Hypoxia increased ovarian cancer invasiveness with increased E-cadherin transcriptional repressor Snail

• Project/Area Number: 18591828
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Shinshu University
• Principal Investigator: HORIUCHI Akiko Shinshu University, Obstetrics and gynecology, Assistant Professor (80334895)
• Co-Investigator(Kenkyū-buntansha): OSADA Ryousuke Shinshu University, Obstetrics and gynecology, Assistant Professor (80418722) ; KONISHI Ikuo Kyoto University, Gynecology and Obstetrics, Professor (90192062)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Hvnoxia / E-cadherin / Ovarian Cancer / invasion / 低酸素 / E-cadherin / HIF

Research Abstract

Recent focusing attention is that the surrounding microenvironment plays in the process of tumorigenesis and tumor progression. We found that Hypoxia increased invasiveness of ovarian cancer cells via decreased E-cadherin expression. In this study, we investigate the mechanism of decreased E-cadherin expression under hypoxia.
Ovarian cancer cell lines were cultured under hypoxia, and the changes of E-cadherin expression was examined. In ovarian cancer cell (SKOV3), the expression of E-cadherin was decreased under hypoxic condition. In contrast, the expression of Snail, SIP1, and TWIST, E-cadherin transcriptional repressor, were increased under hypoxia. Luciferase assay showed that the transcriptional activity of Snail has increased under hypoxia by compared with under normal oxygen. Although both of siRNA for HIF-1α and HIF-2α inhibited the up-regulation of snail by hypoxia, the effect of HIF-1α was higher than that of HIF-2α. Additionally, the invasiveness of ovarian cancer cells was inhibited by HIF-1α siRNA.
These findings suggest that ovarian cancer cells were converted from epithelial character to mesenchymal character and increased invasiveness under hypoxia via upregulation of Snail.

Research Products

• [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas correlating with the cell proliferation: Its inhibition leads to the growth suppression and apoptosis. (2007)
  • Author(s): Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida Y, Shiozawa T, Konishi I
  • Journal Title: Cancer Science 98 Pages: 68-76
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma. (2007)
  • Author(s): Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, Katsuyama Y, Mellilo G, Konishi I.
  • Journal Title: Hum Pathol. 38 Pages: 1310-20
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Interferon-d and cancer immunoediting: Insight from tumorigenesis of uterine leiomyosarcoma. (2007)
  • Author(s): Hayashi T, Kobayashi Y, Horiuchi A, Hiraoka N, Kubota N, Kanai Y, Aburatani H, Konishi I, Sano K.
  • Journal Title: Curr. Res. In Immunology 1 Pages: 33-46
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 女性のライフサイクルの変化と産婦人科医療 卵巣癌 (2007)
  • Author(s): 堀内晶子 小西郁生
  • Journal Title: 産科と婦人科 55 Pages: 51-56
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas correlating with the cell proliferation : Its inhibition leads to the growth suppression and apoptosis (2007)
  • Author(s): Chen, X., Horiuchi, A., Kikuchi, N., Osada, R., Yoshida, Y., Shiozawa, T., Konishi, I
  • Journal Title: Cancer Sri 98 Pages: 68-76
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of hypoxia-inducible factor-1α (HIF-1α), HIF-2α and von Hippel-Lindau (VHL) protein in epithelial ovarian neoplasms and alleic loss of VHL gene : Nuclear expression of HIF-1α is an independent prognostic factor in ovarian carcinoma (2007)
  • Author(s): Osada, R., Horiuchli, A., Kikuchi, N., Yoshida, I., Hayashi, A., Ota, M., Katsuyama, Y., Melillo, G., Konishi, I
  • Journal Title: Hum Pathol 38 Pages: 1310-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (2007) Interferon-y and cancer immunoediting : Insights from tumorgenesis of uterine leiomyosarcoma (2007)
  • Author(s): Hayashi, T., Kobayashi, Y., Horiuchi, A., Hiraoka, N., Kubota, N., Kanai, Y., Aburatani, H., Konishi, I., Sano, K
  • Journal Title: Current Res. in Immunol 1 Pages: 33-46
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 女性のライフサイクルの変化と産婦人科医療 卵巣癌 (2007)
  • Author(s): 堀内晶子, 小西郁生
  • Journal Title: 産科と婦人科 55 Pages: 51-56
• [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas correlating with the cell proliferation : Its inhibition leads to the growth suppression and apoptosis. (2007)
  • Author(s): Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida Y, Shiozawa T, Konishi I
  • Journal Title: Cancer Science 98 Pages: 68-76
• [Journal Article] BRCA1 expression is an important biomarker for chemosensitivity: Suppression of BRCA1 increases the apoptosis via up-regulation of p53 and p21 during cisplatin treatment in ovarian cancer cells. (2006)
  • Author(s): Horiuchi A, Wang C, Kikuchi N, Osada R, Nikaido T, Konishi I.
  • Journal Title: Biomaker Insight 9 Pages: 234-345
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. (2006)
  • Author(s): Osada R, Horiuchi A, Kikuchi N, Ohira S, Ota M, Katsuyama Y, Konishi I.
  • Journal Title: Hum Pathol. 37 Pages: 1414-25
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nuclear Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression. (2006)
  • Author(s): Kikuchi N, Horiuchi A, Osada R, Imai T, Wang C, Chen X, Konishi I.
  • Journal Title: Cancer Science 97 Pages: 1061-9
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 卵巣癌のスクリーニング (2006)
  • Author(s): 堀内晶子 小西郁生
  • Journal Title: 産婦人科の実際 55 Pages: 1870-74
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of semaphorins (SEMA), VEGF and their common receptor neuropilins, and alleic loss of SEMA locus in epithelial ovarian neoplasms : Increased VEGF/SEMA ratio is a poor prognostic factor in ovarian carcinomas (2006)
  • Author(s): Osada, R., Horiuchi, A., Kikuchi, N., Ohira, S., Ota, M., Katsuyama, Y., Konishi, I
  • Journal Title: Hum Pathol 37 Pages: 1414-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nuclear Expression of S100A4 is Associated with Aggressive Behavior of Epithelial Ovarian Carcinoma : An Important Autocrine/Paracrine Factor in Tumor Progression (2006)
  • Author(s): Kikuchi, N., Horiuchi, A., Osada, R., Imai, T., Wang, C., Chen, X., Konishi, I
  • Journal Title: Cancer Sci 98 Pages: 1061-9
  • NAID: 10019378155
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BRCA1 expression is an important biomarker for chemosensitivity : Suppression of BRCA1 increases the apoptosis via up-regulation of p53 and p21 during cisplatin treatment in ovarian cancer cells (2006)
  • Author(s): Horiuchi, A., Wang, C., Kikuchi, N., Osada, R., Nikaido, T., Konishi, I
  • Journal Title: Biomaker Insight 2 Pages: 49-59
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BRCA1 expression is an important biomarker for chemosensitivity : Suppression of BRCA1 increases the apoptosis via up-regulation of p53 and p21 during cisplatin treatment in ovarian cancer cells. (2006)
  • Author(s): Horiuchi A, Wang C, Kikuchi N, Osada R, Nikaido T, Konishi I
  • Journal Title: Biomaker Insight 234・9 Pages: 234-345
• [Journal Article] Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms : increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. (2006)
  • Author(s): Kikuchi N, Horiuchi A, Osada R, Imai T, Wang C, Chen X, Konishi I
  • Journal Title: Hum Pathol 37 Pages: 1414-1425
• [Journal Article] 卵巣癌のスクリーニング (2006)
  • Author(s): 堀内晶子, 小西郁生
  • Journal Title: 産婦人科の実際 55 Pages: 1870-1874
• [Presentation] 正常卵巣表層上皮(OSE)および上皮性卵巣腫瘍におけるE-cadherin転写抑制因子Snail,SlugおよびTwistの発現 (2007)
  • Author(s): 吉田順子、菊地範彦、長田亮介、林 晶子、堀内晶子、小西郁生
  • Organizer: 第59回日本産科婦人科学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2007-04-16
  • Description: 「研究成果報告書概要(和文)」より