MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma
MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2020.07.039
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发表时间：
2021-01-01
影响因子：
25.7
通讯作者：
Balakrishnan, Asha
中科院分区：
文献类型：
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作者：
Komoll, Ronja-Melinda;Hu, Qingluan;Balakrishnan, Asha
背景与目的：肝细胞癌（Hepatocellular carcinoma，HCC）是一种病因复杂、发病率高的恶性肿瘤. HCC对目前的治疗几乎是难治性的，是全世界癌症相关死亡的第四大原因。microRNAs（miRNAs）是HCC中重要的调控因子。我们的目的是确定在肿瘤消退过程中的肿瘤抑制miRNA的条件c-MYC驱动的小鼠模型（LT 2/MYC）的HCC，并评估其治疗潜力HCC treatment.Methods：我们进行了miRNA表达谱的开发和消退LT 2/MYC肿瘤和深入的体外增益和功能丧失分析。在3个HCC小鼠模型中评估腺相关病毒（AAV）载体介导的miR-342 - 3 p治疗的效果。肝癌细胞中的miR-342- 3 p强制表达显示细胞增殖、迁移和集落形成显著降低。体内施用AAV-miR-342- 3 p导致肿瘤发展的显著减弱和总存活率的增加。我们确定了一元羧酸转运蛋白1（MCT 1）作为HCC中miR-342- 3 p的真正靶点。我们发现miR-342- 3 p的肿瘤抑制作用部分是通过调节MCT 1的乳酸转运功能来实现的。重要的是，我们发现与匹配的非肿瘤组织相比，HCC患者的肿瘤中miR-342- 3 p下调，与MCT 1表达呈负相关。我们在TCGA-LIHC data.Conclusions中观察到了类似的发现：在我们的研究中，我们鉴定并验证了miR-3423 p作为HCC中的肿瘤抑制miRNA。我们在不同的HCC小鼠模型中证明了其在显着减弱肿瘤发展和延长生存期方面的治疗效果。miR-342- 3 p作为一种有效的肿瘤抑制因子的鉴定为miRNA介导的HCC发展的减毒开辟了一条治疗途径。肝细胞癌（HCC）是最常见的肝癌类型，影响不同的人群并具有全球影响，是全球癌症死亡的第四大原因。目前没有可以显著延长长期生存期的HCC系统性治疗。因此，迫切需要新的有效治疗方案。为了了解肿瘤消退的分子基础，我们比较了小鼠的肿瘤和消退的肝肿瘤。我们发现一种小的非编码miRNA，miR-342- 3 p，是HCC的肿瘤抑制因子。miR-342- 3 p在肿瘤中的表达较低，而在消退肿瘤中的表达较高。当miR-342- 3 p被递送到患有HCC的小鼠肝脏时，它可以显着减缓肝脏肿瘤的发展并提高生存率。我们的研究强调了miR-342- 3 p干预HCC的治疗潜力。(C)2020年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & 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 adenoassociated 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-3423p 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 noncoding 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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.