Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells.
Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells.
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DOI：
10.2147/jhc.s296234
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发表时间：
2021
影响因子：
4.1
通讯作者：
Chen F
中科院分区：
文献类型：
--
作者：
Wang MJ;Chen JJ;Song SH;Su J;Zhao LH;Liu QG;Yang T;Chen Z;Liu C;Fu ZR;Hu YP;Chen F
肿瘤干细胞（cancer stem cells，CSCs）被认为与肝细胞癌（hepatocellular carcinoma，HCC）的发生、局部复发和治疗耐药有关。探索新的、有效的靶向肝肿瘤干细胞的方法对于肝癌的永久治愈至关重要。检测SIRT 1在肝癌组织和癌细胞系中的表达水平。用SIRT 1抑制剂检测肝CSC标志物的表达、自我更新和致瘤能力。细胞衰老相关标志物用于检测SIRT 1抑制后CSC的衰老。SIRT 1在肝癌细胞系和人肝癌组织的CSC中高表达。体外研究表明，SIRT 1水平的降低可显著下调肝CSC干细胞相关基因的表达，降低CSC干细胞特性。此外，下调SIRT 1通过降低其自我更新能力来抑制肝CSC增殖。此外，SIRT 1表达降低的CSC显示出有限的致瘤性，并在体内形成较小的HCC肿瘤。SIRT 1降低了CSC对化疗药物的敏感性。SIRT 1通过激活p53-p21和p16信号通路抑制CSC的衰老。数据进一步表明，由SIRT 1敲低的CSC形成的肿瘤表现出更高的衰老相关β-半乳糖苷酶（SA-β-Gal）活性，但增殖能力较低。综上所述，这些研究结果表明，诱导肝CSCs衰老是一种有效的肝癌抑制方法，SIRT 1可能成为肝癌治疗的一个有希望的靶点。
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. 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. 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 β-galactosidase (SA-β-Gal) activity but lower proliferative capacity. 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.