INCREASED P-GLYCOPROTEIN MESSENGER-RNA STABILITY IN RAT-LIVER TUMORS IN-VIVO

P-glycoproteins (Pgp) are comprised of a small family of plasma membra ne proteins whose abundance in cultured cells is often associated with the multidrug resistance phenotype. Overexpression of Pgp has been ob served in many types of human cancers, but the molecular basis for thi s overexpression has not been established. We have used primary monola yer cultures of adult rat hepatocytes and a stepwise model of rat live r carcinogenesis to study the regulation of Pgp gene expression. We ob served a marked overexpression of Pgp, specifically the class II Pgp, in both systems. In addition, we observed that a number of unrelated g enes including alpha-tubulin, beta-actin, gamma-actin, cytokeratin 8, cytokeratin 18, and c-myc are overexpressed in cultured hepatocytes, a nd they are also overexpressed during liver carcinogenesis and in tran splantable tumors. Nuclear run-on assays showed no increase in the tra nscriptional activity of Pgp genes in transplantable liver tumors comp ared to normal liver. Studies of in vivo mRNA stability, however, reve aled that all three Pgp mRNAs were relatively stable in transplantable liver tumors (t(1/2) > 12 h), in contrast to what was found in normal liver (t(1/2) < 2 h). In addition, mRNA for several other genes, incl uding alpha-tubulin, c-myc, and cyclin D1, all appear to be stabilized in the tumors. These findings suggest that the overexpression of Pgp genes in rat liver tumors may be the result of a mechanism involving s tabilization of a diverse group of mRNAs. J. Cell. Physiol. 177:1-12, 1998. (C) 1998 Wiley-Liss, Inc.