NDLI: Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Fransvea, Emilia Angelotti, Umberto Antonaci, Salvatore Giannelli, Gianluigi
Description	Country affiliation: Italy Author Affiliation: Fransvea E ( Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy.)
Abstract	UNLABELLED: Hepatocellular carcinoma (HCC) treatment is challenging because the mechanisms underlying tumor progression are still largely unknown. Transforming growth factor (TGF)-beta1 is considered a crucial molecule in HCC tumorigenesis because increased levels of patients' serum and urine are associated with disease progression. The aim of the present study was to investigate the inhibition of TGF-beta signaling and its impact on HCC progression. Human HCC cell lines were treated with a TGF-beta receptor kinase inhibitor (LY2109761) whose selectivity was determined in a kinase assay. Exogenous TGF-beta1 phosphorylates the TGF-beta receptor, consequently activating Smad-2, whereas the drug selectively blocks this effect and dephosphorylates autocrine p-Smad-2 at concentrations ranging from 0.001 to 0.1 microM. A cytotoxic effect documented by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), trypan blue, and propidium iodide staining assays was observed at 10microM, whereas the drug inhibits (P < 0.001) the migration of HCC cells on fibronectin, laminin-5, and vitronectin and invasion through Matrigel (P < 0.001) at concentrations up to 0.1 microM. LY2109761 up-regulates (P < 0.001) E-cadherin mRNA and protein levels. This increase was localized at the cellular membrane where E-cadherin mediates anchorage that is cell-cell dependent. Consistently, a functional monoclonal antibody that inhibits E-cadherin-dependent cell-cell contact restores the migratory and invasive activity. Finally, nonmetastatic HCC tissues from 7 patients were cultured with TGF-beta1 in the presence or absence of LY2109761. E-cadherin expression was reduced by TGF-beta1 and was significantly (P < 0.0001) increased by LY2109761 treatment, measured by quantitative real-time PCR on microdissected tissues and by immunohistochemistry on serial sections. In 72 patients, E-cadherin tissue expression was more weakly expressed in metastatic than in nonmetastatic HCC (P < 0.0001). CONCLUSION: LY2109761 blocks migration and invasion of HCC cells by up-regulating E-cadherin, suggesting that there could be a mechanistic use for this molecule in clinical trials.
File Format	HTM / HTML
ISSN	02709139
Issue Number	5
Volume Number	47
e-ISSN	15273350
Journal	Hepatology
Language	English
Publisher	Wiley
Publisher Date	2008-05-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Discipline Hepatology Cadherins Genetics Carcinoma, Hepatocellular Pathology Physiopathology Liver Neoplasms Transforming Growth Factor Beta Physiology Aged Antineoplastic Agents Therapeutic Use Benzenesulfonates Drug Therapy Cell Line, Tumor Cell Movement Cell Survival Drug Effects Female Gene Expression Regulation, Neoplastic Humans Male Middle Aged Neoplasm Invasiveness Neoplasm Staging Niacinamide Analogs & Derivatives Phenylurea Compounds Pyridines Antagonists & Inhibitors Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

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