c-Myc and transforming growth factor α enhance the development of hepatic lesions due to mutant β-catenin in transgenic mice.
Alterations in the Wnt signaling pathway are associated with diverse cancers, including hepatocellular carcinoma (HCC). The development of HCC is thought to be a multistage process in which multiple genetic alterations are necessary. Few studies have assessed the effect of aberrant Wnt signaling activity in association with other molecular alterations in HCC. Here we sought to determine whether co-overexpression of c-Myc or TGFα, 2 signaling molecules known to contribute to HCC development, enhanced the development of hepatic lesions associated with a stabilized β-catenin. The coexpression of mutant β-catenin with either c-Myc or TGFα within hepatocytes increased the severity of hepatic lesions compared with that associated with any of the transgenes expressed individually. The coexpression of mutant β-catenin with c-Myc or TGFα resulted in severe hepatomegaly necessitating the euthanasia of mice by an average of 156 and 128 d, respectively, after the cessation of doxycycline. The expression of mutant β-catenin alone resulted in mild to moderate hepatomegaly that prompted the euthanasia of mice by an average of 75 d after the cessation of doxycycline. Collectively, these findings indicate that coexpression of c-Myc or TGFα delays the onset of endstage hepatic disease yet enhances the severity of hepatic lesions due to mutant β-catenin.
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Adam S
AS
Jochem
Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Katie E
KE
Holmes
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA; 4Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA; tjstein@wisc.edu.
Timothy J
TJ
Stein
D000704:Analysis of Variance; D000818:Animals; D001947:Breeding / Q000379:methods; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016211:Transforming Growth Factor alpha; D051176:beta Catenin