Immunohistochemical Assessment of the Expression of Biliary Transportation Proteins MRP2 and MRP3 in Hepatocellular Carcinoma and in Cholangiocarcinoma

Abstract

Multidrug resistance-associated protein 2 (MRP2) is a multi-specific organic anion transporter predominantly expressed in the canalicular membrane of hepatocytes, epithelial cells from gallbladder and apical membranes of proximal tubular kidney epithelium whereas multidrug resistance-associated protein 3 (MRP3) is present in the basolateral membrane of hepatocytes and cholangiocytes. This study aims to detect the expression of these transporters in hepatocellular carcinoma (HCC) and in cholangiocarcinoma (CC), searching for evidences for future studies on differential diagnosis and on clinical essays. The immunohistochemical reactivity (IHC) of these transporters was assessed in tissue microarrays of 80 HCC and 56 CC cases using monoclonal antibodies and compared with anatomopathological (AP) variables. The positivity of MRP2 was observed in 92.3% of HCC and in 96.3% of CC. The detection of high MRP2 expression in HCC was not significantly different (p > 0.05) according to the size, number of nodules architectural pattern and growth pattern of HCC and CC. Regarding histological grades, 22/22 well moderately differentiated HCC versus 50/56 poorly differentiated HCC were positive for MRP2. A trend for lower expression in poor differentiation HCC was found. And 50/50 well/moderately differentiated CC versus 2/4 poorly/undifferentiated CC were positive for MRP2. This result showed a reduced expression (p = 0,0004) in poorly differentiated CC. MRP3 positivity was observed in 18.8% of HCC and was not significantly different according to AP parameters. MRP3 was expressed in 44.5% CC, with a trend for lower expression in less differentiated CC and significantly lower rates in the ductular histological subtype (p = 0.023). The high expression of MRP2 in HCC and in CC is conserved regardless most of the anatomopathological parameters, except for a trend of lower expression in less differentiated HCC and CC. The observation of lower MRP3 expression in less differentiated CC and, especially, in the histological subtype with expression of hepatic progenitor cell phenotypes leads to future opportunities to evaluate the expression of this marker in cholangiocarcinomas.

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