**Acknowledgements**

Recently, Fu *et al*. [106] showed that in transgenic mice overexpressing furin, exposed to chemical carcinogens formed more and larger tumours than did control mice. This suggests that furin enhances skin cancer growth. Of interest was that these tumours were induced by chemical carcinogens and not by UV radiation. While enhanced furin levels were shown to enhance skin tumour development, in studies using cultured melanoma and glioma cells, furin inhibition was shown to reduce the processing of the pro-N-cadherin adhesion molecule, enhancing their migratory and aggressive nature [118]. The result of this study suggests that high furin levels may not enhance the metastasis of some tumours. Huang *et al*. [125] when investigating the expression of furin in hepatocellular carcinoma and surrounding tissue in humans, observed that if this ratio was >3.5 this resulted in higher patient survival rates compared to those who had ratios <3.5. This suggests that furin may play a dual role in cancer development, though the exact nature of which is not clear at this stage. Further study on this is warranted, and may result in a better understanding of its role in cancer development, and from which it may be possible to develop specific furin inhibitors which could be used clinically

While it has been shown that UVA and UVB radiation cause different effects on the immune response this could be related to the activity of cell surface metalloproteases found on skin cells. Although the effect of TNFα in UV-induced inflammation has been well documented, little is known if the changes in TACE activity are due to increased protein levels or changes in enzyme activity. The inflammatory environment, seen in the skin, following exposure to UV radiation is known to stimulate the development of mutated cells which possess DNA damage caused directly by UV radiation or indirectly through the generation of ROS. Apart from processing TNFα, TACE also cleaves EGF family members, which would stimulate the growth of these mutated cells, which over time may become cancerous. As TNFα is a powerful inflammatory cytokine, considerable research has been under taken to develop specific TACE inhibitors [55, 56, 80]. Such inhibitors may play an important role in preventing the develop‐ ment of UV-induced skin cancers. An increased knowledge of the roles played by metallo‐ proteases in tumour progression, combined with the use of more selective inhibitors, could

Similar to that of TACE, MMPs are also activated by UV radiation and also play a crucial role in skin tumour cell development and metastasis. Furin and other PCs have been shown to play an important role in activating both TACE and many MMPs in skin cells. Whereas the overexpression and activity of furin exacerbates the cancer phenotype, inhibition of its activity decreases or nullifies its effects, and thus, the development and use of specific inhibitors may

It is known that UV induces furin mRNA in skin cells, though protein levels do not appear to change with respect to time, which suggests a rapid turnover of the enzyme. Further study is needed on how UV radiation activates furin, TACE and MMPs in skin cells. These proteases

lead to effective use of these compounds in cancer therapies [55].

also be a viable route to cancer therapy [23, 86, 102, 127].

to treat these tumours.

**8. Conclusion**

284 Highlights in Skin Cancer

We would like to that the School of Medical Sciences, RMIT University, Bundoora, Australia for supporting this study, and for the awarding of a School of Medical Science's Postgraduate Research Scholarship to RR.
