[Frontiers in Bioscience 14, 2923-2934, January 1, 2009]

Modulation of TGF-beta signaling during progression of chronic liver diseases

Koichi Matsuzaki1

1Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. TGF-beta signaling of hepatocytes is affected by chronic inflammation during progression of chronic liver diseases 3.1. pSmad3C transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by the JNK/pSmad3L pathway
3.2. pSmad3C transmits signaling in mature hepatocytes, while pSmad3L does so in activated mesenchymal cells
3.3. Hepatocytes showing mesenchymal pSmad3L signaling adjacent to collagen fibers in portal tracts of human chronic hepatitis C specimens
3.4. Human hepatic fibro-carcinogenesis: reciprocal change in pSmad3L and pSmad3C pathways
3.5. Epithelial-to-mesenchymal transition during progression of chronic liver diseases: the shift of hepatocytic TGF-beta signaling from pSmad3C to pSmad3L pathways
3.6. Chronic inflammation associated with HCV infection shifts hepatocytic TGF-beta signaling from tumor-suppression to fibro-carcinogenesis, accelerating liver fibrosis and increasing the risk for HCC
3.7. Activated JNK down-regulates the epithelial pSmad3C pathway in favor of up-regulating the mesenchymal pSmad3L pathway in pre-neoplastic hepatocytes
4. Perspectives
5. Acknowledgements
6. References

1. ABSTRACT

A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases.