2. Academic Validation
  3. Inhibition of SIRT1 relieves hepatocarcinogenesis via alleviating autophagy and inflammation

Inhibition of SIRT1 relieves hepatocarcinogenesis via alleviating autophagy and inflammation

  • Int J Biol Macromol. 2024 Jul 27;278(Pt 1):134120. doi: 10.1016/j.ijbiomac.2024.134120.
Xiu-Tao Fu 1,  Jing-Bo Qie 2,  Jia-Feng Chen 1,  Zheng Gao 1,  Xiao-Gang Li 1,  Shan-Ru Feng 1,  En-Fu Dong 1,  Ying-Hong Shi 1,  Zheng Tang 1,  Wei-Ren Liu 1,  Xin Zhang 1,  Ao Huang 1,  Xuan-Ming Luo 3,  Wei-Xun Wu 4,  Qiang Gao 1,  Jian Zhou 5,  Tian Li 6,  Jia Fan 5,  Zhen-Bin Ding 7
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
  • 2 Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 3 Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 4 Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
  • 5 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 6 School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: fmmult@foxmail.com.
  • 7 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China; Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China. Electronic address: ding.zhenbin@zs-hospital.sh.cn.
PMID: 39074701 DOI: 10.1016/j.ijbiomac.2024.134120
Abstract

Imbalanced Sirtuin 1 (SIRT1) levels may lead to liver diseases through abnormal regulation of Autophagy, but the roles of SIRT1-regulated Autophagy in hepatocellular carcinoma are still controversial. In this study, we found that SIRT1 mRNA and protein levels were upregulated in hepatocellular carcinoma, and high SIRT1 expression hinted an advanced stage and a poor prognosis. The differentially expressed proteins were significantly elevated in Autophagy, cellular response to stress, and immune signaling pathways. In a thioacetamide-induced hepatocellular carcinoma mouse model, we found that SIRT1 expression was highly increased with increased Autophagy and excessive macrophage inflammatory response. Next, we established a Hepa 1-6 cells and macrophage co-culture system in vitro to model the alteration of tumor microenvironment, and found that the medium from CCl4-treated or SIRT1-overexpressing Hepa 1-6 cells triggered the polarization of macrophage M1, and the culture medium derived from M1 macrophage promoted Hepa 1-6 cells growth and intracellular oxidative stress. The progression of liver fibrosis in the CCl4-induced liver fibrosis mouse model showed that inhibition of SIRT1 alleviated inflammatory response and ameliorated liver fibrosis. These findings suggest that SIRT1-regulated Autophagy and inflammation are oncogenic in hepatocarcinogenesis.

Keywords

Hepatocarcinogenesis; Inflammation; Sirtuin 1 (SIRT1).

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