Ricerc@Sapienza

Increasing evidence showed that multiple tissue microenvironment cues could play a pivotal role in the behaviour of untransformed as well as in preneoplastic/neoplastic cells. This is particularly relevant in the liver, where the functionality of non-tumoral hepatocytes and the aggressiveness of hepatocellular carcinoma cells appear strictly related to the tissue fibrosis, a pathological background on which invariably cancer develops. An important feature of liver fibrosis is the presence of environmental stimuli, in particular TGFß and mechanical signals, able to promote processes directly involved in liver cell differentiation and tumor progression, primarly the Epithelial to Mesenchymal Transition. A common downstream target of the pathways starting from these signals is the transcriptional factor HNF4, master regulator of hepatocyte differentiation and tumor suppressor in hepatocellular carcinoma.
Aim of this project is to identify molecular and biochemical mechanisms leading to HNF4 inactivation by TGFß and substrate stiffness in the attempt to further dissect the molecular bases of liver cell differentiation and of hepatocyte transformation and liver tumor progression. In particular, starting from literature and our preliminary observations, we plan to study:
1) the mechanisms responsible for the TGFß-induced HNF4 inactivation by analysing the TGFß-induced post-translational modifications (PTMs) on HNF4 protein and the TGFß-dependent epigenetic reprogramming of HNF4 target gene promoters;
2) the mechanisms responsible for the high stiffness-induced inactivation of HNF4 by analysing the involvement of the mechano-trasducer YAP on HNF4 expression and function.
The dissection of molecular mechanisms controlling the response of liver cells to environment stimuli, in terms of differentiation and transformation, appears mandatory to identify new targets and to set up efficient therapeutic protocols for liver fibrosis and hepatocellular carcinoma.