help button home button Am J Pathol Epitomics Buy 2 Antibodies Get 1 Free Special Offer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Santoni-Rugiu, E.
Right arrow Articles by Thorgeirsson, S. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Santoni-Rugiu, E.
Right arrow Articles by Thorgeirsson, S. S.
(American Journal of Pathology. 1999;154:1693-1700.)
© 1999 American Society for Investigative Pathology

Regular Articles

Acceleration of c-myc-Induced Hepatocarcinogenesis by Co-Expression of Transforming Growth Factor (TGF)-{alpha} in Transgenic Mice Is Associated with TGF-ß1 Signaling Disruption

Eric Santoni-Rugiu*{dagger}, Michael R. Jensen*, Valentina M. Factor* and Snorri S. Thorgeirsson*

From the Laboratory of Experimental Carcinogenesis,*
Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland, and the Department of Experimental Pathology,{dagger}
University of Pisa, Pisa, Italy

We have previously shown in transgenic mice that transforming growth factor (TGF)-{alpha} dramatically enhances c-myc-induced hepatocarcinogenesis by promoting proliferation and survival of hepatocellular carcinoma (HCC) cells. As transgenic livers display increased levels of mature TGF-ß1 from the early stages of hepatocarcinogenesis, we have now assessed whether impairment of TGF-ß1 signaling contributes to the deregulation of cell cycle progression and apoptosis observed during this process. Focal preneoplastic lesions lacking expression of TGF-ß receptor type II (TßRII) were detected in c-myc/TGF-{alpha} but not in c-myc livers. In c-myc/TGF-{alpha} mice, 40% (2/5) of adenomas and 90% (27/30) of HCCs showed down-regulation of TßRII expression in comparison with 11% (2/18) of adenomas and 47% (14/30) of HCCs in c-myc mice. Down-regulation of the TGF-ß1-inducible p15INK4B mRNA and reduced apoptotic rates in TßRII-negative HCCs further indicated the disruption of TGF-ß1 signaling. Furthermore, both TßRII-negative and -positive c-myc TGF-{alpha} HCCs, but not c-myc HCCs, were characterized by decreased levels of the cell cycle inhibitor p27. These results suggest 1) an inverse correlation of decreased p27 expression with the particularly strong expression of TGF-{alpha} in these lesions, consistent with the capacity of TGF-{alpha} signaling to post-transcriptionally regulate p27, and 2) the presence of alternative, downstream defects of TGF-ß1 signaling in c-myc/TGF-{alpha} HCCs that may impair the growth-inhibitory response to TGF-ß1. Thus, the accelerated neoplastic development in c-myc/TGF-{alpha} mice is associated with an early and frequent occurrence of TßRII-negative lesions and with reduced levels of p27 in HCC cells, indicating that disruption of TGF-ß1 responsiveness may play a crucial role in the enhancement of c-myc-induced hepatocarcinogenesis by TGF-{alpha}.




This article has been cited by other articles:


Home page
 Toxicol PatholHome page
D. F. Calvisi and S. S. Thorgeirsson
Molecular Mechanisms of Hepatocarcinogenesis in Transgenic Mouse Models of Liver Cancer
Toxicol Pathol, January 1, 2005; 33(1): 181 - 184.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
A. B. Rogers, S. R. Boutin, M. T. Whary, N. Sundina, Zhongming Ge, K. Cormier, and J. G. Fox
Progression of Chronic Hepatitis and Preneoplasia in Helicobacter hepaticus-Infected A/JCr Mice
Toxicol Pathol, October 1, 2004; 32(6): 668 - 677.
[Abstract] [PDF]

Home page
 Cancer Res.Home page
M. Nakau, H. Miyoshi, M. F. Seldin, M. Imamura, M. Oshima, and M. M. Taketo
Hepatocellular Carcinoma Caused by Loss of Heterozygosity in Lkb1 Gene Knockout Mice
Cancer Res., August 15, 2002; 62(16): 4549 - 4553.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
Do Youn Park, Soon Yeol Hwang, and Kang Suek Suh
Expression of Transforming Growth Factor (TGF)-{beta}1 and TGF-{beta} Type II Receptor in Preneoplastic Lesions During Chemical Hepatocarcinogenesis of Rats
Toxicol Pathol, August 1, 2001; 29(5): 541 - 549.
[Abstract] [PDF]

Home page
 Cancer Res.Home page
S. Yang, H. Z. Lin, J. Hwang, V. P. Chacko, and A. M. Diehl
Hepatic Hyperplasia in Noncirrhotic Fatty Livers: Is Obesity-related Hepatic Steatosis a Premalignant Condition?
Cancer Res., July 1, 2001; 61(13): 5016 - 5023.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. F. Calvisi, V. M. Factor, R. Loi, and S. S. Thorgeirsson
Activation of {beta}-Catenin during Hepatocarcinogenesis in Transgenic Mouse Models: Relationship to Phenotype and Tumor Grade
Cancer Res., March 1, 2001; 61(5): 2085 - 2091.
[Abstract] [Full Text]

Home page
 Mol. Cell. Biol.Home page
E. Santoni-Rugiu, J. Falck, N. Mailand, J. Bartek, and J. Lukas
Involvement of Myc Activity in a G1/S-Promoting Mechanism Parallel to the pRb/E2F Pathway
Mol. Cell. Biol., May 15, 2000; 20(10): 3497 - 3509.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
V. M. Factor, D. Laskowska, M. R. Jensen, J. T. Woitach, N. C. Popescu, and S. S. Thorgeirsson
Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model
PNAS, February 29, 2000; 97(5): 2196 - 2201.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 1999 by the American Society for Investigative Pathology.