engleski

Mutations in SMO in human BCC might contribute to impaired signal transduction

The hedgehog signaling pathway is highly conserved through evolution, and plays an important role in the embryonic development of various organ systems including the skin. Aberrant activation of hedgehog signaling caused by mutations in genes encoding important members of this pathway, such as the hedgehog receptor genes PTCH (Patched) and SMO (Smoothened), plays a crucial role in the pathogenesis of cutaneous basal cell carcinomas, which is the most common human cancer. Hedgehog is a signal molecule that binds to transmembrane receptor Patched. Patched binds Smoothened, another transmembrane protein, in the absence of Hedgehog, keeping it in inactive state. Upon Hedgehog binding Patched releases Smoothened and the signal is tranduced intracellulary toward transcription factor Gli1, which appears to play important role in both normal development and neoplasia, as downstream mediator of Hedgehog signaling pathway. We wanted to test the role of SMO in human skin basal cell carcinomas (BCCs). SMO codes for protein Smo, a 7 pass transmembrane protein with extracellular N-terminus and intracellular C-terminus. The gene is located on chromosome 7 and has 12 exons. It is an oncogene and several activating mutations in exons 9 and 10 have been found. We tested the role of SMO in cutaneous basal cell carcinomas by SSCP(Single Strand Conformational Polymorphism) screening of exons 9 and 10. Two inactivating mutations published recently, ex 9 – 1694 Gà T (Trp535Leu) and ex 10 – 1685 Gà A (Arg562Gln) weren’ t confirmed in our samples, but we found one polymorphism in close vicinity, on position 1721 (Ser574Ser), in 3 cases of 16. We intend to prove the importance of coreceptor Smo in Hedgehog/Patched signaling in cell culture by blocking its activity with cyclopamine, a naturally occuring alkaloid, and then test if changes in level of expression of PTCH and GLI 1, which are transcriptional targets of hedgehog signaling, will occur.

SMO ; basocellular carcinoma ; HH-GLI pathway

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