Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Mol Cancer Res. 2014 Feb;12(2):239-49. doi: 10.1158/1541-7786.MCR-13-0336. Epub 2013 Nov 20.
Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.
Angptl2-induced inflammation increases susceptibility to microenvironmental changes, allowing increased oxidative stress and decreased Msh2 expression; therefore, Angptl2 might be a target to develop new strategies to antagonize these activities in premalignant tissue.
慢性炎症作为致癌因素受到了广泛关注。我们最近报道称，血管生成素样蛋白 2（Angptl2）促进了化学诱导的皮肤鳞状细胞癌（SCC）小鼠模型中的炎症致癌和转移。特别是，我们证明了 Angptl2 诱导的炎症增强了皮肤组织对 SCC 发展中“癌前变化”和“恶性转化”的易感性；然而，其作用机制尚不清楚。使用该模型，我们现在报告称，在皮肤上皮细胞中过表达 Angptl2 的转基因小鼠（K14-Angptl2Tg 小鼠）在这些组织中表现出增强的氧化应激。相反，在该模型的背景下，Angptl2 敲除（KO）小鼠在皮肤组织中表现出明显较低的氧化应激以及 SCC 的发生率明显低于野生型小鼠。在化学诱导的 SCC 模型中，抗氧化剂 N-乙酰半胱氨酸（NAC）治疗 K14-Angptl2Tg 小鼠可显著降低皮肤组织中的氧化应激和 SCC 发展的频率。有趣的是，与野生型小鼠相比，模型中的 K14-Angptl2Tg 小鼠还显示出 DNA 错配修复酶 Msh2 的编码 mRNA 的表达明显降低，并且皮肤组织中 Msh2 启动子的甲基化增加。NAC 处理可显著增加 Tg 小鼠皮肤组织中 Msh2 的表达，并使 Msh2 启动子去甲基化。总体而言，这项研究强烈表明，炎症介质 Angptl2 通过增加皮肤组织中的氧化应激和降低 Msh2 表达来加速化学诱导的致癌作用。
Angptl2 诱导的炎症增加了对微环境变化的易感性，导致氧化应激增加和 Msh2 表达降低；因此，Angptl2 可能是开发针对这些活性的新策略以拮抗癌前组织的靶标。
