer research , microrna , angiogenesis , cell cycle , downregulation and upregulation , sirtuin 1 , oncogene , cell , hepatocellular carcinoma , effector , chemistry , biology , pharmacology , microbiology and biotechnology , biochemistry , gene
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. © 2016 Wiley Periodicals, Inc.