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Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma

Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that...

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Autores principales: Yu, Guangsheng, Wang, Jianlu, Xu, Kesen, Dong, Jiahong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293557/
https://www.ncbi.nlm.nih.gov/pubmed/27129291
http://dx.doi.org/10.1042/BSR20160062
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author Yu, Guangsheng
Wang, Jianlu
Xu, Kesen
Dong, Jiahong
author_facet Yu, Guangsheng
Wang, Jianlu
Xu, Kesen
Dong, Jiahong
author_sort Yu, Guangsheng
collection PubMed
description Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that this is part due to the overexpression of the mitochondrial uncoupling protein 2 (UCP2) that in turn mediates resistance to GEM in HCC patients. However, not much is known about regulatory mechanisms underlying UCP2 overexpression in HCC. Differential protein expression in HCC cell lines did not show a concomitant change in UCP2 transcript level, indicating post-transcriptional or post-translational regulatory mechanism. In situ analysis revealed that UCP2 is a putative target of miR-214. miR-214 expression is significantly down-regulated in HCC patient samples as compared with normal adjacent tissues and in cell line, human hepatoblastoma cells (HuH6), with high UCP2 protein expression. We demonstrated using miR-214 mimic and antagomir that the miRNA targeted UCP2 expression by directly targeting the wild-type, but not a miR-214 seed mutant, 3’ UTR of UCP2. Overexpression of miR-214 significantly attenuated cell proliferation. Finally, analysis in 20 HCC patients revealed an inverse correlation in expression of UCP2 and miR-214 (Pearson's correlation coefficient, r=−0.9792). Cumulatively, our data indicate that in the context of HCC, miR-214 acts as a putative tumour suppressor by targeting UCP2 and defines a novel mechanism of regulation of UCP2.
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spelling pubmed-52935572017-02-14 Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma Yu, Guangsheng Wang, Jianlu Xu, Kesen Dong, Jiahong Biosci Rep Original Papers Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that this is part due to the overexpression of the mitochondrial uncoupling protein 2 (UCP2) that in turn mediates resistance to GEM in HCC patients. However, not much is known about regulatory mechanisms underlying UCP2 overexpression in HCC. Differential protein expression in HCC cell lines did not show a concomitant change in UCP2 transcript level, indicating post-transcriptional or post-translational regulatory mechanism. In situ analysis revealed that UCP2 is a putative target of miR-214. miR-214 expression is significantly down-regulated in HCC patient samples as compared with normal adjacent tissues and in cell line, human hepatoblastoma cells (HuH6), with high UCP2 protein expression. We demonstrated using miR-214 mimic and antagomir that the miRNA targeted UCP2 expression by directly targeting the wild-type, but not a miR-214 seed mutant, 3’ UTR of UCP2. Overexpression of miR-214 significantly attenuated cell proliferation. Finally, analysis in 20 HCC patients revealed an inverse correlation in expression of UCP2 and miR-214 (Pearson's correlation coefficient, r=−0.9792). Cumulatively, our data indicate that in the context of HCC, miR-214 acts as a putative tumour suppressor by targeting UCP2 and defines a novel mechanism of regulation of UCP2. Portland Press Ltd. 2016-05-20 /pmc/articles/PMC5293557/ /pubmed/27129291 http://dx.doi.org/10.1042/BSR20160062 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Papers
Yu, Guangsheng
Wang, Jianlu
Xu, Kesen
Dong, Jiahong
Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title_full Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title_fullStr Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title_full_unstemmed Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title_short Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma
title_sort dynamic regulation of uncoupling protein 2 expression by microrna-214 in hepatocellular carcinoma
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293557/
https://www.ncbi.nlm.nih.gov/pubmed/27129291
http://dx.doi.org/10.1042/BSR20160062
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