The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China.
Free Radic Biol Med. 2022 Aug 1;188:447-458. doi: 10.1016/j.freeradbiomed.2022.06.240. Epub 2022 Jul 6.
MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast cancer stemness has not been reported yet. Here, we constructed breast cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44CD24 subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT-qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2, Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1-knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast cancer stem cells (BCSCs) and promoted stemness properties in MCF7 cells.
MTH1 蛋白可以清除受损的（d）NTP 池，并且已经开发出 MTH1 抑制剂来阻碍快速增殖的肿瘤细胞的生长；然而，MTH1 抑制对乳腺癌干细胞特性的影响尚未报道。在这里，我们构建了稳定耗尽 MTH1 的乳腺癌细胞系。MTH1 抑制明显增加了 CD44CD24 亚群的比例，并促进了 MCF7 和 T47D 细胞肿瘤球的形成。RNA 表达谱、RT-qPCR 和 Western blot 显示 MTH1 敲低细胞中主干细胞转录因子 Sox2、Oct4 和 Nanog 的上调。GSEA 表明并通过 Western blot 验证，MTH1 敲低增加了磷酸化 STAT3（Tyr705）的表达。此外，我们间接证明 MTH1 敲低细胞中 8-oxo-dGTP 和 8-oxo-GTP 的浓度增加，以及外源性 8-oxoGTP 而不是 8-oxo-dGTP，可显著增加 STAT3 的磷酸化。总之，这项工作表明 MTH1 抑制增加了乳腺癌干细胞（BCSCs）的比例，并促进了 MCF7 细胞的干细胞特性。
