The Hedgehog signaling pathway has been implicated in development of various tumors, but the exact roles and molecular mechanisms are still not understood. The focus of this research are the tumors harboring BRAF or NRAS mutations, and their differential response to Hedgehog pathway inhibition. Both BRAF and NRAS non-canonically activate the three GLI proteins, but the activity and interplay of this interaction is still unclear. With this project we propose to determine the exact transcriptional targets of GLI1, GLI2 and GLI3 proteins in melanoma with different genetic backgrounds, either harboring a BRAF mutation, a NRAS mutation, or no mutation in these two genes.

Serous ovarian cancer is urgent clinical problem whose molecular background is still unknown. Our previous studies showed aberrant activity of the Hedgehog-GLI (Hh-Gli) signaling pathway in ovarian tumors, but we have shown that aberrant activity is neither the result of mutations nor of promoter hypermethylation of the main pathway regulators. The next to study are microRNAs (miRNAs), one of the main regulators in post-transcriptional regulation of gene expression. Our hypothesis is that changes in the expression of miRNA molecules related to the Hh-Gli signaling pathway contribute to the development of high-grade serous ovarian cancer.

The main focus of this project is to reveal interactions of p53 with protein partners in melanoma that are capable of modifying its function. We are particularly interested in possible interactions of p53 with family members, namely p53 and p73 isoforms, with nm23, especially nm23-H1 and nm23-H2, and Gli family of proteins.