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

Motoyoshi Endo,Tsuyoshi Kadomatsu,Tetsuro Masuda,Haruki Horiguchi,Tomohiro Sawa,Jun Aoi,Satoshi Hirakawa,Masatoshi Jinnin,Keishi Miyata,Takaaki Akaike,Yuichi Oike,Satoshi Fukushima,Aki Ogata,Hironobu Ihn,Haruki Odagiri

doi:10.1158/1541-7786.mcr-13-0336

Abstract

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.

Highlights

The connection between cancer and inflammation was first made in the 19th century [1]
Angiopoietin-like protein 2 (Angptl2) expression in skin tissue increases inflammation and accelerates carcinogenesis by enhancing susceptibility to both "pre-neoplastic change" and "malignant conversion." Our conclusion was based on studies using a skin carcinogenesis mice model employing DMBA/PMA treatment [7], a well-characterized model in which an initiating oncogenic mutation is followed by accumulation of additional oncogenic mutations [8,9,10]
Findings reported here suggest that Angptl2 expression induces skin inflammation and likely accelerates acquisition of oncogenic mutations resulting in carcinogenesis

Summary

Introduction

The connection between cancer and inflammation was first made in the 19th century [1]. Epidemiologic studies have confirmed the idea that chronic inflammation underlies many cancers [2]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Inflammatory mediator in several pathologic settings [3,4,5,6], and demonstrated that increased Angptl expression in skin tissues promotes inflammation and accelerates carcinogenesis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model by increasing susceptibility to "preneoplastic change" and "malignant conversion" [7]. Oncogenic mutations can be antagonized by DNA repair mechanisms, some mediated by members of the mismatch repair (MMR) family, which corrects base mispairings or repairs larger insertion/deletion loops (IDL; refs 11–14). Genetic and biochemical studies indicate that Msh is a critical component of all MMR complexes and, Msh2-null mutants are predicted to completely the lack www.aacrjournals.org

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