Ultraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and inflammation

Exposure to ultraviolet (UV) radiation is associated with approximately 65% of melanoma cases, and 90% of non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While the incidence of most other malignancies has either stabilized or declined, that of NMSC has increased and is developing even in younger age groups. NMSCs account for nearly 15,000 deaths, 3.5 million new cases, and more than 3 billion dollars a year in medical costs in the United States alone, representing a major public health concern. As sun protection efforts have not been proven effective, targeted chemoprevention strategies are much needed. Skin carcinogenesis by DNA damage is considered a predominant paradigm for UV toxicity. Exposure to UV radiation can activate various oncogenes while inactivating tumor suppressor genes, resulting in inappropriate survival and proliferation of keratinocytes that harbor these damages. Moreover, increasing evidence demonstrate that inflammatory responses by the immune cells within the tumor microenvironment also contribute significantly to skin tumorigenesis. Initiation and progression of skin carcinogenesis mediated by UV radiation involve complex pathways, including those of apoptosis, proliferation, autophagy(definition), DNA repair, checkpoint signaling, metabolism, and inflammation. In this review, we highlight the recent advances in two of these key molecular processes that result in UV-mediated skin carcinogenesis. In particular, we discuss 1) pathways that regulate DNA damage repair and 2) the regulation of the inflammatory process its crosstalk with DNA repair potentially leading to non-melanoma skin carcinogenesis.