VEGFR-2, HSP90 and GRP78/BiP expression and HCC recurrence after Liver Transplantation

Abstract

Introduction Liver transplantation (LT) for hepatocellular carcinoma (HCC) is a satisfactory therapeutic choice in patients with “early HCC” selected according to Milan criteria. However, the risk of HCC recurrence after LT is about 7-20% at five years and molecular markers which can predict recurrence are still lacking. We investigated in HCC samples and LC surrounding tissues the significance of VEGFR-2, HSP90, and GRP78/BiP expression in patients with HCC who underwent LT in a western transplantation center and their possible role as molecular markers of recurrence. Methods 42 patients (35 M, 7 F) with early HCC who underwent LT between 2012 and 2013 were enrolled. The tumor recurrence rate was analyzed after a minimum follow-up of 36 months. Immunohistochemical expression of VEGFR-2, HSP90, and GRP78/BiP in HCC tissues and LC surrounding tissues, was correlated with clinicopathological variables and recurrence-free post-LT survival. At statistical analysis t Student’s or Mann Whitney U test were used where appropriate. To assess which variable measured at baseline was predictive of HCC recurrence, the univariate Cox proportional hazards model (Hr) was fitted to each variable. All variables with a P<0.05 underwent multivariate analysis to assess their value as independent predictors. Results Microvascular invasion was observed in 23 of 42 evaluated patients (45.2%). The expression levels of GRP78, HSP90 and VEGFR-2 in the tumor tissue (TT) compared to non-tumor surrounding tissue (NT), analyzed by the Mann Whitney U test detected significantly higher values of expression for HSP90 and VEGFR-2 in the TT compared to NT (p<0.0001 and p<0.001, respectively). Moreover, the correlation between the expression of these molecules and the presence of microvascular invasion was analyzed through a multiple logistic regression analysis and the presence of VEGFR-2 overexpression in tumor tissues positively correlated with the presence of microvascular invasion in HCC (p < 0.03). Finally, on uni- and multivariate analyses the only parameters which were related to the presence of post LT recurrence were MELD score and microvascular invasion (p < 0.02 and p < 0.04, respectively). Conclusion In conclusion, the finding that over-expression of HSP90 and VEGFR-2 in the tumor compared to non-tumor surrounding HCC samples confirm the likely involvement of these molecules in liver carcinogenesis, and particularly of VEGFR-2 in neoplastic angiogenesis, however these results need to be extended to a wider population, to be used as markers of HCC recurrence after LT in addition to traditional ones like MELD score and microvascular invasion.