Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells
Authors: Qing-Gui Liu
Zhiwen Chen
Chang Liu
Ling-Hao Zhao
Tao Yang
Shao-Hua Song
Fei Chen
Jing Su
Min-Jun Wang
Yi-Ping Hu
Jia-Jia Chen
Zhi-Ren Fu
Journal: Journal of Hepatocellular Carcinoma (2021)
Discipline: CLINICAL MEDICINE
Keywords: SIRT1; cellular senescence; hepatocellular carcinoma; liver cancer stem cells; self-renewal
Affiliations: Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Navy Medical University), Shanghai, People's Republic of China., Department of General Surgery, Liver Transplantation Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China., National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China., State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.

Abstract:  Purpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investigate 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, downregulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abilities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more susceptible 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 Œ≤-galactosidase (SA-Œ≤-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. 

Retracted: No

PubPeer comments:
 Figures 2G and 2H appear to have images which overlap. ***  , 
 Figure 4C ***  , 
 The issues above were reported to the journal via email in June 2021. I did not see any update when I checked just now. However, I have found additional cause for concern. Three images in Figure 4H seem to overlap with images in Figure 4B , after rotation, of a paper in PloS one (2015), doi: 10.1371 journal.pone.012096, discussed here (for unrelated concerns): https: pubpeer.com publications 920C52F79FDCA96F22001065710845. I did not look further. ***  ,