Overexpression of a p-glycoprotein in hepatocellular carcinomas from woodchuck hepatitis virus-infected woodchucks (Marmota monax).
The leading cause of human hepatocellular carcinomas (HCCs) is hepatitis B virus (HBV) infection. Woodchucks infected with a closely related hepadnavirus, woodchuck hepatitis virus (WHV), serve as a model for HBV because woodchucks chronically infected with WHV also develop hepatocellular carcinomas. Increased expression of p-glycoprotein (pgp) in human HCCs is a common obstacle in successful cancer chemotherapy. Pgps are encoded by a family of multidrug-resistance (MDR) genes. Livers from uninfected and WHV-infected woodchucks were examined to determine if pgp was expressed in HCCs and if there was a difference in expression between HCCs and nonneoplastic liver. A 170-kd protein was identified by Western blot in HCCs, whereas, constitutive pgp was not detected in normal liver taken from the same animals in 3 of 3 cases. Immunolocalization of the pgp with a panel of monoclonal antibodies revealed intensification of staining in 7 of 20 foci and 12 of 22 HCCs from six animals. Using primers for the human MDR1 gene, a single product was detected by reverse-transcribed polymerase chain reaction (RT-PCR) from HCCs. We have shown an increase in pgp in HCCs compared with normal liver from WHV-infected woodchucks. This is the first example of the induction of a pgp in a naturally hepadnavirus infected rodent system. It suggests the woodchuck can be a useful model for the study of the acquisition of resistance to chemotherapeutic agents in virally induced HCCs.
Dunn
S E
SE
Department of Toxicology, North Carolina State University, College of Veterinary Medicine, Raleigh, USA.
Hughes
C S
CS
LeBlanc
G A
GA
Cullen
J M
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006509:Hepatitis B / Q000150:complications*; D017919:Hepatitis B Virus, Woodchuck; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D008392:Marmota; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger