MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma

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 mi...

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Published in:Journal of hepatology 2021-01, Vol.74 (1), p.122-134
Main Authors: Komoll, Ronja-Melinda, Hu, Qingluan, Olarewaju, Olaniyi, von Döhlen, Lena, Yuan, Qinggong, Xie, Yu, Tsay, Hsin-Chieh, Daon, Joel, Qin, Renyi, Manns, Michael P., Sharma, Amar Deep, Goga, Andrei, Ott, Michael, Balakrishnan, Asha
Format: Article
Language:English
Subjects:
Animal models
Animals
Biological Transport - drug effects
c-Myc protein
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - therapy
Cell migration
Cell Movement - drug effects
Cell proliferation
Cell Proliferation - drug effects
Disease Models, Animal
Down-Regulation
Gene Expression Regulation, Neoplastic - drug effects
Genes, Tumor Suppressor
Hepatocellular carcinoma
Hepatoma
Humans
Lactate transport
Lactic acid
Lactic Acid - metabolism
Liver cancer
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - therapy
MCT1
Mice
MicroRNAs
MicroRNAs - genetics
MicroRNAs - pharmacology
miRNA
Monocarboxylic Acid Transporters - genetics
Monocarboxylic Acid Transporters - metabolism
MYC
Myc protein
RAS
Symporters - genetics
Symporters - metabolism
Transfection - methods
Treatment Outcome
Tumor suppressor genes
Tumors
Tumour metabolism
Tumour regression
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Summary: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. 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. 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. 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. 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 regre
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2020.07.039