miR-21-5p 促进 NASH 相关的肝癌发生。

miR-21-5p promotes NASH-related hepatocarcinogenesis.

机构信息

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.

出版信息

Liver Int. 2023 Oct;43(10):2256-2274. doi: 10.1111/liv.15682. Epub 2023 Aug 3.

DOI:10.1111/liv.15682

PMID:37534739

Abstract

BACKGROUND AND AIMS

The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis.

METHODS

Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively.

RESULTS

In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis.

CONCLUSIONS

Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.

摘要

背景与目的

非酒精性脂肪性肝病（NAFLD）向脂肪性肝炎（NASH）和肝细胞癌（HCC）进展的机制仍不清楚。在这里，我们评估了 hsa-miRNA-21-5p 在 NASH 相关肝癌发生中的作用。

方法

在两个经活检证实的 NAFLD 患者队列（n=199）或 HCC 患者队列（n=366 个 HCC 和 n=11 个 NAFLD-HCC）中评估肝 hsa-miR-21-5p 的表达。NAFLD 肥胖患者的血清/肝代谢组学谱与 hsa-miR-21-5p 相关。WT 和 Mir21 KO 小鼠分别用胆碱缺乏、氨基酸定义（CDAA）饮食喂养 32 周和 66 周，以诱导 NASH 和 NASH-HCC。

结果

在肥胖个体中，hsa-miR-21-5p 的表达随 NAFLD 严重程度的增加而增加，并与肝脂毒性谱相关。CDAA 喂养的 WT 小鼠显示肝 mmu-miR-21-5p 水平升高，并逐渐发展为 NASH 和纤维化，肝脏出现肉眼可辨别的前瘤性结节、增生灶和失调的癌症相关通路。Mir21 KO 小鼠表现出过氧化物酶体增殖物激活受体α（PPARα）激活、增加的线粒体活性、降低的肝损伤和低于 NASH 诊断阈值的 NAS，促炎/纤维化环境恢复到基线水平。与此同时，Mir21 KO 小鼠的前瘤性结节数量减少，肝细胞增殖和致癌信号激活减少，从而免受 NASH 相关的致癌作用。hsa-miRNA-21-5p/PPARα 通路在 HCC 或 NASH 相关 HCC 患者中也同样失调，与 HCC 标志物和更差的预后相关。