Sonja Levanat

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172 Acta Clin Croat,  Vol. 51,   No. 1,  2012Acta Clin Croat 2012; 51:169-188 22nd Ljudevit Jurak International Symposium on Comparative PathologyMOLECULAR MECHANISMS OF SKIN DISEASESSonja Levanat Hereditary Cancer Laboratory, Department of Molecular Medicine, Ruđer Bošković Institute, Zagreb, CroatiaThree main forms of skin cancer, depending on the type of epidermal cells affected, are basal cell carci-noma, squamous cell carcinoma and cutaneous mela-noma. Our research is focused on two of them, i.e. basal cell carcinoma (BCC) as the most common skin neoplasm, and melanoma as the most aggressive skin cancer. Although widespread and with increasing in-cidence, both were not well understood at the level of molecular pathogenesis until recently. Progress over the past decade has identified an array of molecular alterations in these neoplasms that may provide op-portunities for new molecular therapeutics. A number of genetic alterations have been characterized, some of them involving gain-of-function changes in on-cogenes, whereas others involve loss-of-function of genes that act as suppressors of tumor formation. The spectrum of changes differs among these tumor types. Major events in BCC onset and development are various alterations in the Sonic Hedgehog/Patched/Smoothened (SHH/PTCH/SMO) pathway, in par-ticular PTCH1 loss-of-function, as well as gain-of-function by SHH, SMO and GLI. An important role in the genesis of melanoma plays CDKN2A locus on 9p21, encoding a cyclin-dependent kinase inhibitor p16 that acts to inhibit cell cycle progression in the G1 phase by binding and inhibiting CDK4/6 kinases. Loss of p16 leads to deregulated CDK4/6 action and to promotion of cell divisions. Involvement of p16 in melanoma development has been demonstrated ei-ther through loss of heterozygosity (LOH) for DNA markers within chromosome 9p21, or by mutational screenings of p16. We have been investigating the roles of both markers, PTCH and p16, in the pathogenesis of both cancers, cutaneous melanoma and basal cell carcinoma, and suggested the involvement of SHH/PTCH/SMO pathway by different mechanisms. Our particular interest in the role of SHH/PTCH/SMO pathway in various human cancers, which started with BCC and has more recently included melanoma, is motivated by the potential therapeutic use of small molecule antagonists that block the pathway. Anoth-er promising approach in melanoma research is the mitogen-activated protein (MAP) kinase pathway, which is affected in 40% to 60% of these carcinomas. The pathway is activated by mitogenic signaling from the membrane receptors towards the nucleus, which begins with the RAS, a small G protein, to pro-tein kinase BRAF (an enzyme that adds phosphate groups to proteins to alter the substrate’s function). The BRAF mutation (the V600E mutation) constitu-tively activates the pathway by increased kinase activ-ity, leaving the ‘growth’ signal always turned on. It has been shown that RAS with oncogenic potential to induce melanoma in transgenic mice requires the active SHH/PTCH/SMO pathway. Additionally, it was found that RAS mediated by MAP and down-stream AKT signaling regulates the nuclear localiza-tion and transcriptional activity of GLI1, which is a main citoplasmatic oncogene of the SHH/PTCH/SMO pathway in melanoma cells. All these recent findings suggest that an integrated approach to the RAS/AKT and SHH/PTCH/SMO pathways has a great and possibly synergic potential for future thera-pies of BCC and particularly of melanoma. 

Molecular Mechanisms of Skin Diseases

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