miR-21-5p promotes NASH-related hepatocarcinogenesis
© 2023 The Authors. Liver International published by John Wiley & Sons Ltd..
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.
| Errataetall: |
CommentIn: Liver Int. 2023 Nov;43(11):2343-2345. - PMID 37846804 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Liver international : official journal of the International Association for the Study of the Liver - 43(2023), 10 vom: 03. Okt., Seite 2256-2274 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rodrigues, Pedro M [VerfasserIn] |
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| Links: |
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| Themen: |
93-71-0 |
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| Anmerkungen: |
Date Completed 19.09.2023 Date Revised 26.10.2023 published: Print-Electronic CommentIn: Liver Int. 2023 Nov;43(11):2343-2345. - PMID 37846804 Citation Status MEDLINE |
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| doi: |
10.1111/liv.15682 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360344852 |
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| 100 | 1 | |a Rodrigues, Pedro M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a miR-21-5p promotes NASH-related hepatocarcinogenesis |
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| 500 | |a Date Completed 19.09.2023 | ||
| 500 | |a Date Revised 26.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Liver Int. 2023 Nov;43(11):2343-2345. - PMID 37846804 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Liver International published by John Wiley & Sons Ltd. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 650 | 7 | |a MicroRNAs |2 NLM | |
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| 700 | 1 | |a Santos-Laso, Álvaro |e verfasserin |4 aut | |
| 700 | 1 | |a Izquierdo-Sanchez, Laura |e verfasserin |4 aut | |
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| 700 | 1 | |a Eizaguirre, Emma |e verfasserin |4 aut | |
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