KMT2C function in osteosarcoma carcinogenesis and progression
Osteosarcoma (OS) is the most common paediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for OS are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. From WES analysis performed on 8 osteosarcoma biopsies of patients at different stage of the disease (responder and non-responder to therapy and metastatic and non-metastatic), we identified KMT2C, a regulator of chromatin, that showed variations in most samples. Successively, we performed immunohistochemical (IHC) and gene expression analysis of KMT2C on the same OS samples. They showed positivity both in the nucleus and in the cytoplasm, so we noted that there was a nucleus/cytoplasmic trafficking in osteosarcoma cells, also patients with drugs resistance and development of metastasis showed an increase of nucleus/cytoplasmic trafficking and a higher cytoplasmic localization. The osteosarcoma sample that showed the highest value of gene and protein KMT2C expression showed a probably damaging variation on the catalytic domain of the protein (SET) that allows the addition of methyl groups to the specific lysine residues.
The aim will be to better understand the role of KMT2C in carcinogenesis and progression of osteosarcoma and we will perform the IHC and mRNA expression analysis on a large population of patients with conventional high grade OS with known clinical and pathological data, particularly to metastatic progression and responsiveness to therapy. Moreover, we will perform gene expression analysis of genes involved in metastatic pathway and western blot analysis, both before and after siRNA silencing assay, to understand how KMT2C could modulate the metastatic pathway and identify new therapeutic approach.