Autocrine production of TGF-{beta} confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes: Role of EGF receptor ligands

Journal Article · Sun Sep 10 04:00:00 EDT 2006 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2006.05.017· OSTI ID:20858017

Castillo, Gaelle del ^[1]; Murillo, Miguel M ^[1]; Alvarez-Barrientos, Alberto ^[2]; Bertran, Esther ^[3]; Fernandez, Margarita ^[1]; Sanchez, Aranzazu ^[1]; Fabregat, Isabel ^[3]

---

1. Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid (Spain)
2. Fundacion Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Madrid (Spain)
3. IDIBELL-Institut de Recerca Oncologica, Gran Via s/n, Km 2.7, 08907 L'Hospitalet, Barcelona (Spain)

Transforming growth factor-beta (TGF-{beta}) induces apoptosis in fetal rat hepatocytes. However, a subpopulation of these cells survives, concomitant with changes in phenotype, reminiscent of an epithelial-mesenchymal transition (EMT). We have previously suggested that EMT might confer cell resistance to apoptosis (Valdes et al., Mol. Cancer Res., 1: 68-78, 2002). However, the molecular mechanisms responsible for this resistance are not explored yet. In this work, we have isolated and subcultured the population of hepatocytes that suffered the EMT process and are resistant to apoptosis (TGF-{beta}-treated fetal hepatocytes: T{beta}T-FH). We prove that they secrete mitogenic and survival factors, as analyzed by the proliferative and survival capacity of conditioned medium. Inhibition of the epidermal growth factor receptor (EGFR) sensitizes T{beta}T-FH to die after serum withdrawal. T{beta}T-FH expresses high levels of transforming growth factor-alpha (TGF-{alpha}) and heparin-binding EGF-like growth factor (HB-EGF) and shows constitutive activation of the EGFR pathway. A blocking anti-TGF-{alpha} antibody restores the capacity of cells to die. TGF-{beta}, which is expressed by T{beta}T-FH, mediates up-regulation of TGF-{alpha} and HB-EGF expression in those cells. In summary, results suggest that an autocrine loop of TGF-{beta} confers resistance to apoptosis after an EMT process in hepatocytes, through the increase in the expression of EGFR ligands.

• OSTI ID: 20858017
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 15 Vol. 312; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
APOPTOSIS
GROWTH FACTORS
HEPARIN
LIGANDS
LIVER CELLS
NEOPLASMS
PHENOTYPE
RATS
RECEPTORS