Expression of Multidrug Resistance Protein 1 in Human Hepatocellular Carcinoma
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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.
Abstract
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.
참고문헌 (26)
- Altekruse SF, "Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005", J Clin Oncol, 27, pp.1485~1491 (2009)
- Annual report of cancer statistics in Korea in 2008, "The Korea Central Cancer Registry, National Cancer Center", Ministry of Health and Welfare, 19~20 (2010)
- Befeler AS, "Hepatocellular carcinoma: diagnosis and treatment", Gastroenterology, 122, pp.1609~1619 (2002)
- Gottesman MM, "The multidrug transporter, a double-edged sword", J Biol Chem, 263, pp.12163~12166 (1988)
- Moscow JA, "Multidrug resistance", J Natl Cancer Inst, 80, pp.14~20 (1988)
- Fojo AT, "Expression of a multidrug-resistance gene in human tumors and tissues", Proc Natl Acad Sci U S A, 84, pp.265~269 (1987)
- Goldstein LJ, "Expression of a multidrug resistance gene in human cancers", J Natl Cancer Inst, 81, pp.116~124 (1989)
- Ferguson LR, "Multiple drug resistance, antimutagenesis and anticarcinogenesis", Mutat Res, 591, pp.24~33 (2005)
- Tada Y, "MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment", Clin Cancer Res, 6, pp.4618~4627 (2000)
- Enokida H, "CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer", Cancer Res, 64, pp.5956~5962 (2004)
- David GL, "MDR1 promoter hypermethylation in MCF-7 human breast cancer cells: changes in chromatin structure induced by treatment with 5-Aza-cytidine", Cancer Biol Ther, 3, pp.540~548 (2004)
- Baker EK, "Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs", Oncogene, 24, pp.8061~8075 (2005)
- Chen KG, "Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line", Cancer Res, 65, pp.9388~9397 (2005)
- Baker EK, "MDR1, chemotherapy and chromatin remodeling", Cancer Biol Ther, 3, pp.819~824 (2004)
- Shen DW, "Human hepatocellular carcinoma cell lines exhibit multidrug resistance unrelated to MRD1 gene expression", J Cell Sci, 98(Pt 3), pp.317~322 (1991)
- Itsubo M, "Immunohistochemical study of expression and cellular localization of the multidrug resistance gene product P-glycoprotein in primary liver carcinoma", Cancer, 73, pp.298~303 (1994)
- Park JG, "MDR1 gene expression: its effect on drug resistance to doxorubicin in human hepatocellular carcinoma cell lines", J Natl Cancer Inst, 86, pp.700~705 (1994)
- Soini Y, "Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis", J Clin Pathol, 49, pp.470~473 (1996)
- Takanishi K, "Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma", Oncology, 54, pp.231~237 (1997)
- Kong XB, "Overexpression of P-glycoprotein in hepatocellular carcinoma and its clinical implication", World J Gastroenterol, 6, pp.134~135 (2000)
- Ng IO, "Expression of P-glycoprotein in hepatocellular carcinoma: a determinant of chemotherapy response", Am J Clin Pathol, 113, pp.355~363 (2000)
- Kato A, "Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection", J Surg Oncol, 78, pp.110~115 (2001)
- Nakano A, "Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma", Hepatol Res, 25, pp.158~165 (2003)
- Kang YK, "Overexpression of clusterin in human hepatocellular carcinoma", Hum Pathol, 35, pp.1340~1346 (2004)
- Edge SB, "AJCC cancer staging manual. 7th ed", pp.191~195 (2010), Springer
- Vander Borght S, "Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin", Liver Int, 28, pp.1370~1380 (2008)