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

Abstract

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, 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.

Anti-Inflammatory Effects of Aspalathus linearis and Cyclopia spp. Extracts in a UVB/Keratinocyte (HaCaT) Model Utilising Interleukin-1α Accumulation as Biomarker

“…Keratinocytes are the primary targets of UVB-induced toxic effects [4,5], as a result the most commonly occurring skin cancers develop in the epidermal layer through a multistage process involving initiation, promotion and progression [6][7][8]. In the complex process of photocarcinogenesis, two distinct pathways regulating DNA damage repair and inflammation have been identified [9][10][11]. The one pathway occurs upon DNA damage which involves cell cycle arrest, DNA misrepair genetic mutations, cell cycle dysregulation and apoptosis in cells.…”

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

“…Since, COX-2, TNF-α, iNOS, and IL-6 are regulated by NF-κB, their effects were in line with silibinin' inhibitory effect on NF-κB p50 level. Additionally, COX-2 is overexpressed in chronically UVBirradiated skin and UVB-induced SCCs (19,47,48). This shows the importance of silibinin in inhibiting UVB-induced inflammation in a p53-dependent manner.…”

“…In epidermal keratinocytes, UVB radiation activates inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) which then phosphorylates and degrades IκBα (19,43). The activation of NF-κB leads to induction of pro-inflammatory cytokines such as IL-6 and TNF-α (44).…”

“…Additionally, they can accumulate and contribute to skin tumor development and growth. Inflammation is another important factor in the growth and progression of skin cancer (18,19). Exposure to UVB radiation causes cutaneous tissue injury, inflammation and immune suppression (20).…”

“…The inflammation is characterized by erythema and edema due to increased vascular flow and permeability, which then leads to the recruitment and infiltration of various types of inflammatory cells into the affected skin (21). Many studies have shown a clear link between chronic cutaneous inflammation and the development of skin tumors (18,19,(22)(23)(24).…”