Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat

Domenico Alvaro, Paolo Onori, Veronica Drudi Metalli, Gianluca Svegliati-Baroni, Franco Folli, Antonio Franchitto, Gianfranco Alpini, Maria Grazia Mancino, Adolfo Francesco Attili, Eugenio Gaudio

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Abstract

The aim of this study was to explore the intracellular signaling pathways involved in the stimulatory effects of estrogens on cholangiocyte proliferation. We investigated the tyrosine kinase-receptor pathway by evaluating the protein expression of total and phosphorylated mitogen-activated protein kinase (MAPK) isoform p44/p42 (e.g., extracellular signal-regulated kinase [ERK] 1/2), the steroid-receptor coactivator Src and Shc (Src-homology/collagen protein). The study was performed in 3-week-old bile duct-ligated (BDL) rats, BDL rats treated with the antiestrogens, tamoxifen or Ici 182,780, and normal control rats. Proliferation was also evaluated in normal purified cholangiocytes treated with 17β estradiol in the presence or absence of tamoxifen, Ici 182,780, ERK, or Src inhibitors. After bile duct ligation, cholangiocyte proliferation was associated with a marked immunohistochemical nuclear positivity for phosphorylated (p)-ERK1/2, which was inhibited by in vivo treatment with tamoxifen or Ici 182,780. Protein expression of total and p-ERK1/2, and Shc in cholangiocytes isolated from BDL rats was markedly increased compared with controls and was inhibited by in vivo treatment with antiestrogens. In vitro, 17β estradiol-induced proliferation of isolated normal cholangiocyte was associated with increased (P < .01) protein expression of p-ERK1/2, Src, and Shc. Specific inhibitors of ER (Ici 182,780), ERK (U0125), and Src (PP2) inhibited in vitro 17β estradiol-induced cholangiocyte proliferation. In conclusion, this study showed that estrogens induced cholangiocyte proliferation by activating the Src/Shc/ERK pathway. This might suggest that pharmacologic modulation of ER, ERK, and/or Src could be proposed for the treatment of human pathology characterized by dysregulation of cholangiocyte proliferation.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalHepatology
Volume36
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

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Estrogens
Extracellular Signal-Regulated MAP Kinases
Bile Ducts
Collagen
Tamoxifen
Proteins
Estradiol
Estrogen Receptor Modulators
Mitogen-Activated Protein Kinase 3
Steroid Receptors
Mitogen-Activated Protein Kinase 1
Receptor Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinases
Ligation
Protein Isoforms
Pathology
In Vitro Techniques

ASJC Scopus subject areas

  • Hepatology

Cite this

Alvaro, D., Onori, P., Metalli, V. D., Svegliati-Baroni, G., Folli, F., Franchitto, A., ... Gaudio, E. (2002). Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Hepatology, 36(2), 297-304. https://doi.org/10.1053/jhep.2002.34741

Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. / Alvaro, Domenico; Onori, Paolo; Metalli, Veronica Drudi; Svegliati-Baroni, Gianluca; Folli, Franco; Franchitto, Antonio; Alpini, Gianfranco; Mancino, Maria Grazia; Attili, Adolfo Francesco; Gaudio, Eugenio.

In: Hepatology, Vol. 36, No. 2, 2002, p. 297-304.

Research output: Contribution to journalArticle

Alvaro, D, Onori, P, Metalli, VD, Svegliati-Baroni, G, Folli, F, Franchitto, A, Alpini, G, Mancino, MG, Attili, AF & Gaudio, E 2002, 'Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat', Hepatology, vol. 36, no. 2, pp. 297-304. https://doi.org/10.1053/jhep.2002.34741
Alvaro D, Onori P, Metalli VD, Svegliati-Baroni G, Folli F, Franchitto A et al. Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Hepatology. 2002;36(2):297-304. https://doi.org/10.1053/jhep.2002.34741
Alvaro, Domenico ; Onori, Paolo ; Metalli, Veronica Drudi ; Svegliati-Baroni, Gianluca ; Folli, Franco ; Franchitto, Antonio ; Alpini, Gianfranco ; Mancino, Maria Grazia ; Attili, Adolfo Francesco ; Gaudio, Eugenio. / Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. In: Hepatology. 2002 ; Vol. 36, No. 2. pp. 297-304.
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AU - Onori, Paolo

AU - Metalli, Veronica Drudi

AU - Svegliati-Baroni, Gianluca

AU - Folli, Franco

AU - Franchitto, Antonio

AU - Alpini, Gianfranco

AU - Mancino, Maria Grazia

AU - Attili, Adolfo Francesco

AU - Gaudio, Eugenio

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