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Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis.

ABSTRACT: Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction and prevention of HCC in cirrhotic patients remains unclear. The phosphorylation status of AMPK (Thr172) was determined by immunostaining in tissue microarrays of 426 cirrhotic liver tissues. Low expression of p-AMPK was observed in 94 (22.1%) cases. The median follow-up time was 87 months. HCC occurrence probability at 1/3/5/10 years after Hassab procedure was 3.1/9.6/13.8/30.6% in patients with p-AMPK low expression and 0/0.3/0.3/8% in patients with p-AMPK high expression, respectively. HCC occurrence risk was significantly higher in patients with p-AMPK low expression in univariable analysis (HR, 6.25; 95% CI: 3.36-11.60; P?

SUBMITTER: Yang X

PROVIDER: S-EPMC5833839 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis.

Yang Xiaoli X Liu Yan Y Li Menghui M Wu Hao H Wang Yunbing Y You Yu Y Li Peizhi P Ding Xiong X Liu Chang'an C Gong Jianping J

Cell death & disease 20180215 3

Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction and prevention of HCC in cirrhotic patients remains unclear. The phosphorylation status of AMPK (Thr172) was determined by immunostaining in tissue microarrays of 426 cirrhotic liver tissues. Low expression of p-AMPK was observed in 94 (22.1%) cases. The median follow-up time was 87 months. HCC occu ...[more]

PMID: 29449537

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Project description:Abstract Background and Aim Polypharmacy and sarcopenia are increasing public health problems worldwide. However, data on the prevalence, association, and prognostic significance of polypharmacy and sarcopenia in patients with liver cirrhosis are limited. Methods Polypharmacy and sarcopenia were assessed in 239 patients with liver cirrhosis. Polypharmacy was defined as the daily use of six or more medications, and sarcopenia was diagnosed based on muscle strength and mass evaluated on computed tomography. The association between polypharmacy and sarcopenia and their effects on mortality were analyzed using logistic regression and Cox proportional hazards models. Results Among the 239 patients, 52% were men, the median age was 68 years, and the number of medications used per patient was 6. Further, 53% and 29% patients had polypharmacy and sarcopenia, respectively. The number of medications used and the prevalence of sarcopenia increased with age. Patients with polypharmacy and sarcopenia had similar characteristics, such as older age, increased medication use, advanced liver disease, and decreased muscle strength and mass. After adjusting for confounders, polypharmacy was significantly associated with sarcopenia (odds ratio, 2.11; 95% confidence interval [CI], 1.07–4.17). During the median follow‐up of 2.2 years, 62 (26%) patients died. Polypharmacy (hazard ratio [HR], 1.83; 95% CI, 1.01–3.37) and sarcopenia (HR, 2.00; 95% CI, 1.12–3.50) independently predicted mortality. The prognostic significance of polypharmacy was more prominent in older adults than in younger adults (HR, 2.31; 95% CI, 1.01–5.67). Conclusion Polypharmacy and sarcopenia are interrelated and associated with poor prognosis in patients with cirrhosis. Further large, prospective, population‐based studies are required to validate these findings. Polypharmacy and sarcopenia are increasing public health problems worldwide, but the prevalence, association, and prognostic significance of polypharmacy and sarcopenia in patients with liver cirrhosis remain unclear. Our data indicate that polypharmacy and sarcopenia are common, interconnected, and associated with mortality in patients with cirrhosis.

Project description:Autophagy is a pathophysiological phenomenon in liver cirrhosis that can further progress into hepatocarcinoma. Liver cancer stem cells (CSCs) are believed to initiate hepatocarcinogenesis. To investigate the precise mechanism related to the origin of CSCs in liver cirrhosis and hepatocarcinogenesis, we labeled Axin2+ hepatic cells with EGFP in Axin2Cre;Rosa26EGFP transgenic rats, and then stratified clinical and rat liver cirrhosis samples by autophagy flux. Clinical follow-up and lineage tracing in transgenic rat liver cirrhosis revealed that while Axin2/EGFP+ hepatic cells were present in normal livers and cirrhotic livers without aberrant autophagy, hepatic Axin2/EGFP+CD90+ cells were generated exclusively in cirrhotic livers with aberrant autophagy and promoted hepatocarcinogenesis. Aberrant autophagy in liver cirrhosis resulted in hepatocyte growth factor (HGF) expression, leading to activation of Met/JNK and Met/STAT3 signaling in sorted hepatic Axin2/EGFP+ cells and their transition into Axin2/EGFP+CD90+ cells that possess CSC properties. In a transgenic rat liver cirrhosis model, induction or inhibition of autophagy in cirrhotic livers by systemic administration of rapamycin or chloroquine or transfection with Atg3- and Atg7-shRNAs significantly induced or suppressed HGF expression, which in turn increased or reduced generation of EGFP+CD90+ hepatic cells by activating or inactivating Met/JNK and Met/STAT3 signaling, thereby promoting or preventing hepatocarcinogenesis. Systemic treatment with HGF-shRNA, SP600125 or stattic also reduced generation of EGFP(Axin2)+ hepatic cell-originated CD90+ CSCs in aberrant autophagic cirrhotic livers by inactivating HGF/Met/JNK or HGF/Met/STAT3 signaling, further preventing hepatocarcinogenesis. These data suggest that activation of Met/JNK and Met/STAT3 signaling in Axin2+ hepatic cells via autophagy-dependent HGF expression and the resultant generation of Axin2+CD90+ CSCs is a major mechanism of hepatocarcinogenesis in cirrhotic livers.

Project description:BackgroundThe relationship between hepatitis B surface antigen (HBsAg)-positive carrier status and liver cancer has been extensively studied. However, the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown. The epigenetic modification of DNA hydroxymethylation is critical in tumor development. Further, 5-hydroxymethylcytosine (5hmC) is an important base for DNA demethylation and epigenetic regulation. It is also involved in the assembly of chromosomes and the regulation of gene expression. However, the mechanism of action of 5hmC in HBsAg-positive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated.AimTo investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma (HCC) progression from cirrhosis.MethodsForty HBsAg-positive carriers, forty patients with liver cirrhosis, and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants. Free DNA was extracted using a cf-DNA kit. cfDNA was extracted by 5hmC DNA sequencing for principal component analysis, the expression profiles of the three groups of samples were detected, and the differentially expressed genes (DEGs) modified by hydroxymethylation were screened. Bioinformatic analysis was used to enrich DEGs, such as in biological pathways.ResultsA total of 16455 hydroxymethylated genes were identified. Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients, of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers. Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes, of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis. These genes may have potential loci that are undiscovered or unelucidated, which contribute to the development and progression of liver cancer. Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion. The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2.ConclusionThe occurrence and development of liver cancer involves multiple genes and pathways, which may be potential targets for preventing hepatitis B carriers from developing liver cancer.

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Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis.

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Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis.

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