Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20852, USA.
Cell Stem Cell. 2012 Sep 7;11(3):401-14. doi: 10.1016/j.stem.2012.06.007.
The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.
表皮和黏膜上皮的完整性高度依赖于常驻的自我更新干细胞，这使得它们容易受到物理和化学损伤，从而损害上皮干细胞隔室的再生能力。在接受放疗或化疗的癌症患者中，这种情况很常见，其中许多患者会出现黏膜炎，这是一种使人虚弱的疾病，涉及疼痛和深部黏膜溃疡。在这里，我们表明，用雷帕霉素抑制哺乳动物雷帕霉素靶蛋白 (mTOR) 通过防止干细胞衰老来增加原代人口腔角质形成细胞及其常驻自我更新细胞的集落形成能力。雷帕霉素的这种保护作用是通过增加线粒体超氧化物歧化酶 (MnSOD) 的表达来介导的，从而抑制 ROS 的形成和氧化应激。mTOR 抑制也可以防止体内电离辐射导致增殖性基底上皮干细胞丢失，从而保持口腔黏膜的完整性并防止辐射诱导的黏膜炎。
