Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in ERα-positive gastric cancer

BACKGROUND: Oestrogen receptor-alpha (ER alpha) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ER alpha-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. METHODS: We used 17-beta-oestradiol (E2) as a stimulator against the ER alpha pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ER alpha (ER alpha siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ER alpha-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. RESULTS: In ER alpha-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-beta-Oestradiol- induced cell proliferation was suppressed by ICI, ERa siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ER alpha siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ER alpha and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ER alpha and Hh pathways. CONCLUSION: Our data indicate that activation of the ER alpha pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ER alpha-positive gastric cancer. British Journal of Cancer (2010) 102, 738-747. doi:10.1038/sj.bjc.6605517 www.bjcancer.com Published online 19 January 2010 (C) 2010 Cancer Research UK