Dottorato in BIOLOGIA UMANA E GENETICA MEDICA

Titolo della tesi: Study of the role of the hnRNP SYNCRIP in controlling hepatocyte plasticity and intercellular communication

ABSTRACT Microenvironment includes different molecules, e.g. proteins in extracellular matrix and soluble factors, as well as different cell types in tissue. Moreover, in the last years, growing interest focused on Extracellular Vesicles (EV) in microenvironment as regulators of the intercellular communication. Under physiological conditions, microenvironment constitutes an important modulator of epithelial cell fate and represent a barrier to cellular transformation. In pathological conditions, such as cancer, microenvironment changes and it can influence tumor growth and ability to metastasize. Coherently, it’s well known that EVs-carried molecules change in response to different cellular states and, specifically in cancer, EVs composition profoundly differs between untransformed and transformed cells. Starting from this body of evidence and taking into account the role of the Epithelial to Mesenchymal Transition (EMT) as leading process in metastasis of epithelial tumor, in our study we focused on the cell-to-cell communication between hepatocytes, and hepatocytes after TGF-β treatment, and different cells mimicking epithelial tumor niche, investigating on the potential role of extracellular vesicles as carriers of cargo molecules able to modulate the plasticity of recipient cells. Our results demonstrated the EVs-mediated intercellular communication between hepatocytes, as well as hepatocytes undergoing the EMT, and recipient epithelial and hepatic stellate cells, gathering evidence that EVs released by transitional cells are instrumental to reprogram the phenotype of receiving cells. Moreover, our data showed that the hnRNP SYNCRIP, previously identified as main regulator of the loading of specific repertoire of miRNAs into hepatocyte EVs, is required in regulating this EV-mediated signaling. Finally, reported evidence also proved the requirement of SYNCRIP for both the EMT process of hepatocytes and the mesenchymal and migratory properties of HCC cells. Taken together, our findings provide insight into EV-mediated cell-to-cell communication in regulating cellular plasticity of liver cells and identify SYNCRIP as a promising therapeutic target in HCC.