Jagged1 plays a key role in sustaining colon cancer (CRC) progression in a Notch-independent manner

Anno
2018
Proponente Diana Bellavia - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Abstract

The colorectal cancer (CRC) is the second leading causes of cancer-related deaths worldwide. It results from a progressive accumulation of genetic and epigenetic alterations that lead to uncontrolled growth of colonocytes from non-cancer polyps into invasive cancerous lesion. A present estimate is that between 15-30% of CRC cases may have a major hereditary component while the 70-85% of CRC cases are sporadic and the patients have no identifiable genetic risk factors. The huge spectrum of somatic alterations that contribute in sporadic CRC development have been identified in mutations of oncogenes and tumor suppressor genes, such as Wnt/ß-catenin, K-ras, TP53, TGFß, BRAF, etc..
Intriguingly, the ligand-induced Notch signalling has been implicated in various aspects of cancer biology and its role in regulating the intestinal development and homeostasis has already been identified. In fact, several studies demonstrate that alterations of Notch pathway contribute to the CRC onset and malignancy. In particular, it has been suggested that the specific Notch ligand Jagged1 is aberrant expressed in about 50% of human colon tumors and some studies correlate the levels of Jagged1 expression with tumor differentiation parameters and stage of CRC.
We have observed that in several CRC cell lines the ligand Jagged1 is not only abundantly overexpressed but it undergoes to a constitutive processing that ends in the generation of a soluble intracellular domain (Jag1-ICD) capable to move into the nucleus. In this cellular compartment, Jag1-ICD could be involved in regulation of some transcriptional factors empowering the aggressiveness of CRC cells. Thus, the pharmacological blockage of Jagged1 intracellular processing inhibits both the migration ability of CRC cell lines and their proliferation rate.
We aim to better understand the molecular mechanism responsible of such effects Jagged1 dependent in CRC in order to be able to define a new potential target therapy.

ERC
LS1_5, LS1_10, LS4_6
Keywords:
BASI BIOLOGICHE DEL CANCRO, APOPTOSI, EPIGENETICA E REGOLAZIONE GENICA, TRASDUZIONE DEI SEGNALI

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