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Epidermal growth factor receptor (EGFR), an aberrantly overexpressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for nonsmall cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ ABCG2 expression.

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Chronic infection with the hepatitis C virus (HCV) isThe identification of the hepatitis C virus (HCV) in 1989 led to the recognition that hepatitis C is a major cause of end-stage liver disease, accounting for more than 20% of liver transplantations in the United States in 1995. 1 Recognition of the importance of HCV infection has been the result of increasingly reliable methods of detection. An enzyme-linked immunoassay (EIA-1) to detect antibody to HCV (anti-HCV) was introduced in 1990, followed by a more sensitive and specific second-generation serological test (EIA-2) by the middle of 1992. Simultaneously, a second-generation recombinant immunoblot assay (RIBA-2) was introduced as a confirmatory test for the EIA. These assays for antibody were supplemented by sensitive methods to detect HCV RNA in serum, most notably by reverse-transcription polymerase chain reaction (RT-PCR) methods. The HCV RNA can also be characterized according to genotype and serum concentration. Application of these assays to serum from patients undergoing liver transplantation has better defined the role of HCV as a cause of end-stage liver disease and the clinical challenges of hepatitis C both before and after transplantation.Various aspects of HCV infection have been evaluated in liver transplantation, including rate of recurrence, 2-4 transmission from infected donors, 5,6 and the accuracy of serological assays. 7 However, these studies have generally examined isolated features of infection among relatively small numbers of patients or at a single center. We performed systematic testing for HCV in a large, multicenter, prospective study to evaluate donor and recipient predictors of posttransplantation infection, serological changes with transplantation, and genotype and viral levels before and after transplantation.