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Doctoral thesis
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microRNAs in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Number of pages536
Imprimatur date2023
Defense date2023
Abstract

Metabolic (dysfunction)-associated liver disease (MAFLD) is a metabolic disorder that affects around 25% of worldwide population. MAFLD initiates with the excessive lipid accumulation in hepatocytes, i.e. steatosis. Without lifestyle alterations, steatosis may progress to chronic steatohepatitis and fibrosis and subsequently to cirrhosis. These late stages of MAFLD become life-threatening to patients due to portal hypertension and increased risk of liver failure. The numerous alterations occurring in pre-cirrhotic and cirrhotic stages also support the development of hepatocellular carcinoma (HCC), the most prevalent liver cancer with high mortality rates due to the lack of effective treatment options. Multiple molecular actors that are yet understudied have an impact on MAFLD/HCC formation and progression, which emphasizes the importance of properly diagnosing and treating MAFLD/HCC.

MicroRNAs (miRNAs) have gained interest recently as potential therapeutic agents for a number of diseases. By inducing messenger RNAs (mRNAs) to degrade or by preventing their translation, these small non-coding RNAs control the expression of genes. Their dysregulation is highly correlated with a number of hepatic diseases, including steatosis, steatohepatitis/fibrosis, and HCC, as a result of their participation in several physiological processes. Previous studies have described the contribution of particular miRNAs to the metabolic dysregulations seen in pre-cancerous phases, but several other miRNAs remain to be investigated, as well as their function upon hepatocarcinogenesis.

In this project, we investigated the contribution of two different miRNAs, i.e. miR-149 and miR-21, to the development and progression of MAFLD and HCC, respectively. We concentrated on defining miR-21 action in hepatocarcinogenesis developing or not from a background of metabolic dysfunction. Our findings showed that the downregulation of miR-149 restrained the development of hepatic steatosis, as well as hepatic inflammation and fibrosis, in two mouse models of diet-induced MAFLD, through pleotropic mechanisms that remain to be further investigated. Conversely, the loss of miR-21 promoted HCC development, but not its progression, in two distinct mouse models of carcinogenesis due to dysregulation of pro-oncogenic/pro-inflammatory signalling pathways, disturbed inflammatory/immune responses, as well as enhancement of cell proliferation/cycle progression and oncogene expression. Our findings suggested that miR-149 contributes to the development and progression of MAFLD, while miR-21 might inhibit hepatic inflammation and regulate immune cell/inflammatory responses to prevent HCC development.

The findings of our two studies suggested that both miR-21 and miR-149 may play a contradictory role in the onset of hepatic diseases. These two miRNAs could be silenced to improve hepatic steatosis, inflammation, and fibrosis in the early stages of MAFLD. However, this would be harmful in a pre-cancerous setting because it could foster the development of HCC. Nevertheless, these observations highlight the complex and pleotropic action of miRNAs in progressive hepatic pathologies that should be widely investigated prior to being considered as therapeutic candidates in patients diagnosed with MAFLD/HCC.

eng
Keywords
  • MicroRNAs
  • MAFLD
  • HCC
  • Steatosis
  • Steatohepatitis
  • Fibrosis
  • MiRs
Citation (ISO format)
CORREIA DE SOUSA, Marta. microRNAs in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma. 2023. doi: 10.13097/archive-ouverte/unige:170321
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Creation07/14/2023 11:45:22 AM
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