Investigation of the cooperative effects of transforming growth factor alpha and c-myc overexpression in rat liver epithelial cells.
Overexpression of both transforming growth factor (TGF)-alpha and c-myc is consistently reported in hepatic tumors. We transfected rat liver epithelial cells (RLECs) with expression vectors for TGF-alpha, c-myc, or both and analyzed the morphology, biological properties, and tumorigenicity of clones that overexpressed these genes. The transfectants were morphologically indistinguishable from the parental RLECs, but the overexpression of TGF-alpha resulted in changes in growth properties and an enhanced response to the mitogenic effects of hepatocyte growth factor. The concomitant overexpression of c-myc decreased growth factor requirements of the TGF-alpha lc-myc clones compared with RLEC and TGF-alpha clones. The TGF-alpha and TGF-alpha lc-myc clones were tumorigenic in nude mice at frequencies of 27% and 53%, respectively, indicating that the genes cooperate in malignant transformation. However, the untransformed nature and low tumorigenicity of the transfectants suggest that transformation depends on other cellular events in addition to the overexpression of TGF-alpha or c-myc. Characterization of tumor cell lines showed that in contrast to the transfectants, the tumor clones were morphologically transformed, capable of autonomous growth and anchorage-independent growth, and aggressively tumorigenic with a frequency of 100%. Clearly, the tumor cells differed from the transfectants and had undergone biological or genetic alterations (or both) as a consequence of the overexpression of TGF-alpha or c-myc. Our data suggest that the overexpression of TGF-alpha leads to enhanced responsiveness to hepatocyte growth factor, whereas the concomitant overexpression of c-myc confers growth-factor independence, providing a potential explanation of the mechanisms by which the overexpression of these genes results in transformation.
Presnell
S C
SC
Department of Pathology, Medical College of Virginia, Richmond, USA.
Thompson
M T
MT
Strom
S C
SC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000235:genetics; D004847:Epithelial Cells; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes; D016259:Genes, myc; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D004273:DNA, Neoplasm; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor