Carcinogenesis Advance Access originally published online on August 14, 2007
Carcinogenesis 2007 28(12):2624-2631; doi:10.1093/carcin/bgm184
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Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells
1 Department of Pathology
2 Molecular and Cellular Biology Graduate Program
3 Department of Surgery, University of Washington, Seattle, WA 98195, USA
* To whom correspondence should be addressed. Tel: +1 206 616 4550; Fax: +1 206 543 3967; Email: nfausto{at}u.washington.edu
The MYC oncogene induces both cell proliferation and apoptosis. The apoptotic function of MYC is thought to inhibit carcinogenesis; thus, when disrupted, tumorigenic potential is increased. Both MYC and transforming growth factor alpha (TGF
) are commonly over-expressed in hepatocellular carcinomas, and transgenic mice expressing these genes rapidly develop tumors via the suppression of MYC-induced apoptosis by the growth factor. However, the nature of the interactions between MYC and TGF are not well understood. Specifically, it is unclear whether TGF acts only as an anti-apoptotic factor in its interactions with MYC or whether it has substantial effects on cell growth. We investigated whether TGF can provide additional mitogenic signals if it is not required to act as an anti-apoptotic factor. We demonstrate that expression of MYC and TGF in liver progenitor cells (known as oval cells) results in enhanced cell proliferation in culture and the generation of poorly differentiated tumors after inoculation into nude mice. We further demonstrate that while the apoptosis-deficient T58A and S71F alleles of MYC retain their ability to promote oval cell proliferation, they have opposite growth interactions with TGF. The T58A allele has a stimulatory effect on both proliferation and tumorigenicity. In contrast, co-expression of the S71F allele reduces proliferation and slows tumor development. We conclude that the tumorigenic growth effects of MYC in TGF-expressing liver progenitor cells are not solely dependent on its apoptotic activity.
Abbreviations: FACS, fluorescence activated cell sorting; GFP, green fluorescent protein; HCC, hepatocellular carcinoma; MMP, matrix metalloproteinase; PCR, polymerase chain reaction; TACE, TNF-alpha converting enzyme; TGF, transforming growth factor alpha; VEGF, vascular endothelial growth factor
Received June 4, 2007; revised July 29, 2007; accepted August 1, 2007.