Role of SIRT2 in Regulation of Stemness of Cancer Stem-Like Cells in Renal Cell Carcinoma
Background/Aims: Cancer stem cells (CSCs) contribute to tumorgenesis, invasion and metastasis, and are typically resistant to chemotherapy. Recent reports showed that SIRT2 was upregulated in several cancers. However, whether SIRT2 may be a CSC marker in renal cell carcinoma (RCC) is not clear. Methods: The SIRT2 levels in both RCC samples and the corresponding normal kidney samples (NT) were assessed by RT-qPCR and ELISA. The association between SIRT2 levels and patient survival was examined using Bivariate correlation analysis by Spearman’s Rank Correlation Coefficients. The survival of the patients was analyzed using Kaplan-Meier curve. In vitro, 2 RCC cell lines were co-transduced with a lentivirus expressing both a green fluorescent protein and a luciferase reporter under a cytomegalovirus promoter, and another lentivirus expressing a nuclear red fluorescent protein reporter under the control of a SIRT2 promoter for differentiating SIRT2+ vs SIRT2- RCC cells by flow cytometry. The SIRT2+ vs SIRT2- RCC cells were examined for the potential of forming tumor sphere in a tumor sphere formation assay, resistance to fluorouracil-induced apoptosis by CCK-8 assay, and the frequency of forming tumor in vivo after serial adoptive transplantation by bioluminescence. Results: The levels of SIRT2 were higher in RCC samples than NT. The prognosis of RCC patients with high SIRT2 was worse than that of with low SIRT2. Compared to SIRT2- cells, SIRT2+ cells formed more tumor spheres, appeared to be more resistant towards fluorouracil-induced apoptosis, and generated bigger tumors with higher frequency after serial adoptive transplantation. Conclusion: SIRT2 may be highly expressed in the RCC stem-like cells and regulates cancer metastasis. Selective knockout of SIRT2 or elimination of SIRT2+ cells may improve the therapeutic outcome for patients with RCC.