**2. UV-induced inflammation**

High doses of UV can induce inflammation in the skin that results in the appearance of macrophages and other leucocytes [15, 26]. Along with the activation of these cells, many mediators of inflammation are also seen including; prostaglandins [18], nitric oxide (NO) [27] and ROS [12, 17], and cytokines such as interleukin (IL)-1, interferon (IFN)-γ, and TNFα [14, 19, 28, 29]. ROS can cause DNA strand breaks as well as lipid peroxidation, membrane and protein damage [12, 30]. The effects of UV radiation on the levels of these proinflammatory molecules in skin cells are seen in Table 1 [8, 15, 31-33].

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].

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].

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.

High doses of UV can induce inflammation in the skin that results in the appearance of macrophages and other leucocytes [15, 26]. Along with the activation of these cells, many mediators of inflammation are also seen including; prostaglandins [18], nitric oxide (NO) [27] and ROS [12, 17], and cytokines such as interleukin (IL)-1, interferon (IFN)-γ, and TNFα [14, 19, 28, 29]. ROS can cause DNA strand breaks as well as lipid peroxidation, membrane and protein damage [12, 30]. The effects of UV radiation on the levels of these proinflammatory

**2. UV-induced inflammation**

272 Highlights in Skin Cancer

molecules in skin cells are seen in Table 1 [8, 15, 31-33].


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

UVB radiation can increase cyclo-oxygenase (COX)-2 expression and activity in keratinocytes [20, 28, 42]. High levels of COX-2 activity have been observed in human epithelial skin cancers [43]. Nonsteroidal anti-inflammatory drugs can inhibit COX-2 activity and subsequent PGE formation in the skin, and have been used in the treatment of actinic keratosis (AK) [44], BCC, SCC and melanoma [45]. This suggests a role for COX-2 in the formation of skin cancers, and high levels of activity have been observed in many of these tumours [46].

Upregulation of TNFα is a key early response observed in keratinocytes exposed to UVB radiation [8, 38, 47] and represents an important component of the inflammatory cascade in skin. The expression of TNFα mRNA was enhanced a few hours post-UVB irradiation in both keratinocytes and dermal fibroblasts [38, 47]. IL-1α was shown to stimulate TNFα expression in UVB-irradiated keratinocytes [47] and melanocytes [48]. While Bashir *et al.* [38] observed that TNFα expression in keratinocytes was only induced by UVB irradiation, others have shown that UVA can also induce expression in these cells [49, 50]. This increase in TNFα released by the cells is due to elevated gene transcription [38, 49]. The IL-1α formed in the skin, can in turn, induce mast cells to express inflammatory cytokines (e.g. TNFα and IL-1α), as well as prostaglandins which can enhance the inflammation caused by direct UV exposure on the epidermis [15, 20, 28, 51]. Histamine released from the mast cells can induce vasodilation of the surrounding blood vessels, which assists leucocytes in undergoing diapedesis and entering this region [20, 51]. UVB radiation can induce the synthesis and release of IL-6 and IL-8 from irradiated keratinocytes and fibroblasts [33, 36, 37, 51]. IL-8 assists in the homing of leucocytes, primarily neutrophils, from surrounding blood vessels into the inflamed region, while IL-6 can trigger the activation of monocytes and other infiltrating leucocytes to secrete cytokines and chemokines [51]. Figure 1 shows the complex interaction that occurs between different bioactive molecules in the skin following exposure to UV radiation.

TNFα can induce the expression of adhesion molecules and chemokines in surrounding epithelial cells, resulting in the recruitment of inflammatory leucocytes from surrounding blood vessels via diapedesis [15, 20, 51, 52]. These inflammatory cells in turn can express additional cytokines that form a positive feedback loop that further upregulates TNFα as well as downstream TNF − induced chemokines, cytokines, and other pro-inflammatory media‐ tors in irradiated skin [8, 38, 53]. The effects elicited by these infiltrating inflammatory cells occur some hours following exposure to UV irradiation, thereby prolonging the inflammatory response. UVB radiation also induces inducible nitric oxide synthase (iNOS) activity in dermal endothelial cells, through a TNFα-dependent pathway [38, 54].

**3. Tumor necrosis factor α**

TNFα, is a member of the TNF ligand superfamily, and is a type II transmembrane glycoprotein of 234 amino acids possessing an extracellular carboxy-terminus and a cytoplasmic amino group [53, 55, 56]. It can exist in one of two forms; a 26 kDa membrane-bound form (mTNFα) and a 17 kDa soluble form (sTNFα). sTNFα is cleaved from its membrane bound precursor

**Figure 1.** The inflammatory response seen in the skin following exposure to UV radiation. Inflammation can be in‐ duced as a direct result of UV exposure on epidermal cells, or due to the release of secreted molecules, which in turn induce the release of inflammatory mediators from the dermis, as well as attracting inflammatory cells from circula‐ tion into this region of the skin. The infiltrating monocytes and macrophages, which enter the irradiated skin tissue in

The Role of Furin in the Development of Skin Cancer

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

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Numerous cells produce TNFα, including macrophages, leucocytes, dendritic cells, keratino‐ cytes, melanocytes and fibroblasts [8, 47, 57, 58]. It plays a role in apoptosis, cellular prolifera‐ tion, differentiation, inflammation, tumorigenesis, viral replication, immune response to extracellular stimuli, as well as in local andsystemic inflammation [21, 53, 55-57, 59].Most ofthe cellular actions described for TNFα correspond to its secreted, mature soluble form. There is increasing evidence that mTNFα is also biologically active [58]. Both forms of TNFα can specifically bind to one of two receptors: TNF-R1 (CD120a receptor), a 55 kDa protein; TNF-R2 (CD120b receptor), a 75 kDa protein [57]. The receptors are both transmembrane glycopro‐ teins,anddisplayahighdegreeof structuralhomologyandareexpressedonmost celltypes [60].

between Ala76 - Val77 by the action of the metalloprotease TACE [22, 55].

turn, secrete mediators that prolong the inflammatory response. See text for details and references.

TNFα plays a pro-inflammatory role in the skin due to; (a) the direct effects of UV radiation and (b) the indirect effects of inflammatory cells that chemotax to the skin. UV- and inflam‐ matory cell-derived cytokines further enhance TNFα gene transcription in human skin cells [38], which can again increase its production by epidermal cells. In contrast, clustering and internalization of the TNF receptors may lessen the cell's response to TNFα, which may account for why the upregulation of TNFα mRNA is not sustained over time in culture [20]. For further information on the complex interplay of cytokines, chemokines and other media‐ tors in UV-induced inflammation please refer to the following reviews [15, 20, 41, 42].

**Figure 1.** The inflammatory response seen in the skin following exposure to UV radiation. Inflammation can be in‐ duced as a direct result of UV exposure on epidermal cells, or due to the release of secreted molecules, which in turn induce the release of inflammatory mediators from the dermis, as well as attracting inflammatory cells from circula‐ tion into this region of the skin. The infiltrating monocytes and macrophages, which enter the irradiated skin tissue in turn, secrete mediators that prolong the inflammatory response. See text for details and references.
