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

C. Kameda, Masafumi Nakamura, H. Tanaka, A. Yamasaki, Makoto Kubo, M. Tanaka, Hideya Ohnishi, M. Katano

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Abstract

Background: Oestrogen receptor-alpha (ERα) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERα-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. Methods:We used 17-Β-oestradiol (E2) as a stimulator against the ERα pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERα (ERα siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERα-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 ERα-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-Β-Oestradiol-induced cell proliferation was suppressed by ICI, ERα siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERα 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 ERα and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERα and Hh pathways.Conclusion:Our data indicate that activation of the ERα pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERα-positive gastric cancer.

Original languageEnglish
Pages (from-to)738-747
Number of pages10
JournalBritish journal of cancer
Volume102
Issue number4
DOIs
Publication statusPublished - Feb 1 2010

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Estrogen Receptors
Stomach Neoplasms
Cell Proliferation
Small Interfering RNA
Estrogens
Estradiol
Ligands
Estrogen Receptor alpha
Anti-Idiotypic Antibodies
Pharmaceutical Preparations
cyclopamine

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Oestrogen receptor-α contributes to the regulation of the hedgehog signalling pathway in ERα-positive gastric cancer. / Kameda, C.; Nakamura, Masafumi; Tanaka, H.; Yamasaki, A.; Kubo, Makoto; Tanaka, M.; Ohnishi, Hideya; Katano, M.

In: British journal of cancer, Vol. 102, No. 4, 01.02.2010, p. 738-747.

Research output: Contribution to journalArticle

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abstract = "Background: Oestrogen receptor-alpha (ERα) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERα-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. Methods:We used 17-Β-oestradiol (E2) as a stimulator against the ERα pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERα (ERα siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERα-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 ERα-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-Β-Oestradiol-induced cell proliferation was suppressed by ICI, ERα siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERα 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 ERα and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERα and Hh pathways.Conclusion:Our data indicate that activation of the ERα pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERα-positive gastric cancer.",
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