Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells

被引:13
作者
Wang, Min-Jun [1 ]
Chen, Jia-Jia [1 ]
Song, Shao-Hua [2 ]
Su, Jing [1 ]
Zhao, Ling-Hao [3 ]
Liu, Qing-Gui [1 ]
Yang, Tao [1 ]
Chen, Zhiwen [4 ]
Liu, Chang [4 ]
Fu, Zhi-Ren [2 ]
Hu, Yi-Ping [1 ]
Chen, Fei [1 ]
机构
[1] Second Mil Med Univ, Dept Cell Biol, Ctr Stem Cell & Med, Navy Med Univ, Shanghai, Peoples R China
[2] Shanghai Jiao Tong Univ, Dept Gen Surg, Liver Transplantat Ctr, Ruijin Hosp,Sch Med, Shanghai, Peoples R China
[3] Second Mil Med Univ, Natl Ctr Liver Canc, Eastern Hepatobiliary Surg Hosp, Shanghai, Peoples R China
[4] Fudan Univ, State Key Lab Genet Engn, Sch Life Sci, Shanghai, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
SIRT1; hepatocellular carcinoma; liver cancer stem cells; cellular senescence; stemness; self-renewal; TUMOR-INITIATING CELLS; CELLULAR SENESCENCE; PROMOTES; DISEASE; CHEMORESISTANCE; MAINTENANCE; ACTIVATION; RESISTANCE; TARGET; AXIS;
D O I
10.2147/JHC.S296234
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investi-gate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer. Methods: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1. Results: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, down-regulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abil-ities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more suscep-tible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated beta-galactosidase (SA-beta-Gal) activity but lower proliferative capacity. Conclusion: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.
引用
收藏
页码:685 / 699
页数:15
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