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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.accessioned2020-12-02T12:41:01Z
dc.date.available2020-12-02T12:41:01Z
dc.date.issued2021-01-01
dc.identifier.citationJ Hepatol. 2020 Jul 30:S0168-8278(20)30492-X. doi: 10.1016/j.jhep.2020.07.039. Epub ahead of print.en_US
dc.identifier.issn01688278
dc.identifier.doi10.1016/j.jhep.2020.07.039
dc.identifier.urihttp://hdl.handle.net/10033/622628
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.description.sponsorshipDeutsche Krebshilfeen_US
dc.language.isoenen_US
dc.rightsAttribution-NonCommercial 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/*
dc.subjectHepatocellular carcinomaen_US
dc.subjectLactate transporten_US
dc.subjectLiver canceren_US
dc.subjectMCT1en_US
dc.subjectMicroRNAsen_US
dc.subjectMYCen_US
dc.subjectRASen_US
dc.subjectTumour metabolismen_US
dc.subjectTumour regressionen_US
dc.titleMicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinomaen_US
dc.typeArticleen_US
dc.identifier.eissn16000641
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.identifier.eid2-s2.0-85093503509
dc.identifier.scopusidSCOPUS_ID:85093503509
dc.identifier.piiS016882782030492X
dc.source.volume74
dc.source.issue1
dc.source.beginpage122
dc.source.endpage134
dc.source.journaltitleJournal of Hepatology


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