Ricerc@Sapienza

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide and it is characterized by high incidence of recurrence. Indeed, the mortality-to-incidence ratio is high as a consequence of the development of chemo-resistance and frequent metastasis. Notch signaling is thought to play a pivotal role in OC. Among the four Notch receptors, Notch3 is frequently over-expressed in OC and several studies disclosed its involvement in chemo-resistance and promotion of metastasis, thus contributing to poor overall survival of OC patients. In this scenario, the Epithelial-to-Mesenchymal Transition (EMT) process should be taken into account, as the acquisition of the mesenchymal phenotype is associated with drug resistance and metastatic capacity of malignant cells. Specifically, it has been suggested that Notch signaling regulates EMT in OC but the underlying molecular mechanism is poorly understood and needs further investigation. Since Notch3 is crucial for the pathogenesis and tumor progression of OC, Notch3 should be considered as a prognostic marker and selective targeting of Notch3 may represent a promising therapeutic approach for OC patients. We have shown that the prolyl-isomerase Pin1 positively regulates Notch3 protein in T-cell acute lymphoblastic leukemia and we hypothesized to observe the same relationship also in OC context. Therefore, the main aim of the proposed research is to broaden our knowledge of the role of Notch3 in OC metastasis and chemotherapy resistance, focusing our attention on its function and regulation by Pin1 isomerase. Evaluating how Pin1 inhibition affects Notch3-dependent OC behavior may aid in developing novel therapeutic strategies to restore chemo-sensitivity and reduce the incidence of metastasis.