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The Murine Choline-Deficient, Ethionine-Supplemented CDE Diet Model of Chronic Liver Injury
Published on: October 21, 2017
NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which
Mark Williams1,2, Xinhui Liu1,3,4, Yueqi Zhang1,2
1Department of Physiology, Michigan State University, East Lansing, Michigan, 48824, USA.
Abstract:
Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5+/- mouse model of HCC, which is characterized by altered expression of a subset of genes including p21WAF1/CIP1 and proinflammatory cytokine genes, increased putative hepatic progenitors, and expansions of activated and tissue-resident memory (TRM) CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs), and alternatively activated M2 macrophages. Importantly, prophylactic metformin treatment reversed these characteristics including aberrant p21WAF1/CIP1 expression and subsequently reduced HCC incidence in Ncoa5+/- male mice. Heterozygous deletion of the p21WAF1/CIP1 gene alleviated the key features associated with the protumorigenic niche in the livers of Ncoa5+/- male mice. Moreover, transcriptomic analysis reveals that preneoplastic livers of Ncoa5+/- mice are similar to the livers of nonalcoholic steatohepatitis patients as well as the adjacent noncancerous liver tissues of a subset of HCC patients with a relatively poor prognosis. Together, our results suggest that p21WAF1/CIP1 overexpression is essential in the development of protumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21WAF1/CIP1 overexpression and protumorigenic microenvironment.
Insights
Metformin prevents hepatocellular carcinoma (HCC) by reversing a protumorigenic liver microenvironment in Ncoa5+/- mice. This involves normalizing p21WAF1/CIP1 expression and reducing inflammation, offering new therapeutic strategies for HCC prevention.
Area of Science:
- Hepatology and Cancer Biology
- Immunology
- Molecular Mechanisms of Disease
Background:
- Limited prevention and treatment options for hepatocellular carcinoma (HCC) necessitate understanding its molecular drivers.
- Ncoa5 deficiency in mice creates a protumorigenic liver niche, characterized by specific gene expression changes and immune cell infiltration.
Purpose of the Study:
- To investigate the molecular mechanisms of HCC development in Ncoa5+/- mice.
- To evaluate the potential of metformin as a preventive agent against HCC.
- To identify key molecular targets for HCC prevention and treatment.
Main Methods:
- Utilized a Ncoa5+/- mouse model of HCC.
- Analyzed liver tissue for gene expression, progenitor cells, and immune cell populations (CD8+ T lymphocytes, MDSCs, M2 macrophages).
- Administered prophylactic metformin and assessed its effects on HCC incidence and the protumorigenic niche.
- Investigated the role of p21WAF1/CIP1 by generating Ncoa5+/- mice with heterozygous deletion of the p21WAF1/CIP1 gene.
- Performed transcriptomic analysis to compare mouse models with human liver disease.
Main Results:
- Ncoa5+/- mice developed a protumorigenic liver niche with altered p21WAF1/CIP1 expression and specific immune cell expansions.
- Metformin treatment reversed these protumorigenic characteristics and reduced HCC incidence in Ncoa5+/- male mice.
- Genetic deletion of p21WAF1/CIP1 alleviated key features of the protumorigenic niche.
- Transcriptomic data revealed similarities between preneoplastic Ncoa5+/- livers and human nonalcoholic steatohepatitis and HCC tissues.
Conclusions:
- p21WAF1/CIP1 overexpression is crucial for developing the protumorigenic microenvironment in Ncoa5-deficient livers.
- Metformin prevents HCC development by mitigating p21WAF1/CIP1 overexpression and the associated protumorigenic microenvironment.
- The findings suggest p21WAF1/CIP1 as a potential therapeutic target for HCC prevention and treatment.
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