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

• Published in: Journal of hepatology Vol. 74; no. 1; pp. 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: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Elsevier Science Ltd
• 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; Liver cancer; RAS; MicroRNAs; MYC; MCT1; Tumour regression; Hepatocellular carcinoma; Lactate transport; Tumour metabolism
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2020.07.039

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 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. [Display omitted] •Distinct global microRNA landscape in regressing liver tumours compared with tumours.•Identification and validation of miR-342-3p as a tumour suppressor in HCCs.•MiR-342-3p significantly attenuates tumour development in 3 mouse models of HCC.•MiR-342-3p prolongs survival of LT2/MYC and LT2/RAS mice with liver tumours.•MiR-342-3p plays a role in metabolic reprogramming in HCC, by targeting MCT1.