Abstract
The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.
Highlights
Skin squamous cell carcinomas (SCC) are the second most frequent human non-melanoma skin cancers, with an incidence of 16 in 100,000 people in Europe [1, 2]
In this study we addressed the role of p38γ and p38δ kinases in skin carcinogenesis and skin inflammation
The role of p38γ in skin carcinogenesis has not been addressed either; in contrast, a role for p38δ in skin tumour formation has been described [24]. p38δ deficiency has been shown to reduce tumour formation in the chemical DMBA/TPA model, which was accompanied by a decrease in proliferation in the epidermis [24]
Summary
Skin squamous cell carcinomas (SCC) are the second most frequent human non-melanoma skin cancers, with an incidence of 16 in 100,000 people in Europe [1, 2]. Inflammatory processes often facilitate cancer development by promoting immune cell infiltration. Studies in mice deficient in p38γ, p38δ, or both show that these kinases have a pro-tumourigenic role and are needed for tumour development; p38δ deficiency reduced tumour formation in the chemical DMBA/TPA (7,12-dimethylbenz[a]anthracene/12-Otetradecanoylphorbol-13-acetate)-dependent model of skin carcinogenesis and in K-Ras-driven lung carcinogenesis [24]. Combined p38γ and p38δ (p38γ/δ) deletion severely reduces chemical azoxymethane (AOM)/DSS-induced colon tumour formation in a colitis-associated model of colorectal cancer (CAC) [16]. The two-stage DMBA/ TPA chemical carcinogenesis model depends on proinflammatory processes [26], and we used this method to analyse p38γ and p38δ activity in skin inflammation and skin tumour promotion/progression. P38γ or p38δ deletion reduced skin tumour formation compared to WT, and interestingly, p38γ/δ-deficient mice were much more resistant to DMBA/TPA-induced tumourigenesis. Our work shows the pro-oncogenic role of p38γ and p38δ in the skin, and confirms these two kinases as potential targets for cancer treatment and/or prevention
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