Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces (ϳ66%) UVBinduced basal cell carcinoma formation in Ptch1 ؉/؊ mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1 ؉/؊ mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.

An increasing progress on the role of Hedgehog (Hh) signaling for carcinogenesis has been achieved since the link of Hh pathway to human cancer was firstly established. In particular, the critical role of Hh signaling in the development of Basal cell carcinoma (BCC) has been convincingly demonstrated by genetic mutation analyses, mouse models of BCCs, and successful clinical trials of BCCs using Hh signaling inhibitors. In addition, the Hh pathway activity is also reported to be involved in the pathogenesis of Squamous Cell Carcinoma (SCC), melanoma and Merkel Cell Carcinoma. These findings have significant new paradigm on Hh signaling transduction, its mechanisms in skin cancer and even therapeutic approaches for BCC. In this review, we will summarize the major advances in the understanding of Hh signaling transduction, the roles of Hh signaling in skin cancer development, and the current implications of “mechanism-based” therapeutic strategies.

The influence of UV irradiation on pigmentation is well established, but the molecular and cellular mechanisms controlling dendrite formation remain incompletely understood. MicroRNAs (miRNAs) are a class of small RNAs that participate in various cellular processes by suppressing the expression of target mRNAs. In this study, we investigated the expression of miRNAs in response to UVB irradiation using a microarray screen and then identified potential mRNA targets for differentially expressed miRNAs among the genes governing dendrite formation. We subsequently determined the ability of miRNA 340 (miR-340) to suppress the expression of RhoA, which is a predicted miR-340 target gene that regulates dendrite formation. The overexpression of miR-340 promoted dendrite formation and melanosome transport, and the downregulation of miR-340 inhibited UVBinduced dendrite formation and melanosome transport. Moreover, a luciferase reporter assay demonstrated direct targeting of RhoA by miR-340 in the immortalized human melanocyte cell line Pig1. In conclusion, this study has established an miRNA associated with UVB irradiation. The significant downregulation of RhoA protein and mRNA expression after UVB irradiation and the modulation of miR-340 expression suggest a key role for miR-340 in regulating UVB-induced dendrite formation and melanosome transport. Melanocytes originate from neural crest-derived melanoblasts, which migrate and differentiate in the basal layer of the epidermis (1). A hallmark of melanocytes is their ability to form dendrites, which are specialized cell structures that transport melanosomes to their tips for transfer to the surrounding keratinocytes in response to growth factors and UV irradiation. Following skin penetration by UV rays and subsequent DNA damage, thymidine dinucleotide fragments induce melanogenesis and cause the melanocyte to produce melanosomes (2).These melanosomes are then transferred to neighboring keratinocytes through the intricate network of melanocyte dendrites, contributing to skin darkening and thereby providing protection from UV radiation (3, 4). Melanocyte dendrites can vary markedly in length and number in response to different growth factors and, in a manner analogous to the way in which neural cells seek out target neurons, these dendrites form growth cone-like structures that attach to keratinocytes. Melanocyte-keratinocyte adhesion is a prerequisite for the transfer of melanosomes to keratinocytes; therefore, the formation of melanocyte dendrites, particularly of the appropriate length and number, is essential for efficient melanosome transfer. Due to the importance of dendricity for melanocyte activity, cutaneous pigmentation, and photoprotection, it is critical to determine the precise mechanisms involved in the regulation of melanocyte dendrite formation.It is well known that melanocytes are sensitive to UV irradiation, with substantial evidence suggesting that it plays a pivotal role in regulating melanocyte dendricity. Studies have shown that UV irradiation induce...