**1. Introduction**

Skin cancer represents a major, and growing, public health problem, and is the most common type of cancer observed in Caucasians [1-3]. The three most common forms of skin cancer are basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. BCC and SCC are together known as non-melanoma skin cancers (NMSC), and are both derived from keratino‐ cytes whereas melanomas are derived from melanocytes [3-6]. SCCs can undergo metastasis; BCCs rarely do, while melanomas can be highly metastatic [5, 6].

The ultraviolet (UV) radiation component of sunlight is acknowledged to be the main carci‐ nogen implicated in the formation of skin cancer. UV radiation can be divided into three components: UVC (100-280 nm), UVB (280-320 nm) and UVA (320-400 nm). Ozone depletion, seasonal and weather variations affect the amount of UV radiation reaching the Earth's surface [7]. UVC and most of the UVB radiation emitted from the sun is blocked from reaching the Earth's surface by the ozone layer. The component of UV light that reaches the Earth's surface consists of 90-95% UVA and 5-10% UVB [3, 8]. The penetration of shorter-wavelength UVB radiation is predominantly confined to the epidermis while UVA penetrates into the dermis because of its longer wavelength [9].

UVB can cause sunburn, inflammation, DNA mutations and membrane damage as well as skin cancer [8, 10, 11]. It is known that UVB directly damages DNA and can induce Reactive Oxygen Species (ROS) by interactions with chromophores in the skin [12]. The DNA damage caused by UVB irradiation typically results in the formation of cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) photoproducts. The mutations are frequently found in the p53, p16, PTCH and INK4α/CDKN2A genes of skin cancer patients [13, 14]. Inflammation plays a significant role in creating an environment where cells possessing mutated DNA can become carcinogenic. UVA can cause premature skin ageing, wrinkle formation, blotching and induces sunburn cell formation in the epidermis, as well as skin cancer [8, 10, 15]. It affects keratinocytes

© 2013 Ravi and Piva; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

at a transcriptional level by altering the expression of genes involved in apoptosis, cell cycle, DNA repair, signal transduction, RNA processing and translation, and metabolism [9]. UVA can cause DNA damage by generating ROS [12] resulting in genomic damage e.g. singlestranded breaks, protein-DNA crosslinks, and oxidative base damage (i.e. 8-oxo-7,8-dihy‐ droxyguanine) [16]. It can also initiate signal transduction pathways [13, 17] as well as inducing the expression of cytokines such as Interleukin (IL)-6, heme oxygenase-1, and cyclo-oxygenase [18] as well as inflammatory mediators such as tumor necrosis factor-α (TNFα) [15, 19].

Inflammatory mediators such as IL-1, TNFα and IL-6 have been postulated to play a major role inbothmelanoma[34]andNMSCformation[26,35,36].Malemiceareknowntobemoresensitive toUVB-inducedskincarcinogenesisthanfemalemice[4],whichisconsistentwithhumanstudies showingmenhavingahigherincidenceof skincancerthanwomen[20].Damian*et al*.[20]found that while women developed a larger inflammatory response to UVB radiation, men had lower antioxidant levels in the skin resulting in a higher level of oxidative damage to DNA, and were more sensitive to UV immunosuppression. This suggests that UV-induced immunosuppres‐ sion and DNA damage plays a greater role in the formation of skin cancers in men compared to women [20]. IL-1α and IL-1β are both induced in keratinocytes exposed to UVB radiation [31, 37]. IL-1α has been shown to enhance the expression and release of TNFα from UVB-irradiat‐ edkeratinocytes[38,39],whileIL-1βenhancestheexpressionofmatrixmetalloprotease(MMP)-9 in these irradiated cells [40]. Apart from IL-1β, UVB can stimulate MMP-9 expression in human

skin via the induction of Activator protein-1 (AP-1) and NFκB activities [41].

Fever

NK cells

Erythema

**Table 1.** Effect of UV radiation on the expression of bioactive molecules in human skin cells

Severe sunburn

TNFα Keratinocytes

IL-1α Keratinocytes

IL-1β Keratinocytes

IL-6 Keratinocytes,

IL-10 Macrophages

PGE2 Keratinocytes,

IL-I2p40 (not bioactive) Mast cells Dermal fibroblasts Langerhans cells

Langerhans cells

Langerhans cells

Langerhans cells

Melanocytes

Keratinocytes, Dendritic cell, Langerhans cells

Mast cells

IFNγ T cells Triggers apoptosis

Histamine Mast Cells Increases release of PG

**Mediator Produced By Function References**

adhesion molecule expression

inhibited by IL-1 receptor antagonist

Decreases antigen presentation, Increases IL-1 receptor antagonist

T-cell mediated tumour cell destruction

Inhibit lymphocyte functions like IL-2 and IFNγ

Decreases antigen presentation Increases IL-4, decreases IL-12

Decreases Th1 response Decreases antigen presentation

Langerhans cell migration, sunburn cell information, stimulates prostaglandin (PG) synthesis, changes in

Simulates PG synthesis, increases TNFα and IL-6,

Blocks cytokine production by T cells, macrophages and

Langerhans cell migration [15, 31, 33]

[15, 31, 33]

The Role of Furin in the Development of Skin Cancer

http://dx.doi.org/10.5772/55569

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[15, 33]

[8, 15, 33]

[8, 15, 32, 33]

[33]

[33]

[33]

[15, 33]

[8, 15, 33]

While UVB has been thought to be the main contributor toward skin cancers, based largely on the DNA action spectrum of UV radiation, UVA has more recently been acknowledged as playing an important role in this process [9, 11, 20]. While UVA does not produce an inflam‐ matory response like that of UVB, it produces ROS and as such activates many of the same signalling pathways [13]. It is clear that doses of UVB, UVA and solar stimulated UV that are too low to cause inflammation can induce mutations in epidermal cells. However, this does not exclude a role for ROS from inflammatory cells contributing to skin carcinogenesis, but it may be important for tumour progression [20]. UV-induced inflammation seen in the skin involves the action of many molecules. Of these inflammatory molecules TNFα plays a major role in UV-irradiated inflammation in the skin [15, 19]. TNFα is cleaved from its membranebound precursor by the action of the metalloprotease, Tumour Necrosis Factor-α Converting Enzyme (TACE) [21, 22]. While UVB radiation increases the release of TNFα from skin cells, it is not known whether this is due to increased TACE activity and/or expression. However, before TACE is activated it is cleaved from its proform by the action of furin, a proprotein convertase [23, 24]. Furin can cleave other proteases such as matrix metalloproteases (MMPs) [23, 24]. Exposure to UVB radiation also increases MMP activity in skin cells [25]. While furin is expressed in skin cells, the effect UV radiation has on its expression and/or activity and that of the proteases it activates is not fully known. As a result of elevated furin levels in a mutated cell, enhanced TACE activity would see an increase in the secretion of TNFα thereby sustaining a localised inflammatory environment allowing for the development of carcinogenic cells. As furin activates MMP activity, these carcinogenic cells have the potential to become metastatic. This review investigates the role that furin plays in the activation of TACE and MMPs and the effect that this has on a skin cells exposed to UV radiation, as well as that its role in cancer cells which undergoes metastasis, and how an understanding of the role played by this proprotein convertase, may assist in the design of new inhibitors which have therapeutic potential.
