Data from Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Abstract

<div>Abstract<p>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-<i>Angptl2</i> Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, <i>Angptl2</i> 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-<i>Angptl2</i> Tg mice with the antioxidant <i>N</i>-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-<i>Angptl2</i> 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 <i>Msh2</i> promoter in skin tissues. <i>Msh2</i> expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was <i>Msh2</i> promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased <i>Msh2</i> expression in skin tissue.</p><p><b>Implications:</b> 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. <i>Mol Cancer Res; 12(2); 239–49. ©2013 AACR</i>.</p></div>