Cargando…

fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma

Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to...

Descripción completa

Detalles Bibliográficos
Autores principales: Ge, Yunxia, Yan, Xiaodan, Jin, Yiguang, Yang, Xinyu, Yu, Xiang, Zhou, Liqing, Han, Sichong, Yuan, Qipeng, Yang, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692503/
https://www.ncbi.nlm.nih.gov/pubmed/26710269
http://dx.doi.org/10.1371/journal.pgen.1005726
_version_ 1782407267615768576
author Ge, Yunxia
Yan, Xiaodan
Jin, Yiguang
Yang, Xinyu
Yu, Xiang
Zhou, Liqing
Han, Sichong
Yuan, Qipeng
Yang, Ming
author_facet Ge, Yunxia
Yan, Xiaodan
Jin, Yiguang
Yang, Xinyu
Yu, Xiang
Zhou, Liqing
Han, Sichong
Yuan, Qipeng
Yang, Ming
author_sort Ge, Yunxia
collection PubMed
description Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to study how miRNAs impact lncRNAs expression and its biological significance in hepatocellular carcinoma (HCC). LncRNA HOTTIP is a vital oncogene in HCC, one of the deadliest cancers worldwide. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expression via the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays. Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients. In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonizing endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo mouse xenograft model also support the tumor suppressor role of both miRNAs. Besides the known targets (multiple 5’ end HOX A genes, i.e. HOXA13), glutaminase (GLS1) was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in HCC. Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencingGLS1, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition. These results elucidate that the miR-192/-204-HOTTIP axis might be an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications.
format Online
Article
Text
id pubmed-4692503
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-46925032016-01-12 fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma Ge, Yunxia Yan, Xiaodan Jin, Yiguang Yang, Xinyu Yu, Xiang Zhou, Liqing Han, Sichong Yuan, Qipeng Yang, Ming PLoS Genet Research Article Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to study how miRNAs impact lncRNAs expression and its biological significance in hepatocellular carcinoma (HCC). LncRNA HOTTIP is a vital oncogene in HCC, one of the deadliest cancers worldwide. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expression via the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays. Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients. In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonizing endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo mouse xenograft model also support the tumor suppressor role of both miRNAs. Besides the known targets (multiple 5’ end HOX A genes, i.e. HOXA13), glutaminase (GLS1) was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in HCC. Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencingGLS1, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition. These results elucidate that the miR-192/-204-HOTTIP axis might be an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications. Public Library of Science 2015-12-28 /pmc/articles/PMC4692503/ /pubmed/26710269 http://dx.doi.org/10.1371/journal.pgen.1005726 Text en © 2015 Ge et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ge, Yunxia
Yan, Xiaodan
Jin, Yiguang
Yang, Xinyu
Yu, Xiang
Zhou, Liqing
Han, Sichong
Yuan, Qipeng
Yang, Ming
fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title_full fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title_fullStr fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title_full_unstemmed fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title_short fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma
title_sort fmirna-192 and mirna-204 directly suppress lncrna hottip and interrupt gls1-mediated glutaminolysis in hepatocellular carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692503/
https://www.ncbi.nlm.nih.gov/pubmed/26710269
http://dx.doi.org/10.1371/journal.pgen.1005726
work_keys_str_mv AT geyunxia fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT yanxiaodan fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT jinyiguang fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT yangxinyu fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT yuxiang fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT zhouliqing fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT hansichong fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT yuanqipeng fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma
AT yangming fmirna192andmirna204directlysuppresslncrnahottipandinterruptgls1mediatedglutaminolysisinhepatocellularcarcinoma