Calvisi, Diego Francesco and Simile, Maria Maddalena and Ladu, Sara and Frau, Maddalena and Evert, Matthias and Tomasi, Maria Lauda and Demartis, Maria I. and Daino, Lucia Maria Elisa and Seddaiu, Maria Antonietta and Brozzetti, Stefania and Feo, Francesco and Pascale, Rosa Maria (2011) Activation of MYBL2-LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of human hepatocellular carcinoma with mutant p53. Hepatology, Vol. 53 (4), p. 1226-1236. eISSN 1527-3350. Article.
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Upregulation of MYBL2 gene occurs in human hepatocellular carcinoma (HCC), and is associated with faster progression of rodent hepatocarcinogenesis. We evaluated, in distinct human HCC prognostic subtypes (as defined by patients' survival length), activation of MYBL2 and MYBL2-related genes, and relationships of p53 status with MYBL2 activity. Highest total and phosphorylated protein levels of MYBL2, E2F1-DP1, inactivated pRB, and CYCLIN B1 occurred in HCC with poorer outcome (HCCP), compared to HCC with better outcome (HCCB). In HCCP, highest LIN9-MYBL2 complex (LINC), and lowest inactive LIN9-p130 complex levels occurred. MYBL2 positively correlated with HCC genomic instability, proliferation and microvessel density, and negatively with apoptosis. Higher MYBL2/LINC activation, in HCC with mutated p53, contrasted with LINC inactivation in HCC harboring wild-type p53. siRNA-mediated MYBL2/LINC silencing reduced proliferation, induced apoptosis and DNA damage at similar levels in HCC cell lines, irrespective of p53 status. However, association of MYBL2/LINC silencing with doxorubicin-induced DNA damage caused stronger growth restraint in p53-/- Huh7 and Hep3B cells, than in p53+/+ Huh6 and HepG2 cells. Doxorubicin triggered LIN9 dissociation from MYBL2 in p53+/+ cell lines, and increased MYBL2-LIN9 complexes in p53-/- cells. Doxorubicin-induced MYBL2 dissociation from LIN9 led to p21WAF1 upregulation in p53+/+, but not in p53-/- cell lines. Suppression of p53 or p21WAF1 genes abolished DNA damage response, enhanced apoptosis, and inhibited growth in doxorubicin-treated cells harboring p53+/+. In conclusion, we showed that MYBL2 activation is crucial for human HCC progression. In particular, our data indicate that MYBL2-LIN9 complex integrity contributes to survival of DNA damaged p53-/- cells. Thus, MYBL2 inhibition could represent a valuable adjuvant for treatments against human HCC with mutated p53.
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