Se. Dunn et al., OVEREXPRESSION OF A P-GLYCOPROTEIN IN HEPATOCELLULAR CARCINOMAS FROM WOODCHUCK HEPATITIS VIRUS-INFECTED WOODCHUCKS (MARMOTA-MONAX), Hepatology, 23(4), 1996, pp. 662-668
The leading cause of human hepatocellular carcinomas (HCCs) is hepatit
is B virus (HBV) infection. Woodchucks infected with a closely related
hepadnavirus, woodchuck hepatitis virus (WHV), serve as a model for H
BV because woodchucks chronically infected with WHV also develop hepat
ocellular carcinomas. Increased expression of p-glycoprotein (pgp) in
human HCCs is a common obstacle in successful cancer chemotherapy. Pgp
s 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 express
ion between HCCs and nonneoplastic liver. A 170-kd protein was identif
ied by Western blot in HCCs, whereas, constitutive pgp was not detecte
d in normal liver taken from the same animals in 3 of 3 cases. Immunol
ocalization 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) fro
m 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 i
nduction of a pgp in a naturally hepadnavirus infected rodent system.
It suggests the woodchuck can be a useful model for the study of the a
cquisition of resistance to chemotherapeutic agents in virally induced
HCCs.