Gene Expression of ABC Proteins in Hepatocellular Carcinoma, Perineoplastic Tissue, and Liver Diseases

BackgroundThe development of hepatocellular carcinoma (HCC) is a frequent event during the natural history of cirrhosis. Effective treatment is, however, hampered by drug resistance related to the expression of multidrug resistance (MDR) proteins belonging to the ABC family transporters. Studying expression of genes coding for these proteins may help to explain the potential sensitivity of HCC to chemotherapy.Material and MethodsThe expression of MRP1, MRP2, MRP3, MDR1, and MDR3 was investigated by quantitative RT-PCR analyses in paraffin-embedded tissues obtained from 9 cases of HCC, 16 cases of cirrhosis, 10 cases of chronic extrahepatic cholestasis, and 16 cases of normal liver. In HCC cases, gene expression was assessed both in neoplastic and perineoplastic tissue after microscopically assisted microdissection.ResultsMRP1 was significantly and similarly overexpressed in HCC and perineoplastic tissue. MRP2 and MDR1 were also increased in HCC, but the level of expression did not correlate with that of perineoplastic tissue. The level of expression was either reduced or normal in cirrhotic liver and during chronic cholestasis. Expression of MDR3 was unchanged in all conditions investigated.ConclusionsThe genetic expression of multi-drug resistance proteins, in particular MRP1, MRP2, and MDR1, is increased during HCC. In the case of MRP1, the extent of expression is similar in neoplastic and perineoplastic tissue, but this is not the case for MRP2 and MDR1. The assessment of ABC protein expression pattern may provide important information for the diagnosis and treatment of HCC.

[1]  D. Hipfner,et al.  Structural, mechanistic and clinical aspects of MRP1. , 1999, Biochimica et biophysica acta.

[2]  S. Bonin,et al.  RNA quantitative analysis from fixed and paraffin-embedded tissues. , 1998, Methods in molecular biology.

[3]  C. Tiribelli,et al.  Prevalence of chronic liver disease in the general population of northern Italy: The dionysos study , 1994, Hepatology.

[4]  S. Bonin,et al.  RNA extraction from formalin-fixed and paraffin-embedded tissues. , 1998, Methods in molecular biology.

[5]  U. Beuers,et al.  Downregulation of the hepatocellular organic anion transporters OATP-C and MRP2 in patients with primary sclerosing cholangitis , 2000 .

[6]  F. Thévenod,et al.  Up-regulation of Multidrug Resistance P-glycoprotein via Nuclear Factor-κB Activation Protects Kidney Proximal Tubule Cells from Cadmium- and Reactive Oxygen Species-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[7]  P. Bosma,et al.  Congenital Jaundice in Rats with a Mutation in a Multidrug Resistance-Associated Protein Gene , 1996, Science.

[8]  C. Tiribelli,et al.  Treatment options in Western hepatocellular carcinoma: a prospective study of 224 patients. , 1998, Journal of hepatology.

[9]  A. Duncan,et al.  Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. , 1992, Science.

[10]  F Uggeri,et al.  Abc protein transport of MRI contrast agents in canalicular rat liver plasma vesicles and yeast vacuoles. , 2001, Biochemical and biophysical research communications.

[11]  D. Keppler,et al.  Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma , 2001, International journal of cancer.

[12]  T. Lu,et al.  Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo. , 2000, Blood.

[13]  S. Bonin,et al.  RNA quantitative analysis from fixed and paraffin-embedded tissues: membrane hybridization and capillary electrophoresis. , 1998, BioTechniques.

[14]  A. Groen,et al.  The role of phospholipids in bile formation: what can we learn from animals and human disease? , 2000 .

[15]  M. Colombo,et al.  Hepatocellular carcinoma in Italian patients with cirrhosis. , 1991, The New England journal of medicine.

[16]  B. Sarkadi,et al.  An inventory of the human ABC proteins. , 1999, Biochimica et biophysica acta.

[17]  S. Bonin,et al.  Cohort effect of HCV infection in liver cirrhosis assessed by a 25 year study. , 2000, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[18]  U. Beuers,et al.  Hepatobiliary transport. , 2000, Journal of Hepatology.

[19]  T. Godfrey,et al.  Quantitative mRNA expression analysis from formalin-fixed, paraffin-embedded tissues using 5' nuclease quantitative reverse transcription-polymerase chain reaction. , 2000, The Journal of molecular diagnostics : JMD.

[20]  Kenzo Kobayashi,et al.  Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis , 1990, Hepatology.

[21]  M. Müller,et al.  Transcriptional Control of Hepatocanalicular Transporter Gene Expression , 2000, Seminars in liver disease.

[22]  F Uggeri,et al.  Molecular mechanisms for the hepatic uptake of magnetic resonance imaging contrast agents. , 1999, Biochemical and biophysical research communications.

[23]  U. Lehmann,et al.  Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. , 2001, Methods.

[24]  C. Tiribelli,et al.  The spectrum of liver disease in the general population: lesson from the Dionysos study. , 2001, Journal of hepatology.

[25]  M. Sorrell,et al.  Hepatocellular carcinoma , 1999, The Lancet.

[26]  K. Zatloukal,et al.  Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases , 2001, Hepatology.

[27]  G. Brandi,et al.  Drinking habits as cofactors of risk for alcohol induced liver damage , 1997, Gut.

[28]  J. Bruix,et al.  Prognostic prediction and treatment strategy in hepatocellular carcinoma , 2002, Hepatology.

[29]  J. Baak,et al.  Increased expression of multidrug resistance related proteins Pgp, MRP1, and LRP/MVP occurs early in colorectal carcinogenesis. , 1999, Journal of clinical pathology.

[30]  S A Curley.  Radiofrequency Ablation of Malignant Liver Tumors , 2001, The oncologist.

[31]  G. Hooiveld,et al.  Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[32]  M. Makuuchi,et al.  Results of surgical and nonsurgical treatment for small‐sized hepatocellular carcinomas: A retrospective and nationwide survey in Japan , 2000, Hepatology.

[33]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.

[34]  X. Forns,et al.  Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center. , 2001, Journal of hepatology.

[35]  G. Stanta,et al.  RNA extracted from paraffin-embedded human tissues is amenable to analysis by PCR amplification. , 1991, BioTechniques.

[36]  S. Cole,et al.  Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. , 2001, Toxicology.