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Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation

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posted on 25.04.2017, 10:25 by Raúl González, Ángel J. De la Rosa, Alessandro Rufini, María A. Rodríguez-Hernández, Elena Navarro-Villarán, Trinidad Marchal, Sheila Pereira, Manuel De la Mata, Martina Müller-Schilling, Juan M. Pascasio-Acevedo, María T. Ferrer-Ríos, Miguel A. Gómez-Bravo, Francisco J. Padillo, Jordi Muntané
BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. METHODS: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. RESULTS: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. CONCLUSIONS: The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.

Funding

Instituto de Salud Carlos III (PI13/00021), Consejería de Economía, Innovación, Ciencia y Empleo (CTS-6264) and Consejería de Salud (PI13/00025). CIBERehd founded by Instituto de Salud Carlos III and co-financed by European Development Regional Fund "A way to achieve Europe" ERDF for their support.

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Citation

PLoS One, 2017, 12 (3), pp. e0174326

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

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VoR (Version of Record)

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PLoS One

Publisher

Public Library of Science

eissn

1932-6203

Acceptance date

07/03/2017

Copyright date

2017

Available date

25/04/2017

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174326

Language

en

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