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

miR-21-5p promotes NASH-related hepatocarcinogenesis

Pedro M Rodrigues  1   2   3   4 , Marta B Afonso  1 , André L Simão  1 , Tawhidul Islam  1 , Maria M Gaspar  1 , Colm J O'Rourke  5 , Monika Lewinska  5 , Jesper B Andersen  5 , Enara Arretxe  6 , Cristina Alonso  6 , Álvaro Santos-Laso  2 , Laura Izquierdo-Sanchez  1   2 , Raúl Jimenez-Agüero  2 , Emma Eizaguirre  2 , Luis Bujanda  2   3 , Maria J Pareja  7 , Carina Prip-Buus  8 , Jesus M Banales  2   3   4   9 , Cecília M P Rodrigues  1 , Rui E Castro  1
Affiliations

miR-21-5p promotes NASH-related hepatocarcinogenesis

Pedro M Rodrigues et al. Liver Int. 2023 Oct.

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.

Keywords: HCC; NASH; PPARα; hsa-miR-21-5p; lipid metabolism.

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