Abstract
Background & AimsPatients 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.MethodsHCC 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.ResultsThe 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.ConclusionsThe 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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world, and the third most common cause of cancer-related mortality worldwide (600,000 deaths per year) [1, 2]
The in vitro study demonstrated that hepatitis B virus (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 expression of TAp63 and ΔNp63, as well as TAp73 and ΔNp73 isoforms were significantly increased in differentiated (Fig 1A) (p 0.001), but reduced in moderately-poorly differentiated (Fig 1B) (p 0.01), hepatocellular carcinoma (HCC) from HBV-infected patients compared to other etiologies
Summary
Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world, and the third most common cause of cancer-related mortality worldwide (600,000 deaths per year) [1, 2]. A meta-analysis of gene expression profiles identified three robust HCC subclasses (termed S1, S2, and S3), characterized by an aberrant activation of the TGF-β and Wnt/β-catenin signaling pathways (S1), Myc and Akt activation, as well as down-regulation of IFN-target genes (S2), and activation of p53 and p21 target genes, and genes associated with hepatocyte differentiation (S3) [4]. In this context, reduced expression of p53 in HCC was related to the most aggressive S1 and S2 subclasses [5].
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