Ruolo dei geniYes associated Protein(Yap) eConnective Tissue Growth Factor(CTGF) nella progressione della cancerogenesi epatica

Aim:The aim of this project is to contribute to the development of new therapeutic strategies based on early detection of tumour markers. We study Yes-associated protein (YAP) and Connective tissue growth factor (CTGF) molecules involved in the progression of the hepatocellular carcinoma (HCC).YAP is a transcriptional co-activator of gene expression. Recent studies have shown that YAP is phosphorylated and inhibited by the Hippo tumour suppressor pathway. CTGF is a target of YAP. We investigated in rat liver preneoplastic and neoplastic lesions the expression of YAP and of CTGF and their contribution to lesions progression.Methods:We prepared from Fisher (F344) and Brown Norway (BN) rats, susceptible and resistant to HCC development respectively, initiated liver (Fi, 6 weeks after initiation), early low-grade dysplastic nodules (12 weeks), dysplastic nodules (mostly low-grade of dysplasia in BN and high-grade of dysplasia in F344 rats; 32 weeks) and HCCs (57-60 weeks). CTGF and YAP expressions have been evaluated by qReal time PCR and IHC.Results:qReal time PCR shows YAP higher expression in HCC with respect to the control, in both rat strains. YAP and CTGF expression is highest in early Fi of F344 rats compared to controls and they remain higher, particularly in F344 rats, during progression to more malignant stages. IHC shows YAP accumulation in the cytoplasm but not in the nuclei of actively proliferating preneoplastic liver, while YAP accumulates in nuclei of neosplastic hepatocytes.Conclusion:YAP accumulates in cytoplasm of early preneoplastic in F344 rats lesions and its expression reaches F344 lesions values only in HCC of BN rats. qRT PCR shows overexpression of YAP in earlier lesions of F344 rats and in later lesions of both rat strains. CTGF is highest 4 weeks after initiation, and only in HCC of BN strain. CTGF and YAP could be used as a tumoral therapeutic markers of HCC.