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The Korean Journal of Pathology 2011;45(3): 281-289.
doi: https://doi.org/10.4132/KoreanJPathol.2011.45.3.281
Expression of Multidrug Resistance Protein 1 in Human Hepatocellular Carcinoma.
Yun Kyung Kang
Department of Pathology, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea. jadepaka@hanmail.net
BACKGROUND: Multidrug resistance protein 1 (MDR1) encoded by ATP-binding cassette, sub-family B (Mdr/Tap), member 1 (ABCB1) mediates cross-resistance to antineoplastic drugs, and its expression is related to tumor aggressiveness. METHODS: MDR1 expression was investigated in 100 hepatocellular carcinomas (HCCs) by immunohistochemical staining. The epigenetic mechanisms underlying ABCB1 transcriptional regulation were investigated in cell lines. RESULTS: MDR1 was normally localized in the bile canalicular surface of the hepatocytes. Among 100 HCCs, 45 showed canalicular/luminal (CL) staining similar to the normal pattern, another 45 displayed membranous/cytoplasmic (MC) overexpression, and the remaining 10 revealed loss of expression. MC pattern or null staining of HCCs correlated with a higher histological grade and had a poorer prognosis than HCCs with a CL pattern (p<0.05). They also tended to have a poor prognosis by multivariate survival analysis. The ABCB1 promoter was hypomethylated regardless of MDR1 expression or ABCB1 mRNA levels in 10 HCC cell lines. Histone deacetylase inhibitor treatment induced ABCB1 upregulation in 4 cell lines with low or moderate ABCB1 levels. CONCLUSIONS: Our findings suggest that either an increase or a loss of MDR1 expression may contribute to the poor outcome of HCCs; histone deacetylation may be one of the epigenetic mechanisms directing the ABCB1 expression in HCCs.
Key Words: Carcinoma, hepatocellular; MDR1 protein, human; Immunohistochemistry; Survival analysis; Epigenesis, genetic