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 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.