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

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.

Angiopoietin-like-2: a multifaceted protein with physiological and pathophysiological properties

“…Similarly, in human sun-exposed squamous carcinoma skin tissues, DNA repair enzyme Msh2 levels were inversely correlated with angptl2 expression (Ref. 18). In human with lung cancer, the tumour-derived angptl2 levels correlated with poor disease-free survival (Ref.…”

“…60). In contrast, all the other studies proposed that angptl2 promotes or is associated with carcinogenesis and metastasis ( Refs 7,10,17,18,34,35,36,37,38,39,61,62). The first experimental evidence demonstrating that angptl2 contributes to both carcinogenesis and metastasis was provided by the team of Dr Oike in Japan, using a mouse model of chemically induced skin cancer in both K14-angptl2 transgenic mice and angptl2-knockout mice .…”

“…18). Angptl2 derived from inflammatory cells such as activated macrophages and neutrophils, and angptl2-induced activation of NFκB-dependent pathway could be sources of reactive oxygen species (ROS) leading to oxidative stress (Ref.…”

Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence

“…For instance, epigenetic changes of tumor suppressor genes through DNA methylation in pre-neoplastic tissues may result in accelerated carcinogenesis [16, 17]. The dynamic regulation of proteins involved in cellular apoptosis by micro-RNAs may significantly impact both tumor promotion and progression [18].…”

There and Back Again: The Middle Earth of DNA Repair

“…The ability of the pro-inflammatory factor angiopoietin-like protein 2 (ANGPTL2) to induce tumor formation and progression was shown to be linked to oxidative stress and reduced Msh2 expression, providing fresh insight into the mechanisms underlying UV-induced carcinogenesis. 22 Further implicating the contribution of the microenvironment, chronic hypoxia was shown to result in decreased expression of BER factors in colorectal cancers, resulting in altered DNA repair capacity. 23 Furthermore, UV-A radiation was shown to induce oxidative stress, and resultant extensive oxidation of nucleotide excision repair proteins increased susceptibility to UV-B--mediated DNA damage, 24 thus bringing new and unexpected understanding to the mechanisms of UV-induced DNA damage.…”