Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro

Journal Article · Sun May 15 04:00:00 EDT 2005 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2005.02.004· OSTI ID:20717606

Varley, Claire ^[1]; Hill, Gemma ^[1]; Pellegrin, Stephanie ^[2]; Shaw, Nicola J ^[1]; Selby, Peter J ^[2]; Trejdosiewicz, Ludwik K ^[2]; Southgate, Jennifer ^[1]

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1. Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University of York, Heslington, York YO10 5YW (United Kingdom)
2. Cancer Medicine Research Unit, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds LS9 7TF (United Kingdom)

Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are mitotically quiescent and G0 arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing. Transcripts for HER-1, HER-2, and HER-3 were expressed by quiescent human urothelium in situ. Expression of HER-1 was upregulated in proliferating cultures, whereas HER-2 and HER-3 were more associated with a growth-arrested phenotype. NHU cells could be propagated in the absence of exogenous EGF, but autocrine signaling through HER-1 via the MAPK and PI3-kinase pathways was essential for proliferation and migration during urothelial wound repair. HB-EGF was expressed by urothelium in situ and HB-EGF, epiregulin, TGF-{alpha}, and amphiregulin were expressed by proliferating NHU cells. Urothelial wound repair in vitro was attenuated by neutralizing antibodies against HER-1 ligands, particularly amphiregulin. By contrast, the same ligands applied exogenously promoted migration, but inhibited proliferation, implying that HER-1 ligands provoke differential effects in NHU cells depending upon whether they are presented as soluble or juxtacrine ligands. We conclude that proliferation and migration during wound healing in NHU cells are mediated through an EGFR autocrine signalling loop and our results implicate amphiregulin as a key mediator.

• OSTI ID: 20717606
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 306; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
BIOLOGICAL REPAIR
BLADDER
CATTLE
CELL CYCLE
CELL PROLIFERATION
ELECTRON SPIN RESONANCE
GENE REGULATION
GROWTH FACTORS
HEALING
HEPARIN
IN VITRO
INOSITOL
LIGANDS
PHENOTYPE
RECEPTORS
URINE
WOUNDS