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Activation of v-Myb avian myeloblastosis viral oncogene homolog-like2 (MYBL2)-LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of hepatocellular carcinoma with mutant p53

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 v-Myb avian myeloblastosis viral oncogene homolog-like2 (MYBL2)-LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of hepatocellular carcinoma with mutant p53. Hepatology, Vol. 53 (4), p. 1226-1236. ISSN 0270-9139. eISSN 1527-3350. Article.

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DOI: 10.1002/hep.24174

Abstract

Up-regulation of the v-Myb avian myeloblastosis viral oncogene homolog-like2 B-Myb (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 patient 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 retinoblastoma protein (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 was in contrast with LINC inactivation in HCC harboring wildtype p53. Small interfering RNA (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 up-regulation 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+/+. Conclusion: We show 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.

Item Type:Article
ID Code:6192
Status:Published
Refereed:Yes
Uncontrolled Keywords:LINC, tumor progression, genomic instability, DNA damage, doxorubicin
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Wiley
ISSN:0270-9139
eISSN:1527-3350
Copyright Holders:© 2011 by the American Association for the Study of Liver Diseases
Deposited On:27 Jun 2011 12:28

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