Balzani, Stella (2012) L'Attivazione del complesso MYBL2-LIN9 contribuisce all'epatocancerogenesi umana ed identifica un sottogruppo di epatocarcinomi con p53 mutato. Doctoral Thesis.
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Aim: MYBL2 is a transcription factor belonging to the Myb proto-oncogene family expressed in proliferating cells. MYBL2 and E2F1-3 regulate the expression of G2/M genes in rat embryonic fibroblasts and human ganglioblastoma. MYBL2 and LIN9 are both required for transcription of G2/M genes, Cyclin B1 and Survivin, in undifferentiated embryonic carcinoma cells. Our aim is to evaluate, in distinct human HCC prognostic subtypes defined HCCB (better) and HCCP (poorer) on bases of patient survival length, the activation of MYBL2 and MYBL-related genes, and the relationships of p53 with MYBL2 activity.
Methods: Random Amplified Polymorphic DNA (RAPD): Primers were used to score genomic alterations in human HCCS.
q-Real Time PCR: Primers for h MYBL2 and RNR-18 genes were used.
Immunoblot and Immunoprecipitation Analysis: Protein concentration was determined using BSA as standard. Membranes were probed with specific primary antibodies.
Results: Highest total and phosphorylated protein levels of MYBL2, E2F1-DP1, pRB, cyclin B1 and LIN9-MYBL2 complex (LINC) occurred in HCCP, compared to HCCB. MYBL2 positively correlated with HCC GI, proliferation, and microvessel density, and negatively with apoptosis. We found higher MYBL2/LINC activation in HCC with mutated p53 while LINC inactivation in HCC harboring wildtype p53 (HCCB).
Conclusions: LINC integrity contributes to survival of DNA damaged p53-/- cells. MYBL2 inhibition could represent a valuable adjuvant for treatments against human HCC with mutated p53.
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