Suppression of skin tumorigenesis in CD109-deficient mice.
Suppression of skin tumorigenesis in CD109-deficient mice.
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DOI：
10.18632/oncotarget.12653
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发表时间：
2016-12-13
期刊：
影响因子：
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通讯作者：
Takahashi M
中科院分区：
文献类型：
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作者：
Sunagawa M;Mii S;Enomoto A;Kato T;Murakumo Y;Shiraki Y;Asai N;Asai M;Nagino M;Takahashi M
CD109是一种糖基磷脂酰肌醇锚定糖蛋白，在几种类型的人类癌症中高度表达，尤其是鳞癌。我们以前报道过CD109基因缺陷的小鼠表现出表皮增生和慢性皮肤炎。虽然我们发现CD109在体内调节角质形成细胞的分化，但CD109在肿瘤发生中的作用仍不清楚。在这项研究中，我们利用CD109基因缺陷的慢性皮肤炎症小鼠的两阶段致癌模型，研究了CD109在皮肤肿瘤发生中的作用。免疫组织化学分析显示CD109基因缺陷小鼠真皮中转化生长因子-β蛋白的表达水平高于野生型小鼠。此外，免疫荧光分析显示CD109缺陷小鼠的原代角质形成细胞中Smad2的磷酸化和Nrf2的表达高于野生型小鼠。虽然在致癌模型中，野生型和CD109缺陷小鼠从乳头状瘤到癌的转化率没有显著差异，但我们观察到CD109缺陷小鼠的乳头状瘤比野生型小鼠更少、更小。与野生型皮肤相比，7，12-二甲基苯(α)蒽处理后24小时，CD109基因缺陷皮肤的细胞凋亡和DNA损伤标志物水平显著降低。此外，突变特异性聚合酶链式反应显示，在该模型中，CD109缺陷皮肤中H-ras基因的突变频率低于野生型皮肤。这些结果提示CD109缺陷通过增强转化生长因子-β/Smad/Nrf2通路的活性和降低H-ras基因突变频率来抑制皮肤肿瘤的发生。
CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-β protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109-deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109-deficient skin compared with in wild-type skin at 24 h after 7, 12-dimethylbenz (α) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-β/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene.