Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
Cancer Lett. 2015 Sep 1;365(2):223-8. doi: 10.1016/j.canlet.2015.05.022. Epub 2015 Jun 5.
We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition.
我们之前报道过，蛋白磷酸酶 6（Ppp6c）催化亚基编码基因的缺失会使小鼠皮肤组织容易形成由 DMBA 引发的乳头瘤。在这里，我们证明 Ppp6c 的缺失是 UVB 诱导的鳞状细胞癌发生中的肿瘤促进剂。在 UVB 照射后，缺乏 Ppp6c 的角质细胞的小鼠比对照小鼠表现出更高的皮肤鳞状细胞癌发生率。时程实验表明，在 UVB 照射后，缺乏 Ppp6c 的角质细胞上调了 p53、PUMA、BAX 和 cleaved caspase-3 蛋白的表达。在缺乏 Ppp6c 的角质细胞中诱导的 UVB 肿瘤显示出高频率的 p53 和 γH2AX 阳性细胞，提示存在 DNA 损伤。流行病学和分子数据强烈表明，来自阳光的 UVB 会诱导角质细胞中的 p53 基因突变，是人类皮肤癌的主要致病因素。我们的分析表明，PP6 缺乏是驱动携带 UVB 诱导突变 p53 的起始角质细胞生长的分子事件的基础。了解 PP6 在预防 UV 诱导的肿瘤发生中的功能可能会为预防和治疗这种情况提供策略。
