Show simple item record

dc.contributor.authorKomoll, Ronja-Melinda
dc.contributor.authorHu, Qingluan
dc.contributor.authorOlarewaju, Olaniyi
dc.contributor.authorvon Döhlen, Lena
dc.contributor.authorYuan, Qinggong
dc.contributor.authorXie, Yu
dc.contributor.authorTsay, Hsin-Chieh
dc.contributor.authorDaon, Joel
dc.contributor.authorQin, Renyi
dc.contributor.authorManns, Michael P
dc.contributor.authorSharma, Amar Deep
dc.contributor.authorGoga, Andrei
dc.contributor.authorOtt, Michael
dc.contributor.authorBalakrishnan, Asha
dc.date.accessioned2020-12-09T10:13:26Z
dc.date.available2020-12-09T10:13:26Z
dc.date.issued2020-07-30
dc.identifier.citationJ Hepatol. 2020 Jul 30:S0168-8278(20)30492-X. doi: 10.1016/j.jhep.2020.07.039. Epuben_US
dc.identifier.pmid32738449
dc.identifier.doi10.1016/j.jhep.2020.07.039
dc.identifier.urihttp://hdl.handle.net/10033/622639
dc.description.abstractBackground & aims: Hepatocellular carcinoma (HCC) is a cancer with multiple aetiologies and widespread prevalence. Largely refractory to current treatments, HCC is the fourth leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) are important regulators in HCCs. We aimed to identify tumour suppressor miRNAs during tumour regression in a conditional c-MYC-driven mouse model (LT2/MYC) of HCC, and to evaluate their therapeutic potential for HCC treatment. Methods: We performed miRNA expression profiling of developed and regressing LT2/MYC tumours and in-depth in vitro gain- and loss-of-function analyses. The effect of adeno-associated virus (AAV) vector-mediated miR-342-3p treatment was evaluated in 3 HCC mouse models. Results: We identified miR-342-3p as a tumour suppressor miRNA in HCC, with increased expression in regressing tumours. Forced miR-342-3p expression in hepatoma cells showed significantly decreased cell proliferation, migration, and colony formation. In vivo administration of AAV-miR-342-3p led to significant attenuation of tumour development and increased overall survival. We identified monocarboxylic acid transporter 1 (MCT1) as a bona fide target of miR-342-3p in HCC. We show that the tumour suppressor role of miR-342-3p is executed partly by modulating the lactate transport function of MCT1. Importantly, we find miR-342-3p downregulated in tumours from patients with HCC compared with matched non-tumour tissues, inversely correlating with MCT1 expression. We observed similar findings in TCGA-LIHC data. Conclusions: In our study, we identified and validated miR-342-3p as a tumour suppressor miRNA in HCC. We demonstrated its therapeutic efficacy in significantly attenuating tumour development, and prolonging survival, in different HCC mouse models. Identification of miR-342-3p as an effective tumour suppressor opens a therapeutic avenue for miRNA-mediated attenuation of HCC development. Lay summary: Hepatocellular carcinoma (HCC), the most common type of liver cancer, affects diverse populations and has a global impact, being the fourth leading cause of cancer deaths worldwide. There are currently no systemic therapies for HCC that can significantly prolong long-term survival. Thus, novel effective treatment options are urgently required. To understand the molecular basis of tumour regression, we compared tumours and regressing liver tumours in mice. We show that a small non-coding miRNA, miR-342-3p, is a tumour suppressor in HCC. Expression of miR-342-3p is low in tumours and high in regressing tumours. When miR-342-3p is delivered to mouse livers with HCC, it can significantly slow down liver tumour development and improve survival. Our study highlights the promising therapeutic potential of miR-342-3p intervention in HCC.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectHepatocellular carcinomaen_US
dc.subjectLactate transporten_US
dc.subjectLiver canceren_US
dc.subjectMCT1en_US
dc.subjectMYCen_US
dc.subjectMicroRNAsen_US
dc.subjectRASen_US
dc.subjectTumour metabolismen_US
dc.subjectTumour regressionen_US
dc.titleMicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma.en_US
dc.typeArticleen_US
dc.identifier.eissn1600-0641
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
dc.identifier.journalJournal of hepatologyen_US
dc.source.journaltitleJournal of hepatology
dc.source.countryNetherlands


Files in this item

Thumbnail
Name:
Publisher version
Thumbnail
Name:
Komoll et al.pdf
Embargo:
2021-07-30
Size:
13.23Mb
Format:
PDF
Description:
original manuscript
Thumbnail
Name:
komoll_JHep_2020_Supplementary ...
Embargo:
2021-07-30
Size:
1.573Mb
Format:
PDF
Description:
supplemental materials

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International