大阪公立大学大学院医学研究科病態生理学Department of Pathophysiology,Osaka Metropolitan University Graduate School of Medicine― 177 ―Viral hepatocarcinogenesis, which used to account for more than half of all hepatocarcinoma, has been on the decline due to the development of useful viral drugs. On the other hand, obesity-induced hepatocarcinogenesis, which is caused by obesity and diabetes, is on the rise, and elucidation of the pathogenic mechanism and identification of therapeutic targets are urgent issues. Previously, we have established a model of obesity-induced hepatocarcinogenesis. Using this model, we have reported that obesity-increased gut microbiota-derived metabolites induce cellular senescence of hepatic stellate cells and promote the release of SASP (senescence-associated secretory phenotype) factor, which induces hepatic stellate cells to function as CAFs (cancer-associated fibroblasts) and form a tumor-promoting microenvironment 1-3). In this study, we aimed to find a way to regulate these CAF-activated hepatic stellate cell by isolating hepatic stellate cell from normal mouse liver and tumor and non-tumor areas of obesity-induced hepatocarcinoma and performing single-cell RNA-seq analysis. We also performed pseudotime analysis, in which cells are sequentially arranged based on the similarity of gene expression, to obtain information on the continuous changes in cell characteristics. We then searched for upstream factors that regulate the genes by enrichment analysis, and extracted five transcription factors as candidates for upstream factors. Knockdown of these candidate factors extracted by enrichment analysis in senescent hepatic stellate cells isolated from the tumor region of hepatocellular carcinoma was performed, and suppression of SASP factor expression was confirmed. In the future, we will evaluate the function of the factors involved in the suppression of CAF-activation and their potential as therapeutic targets by using an in vivo system with an obesity-induced liver cancer model.Abstractobesity-induced liver cancer using bioinformatics analysisバイオインフォマティクス解析を用いた肥満誘導性肝がん新規治療標的の探索Identification for new therapeutic targets for山岸 良多Ryota Yamagishi
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