miR‐21‐5p promotes NASH‐related hepatocarcinogenesis

Abstract

Background and AimsThe 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.MethodsHepatic 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.ResultsIn 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.ConclusionsHsa‐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.

Absolute Quantification of Selected microRNAs Expression in Endometrial Cancer by Digital PCR

“…However, obesity and changes in miRNAs were described in previous works as a cancer risk factor [ 55 ]. Rodrigues et al also showed increased miR-21-5p expression in obese individuals with hepatocarcinogenesis [ 56 ].…”

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

“…The reduction of miR-122 has been identified as a direct inducer of MASH-associated HCC [ 51 ]. Likewise, research conducted by Rodrigues et al revealed that miR-21 acts as a crucial instigator of the whole-spectrum MASLD advancement and assumes an equally significant part in the evolution of MASLD to HCC [ 52 ]. It is worth mentioning that several miRNAs are differentially expressed in the transitions from MASLD to MASH to HCC, with some being overexpressed in tumors (miR-155, miR-193b, miR-182) while others are downregulated in HCC (miR-20a, miR-200c, miR-483) [ 53 , 54 , 55 ].…”