A novel mechanism of endometrial cancer development involving microRNAs

• Project/Area Number: 17K11280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kyushu University
• Principal Investigator: ASANOMA KAZUO 九州大学, 医学研究院, 准教授 (30380413)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: マイクロRNA / 上皮間葉移行 / 子宮体癌 / 転写調節 / 一塩基多型

Outline of Final Research Achievements

BHLHE40 and BHLHE41 (BHLHE40/41) are transcription factors involved in multiple cell activities including epithelial-to-mesenchymal transition (EMT). However, the expression mechanism of BHLHE40/41 in EMT remains unclear. In the present study, we showed that the expression levels of BHLHE40/41 were negatively correlated with those of the microRNA (MIR) 130 family in endometrial cancer (EC) specimens. Our in vitro assays indicated that the expression of BHLHE40/41 was suppressed directly by the MIR130 family in a 3’-untranslated region-mediated manner. In EC cells, the MIR130 family promoted EMT and tumor cell invasion by suppressing the expression of BHLHE40/41. We identified the critical promoter region of the MIR301B-MIR130B cluster for its basal transcription by SP1. We also found that BHLHE40/41 suppressed the expression of MIR301B and MIR130B, and we identified a binding site in the promoter region for BHLHE40/41.

Academic Significance and Societal Importance of the Research Achievements

我々は子宮体癌の進展機序である上皮間葉移行においてBHLHE40/41とMIR130ファミリーとの互いの発現制御機構が関わることを世界で初めて見出した。BHLHE40/41とMIR130ファミリーは子宮体癌症例の進展を予測する分子マーカーとして有用であること、また、MIR130 family-BHLHE40/41経路を標的とした分子治療戦略は子宮体癌の進展を抑制する方策として有望であると考える。

Research Products

• [Journal Article] Dual specificity phosphatase 6 plays a critical role in the maintenance of a cancer stem‐like cell phenotype in human endometrial cancer (2020)
  • Author(s): Kato Masaya、Onoyama Ichiro、Yoshida Sachiko、Cui Lin、Kawamura Keiko、Kodama Keisuke、Hori Emiko、Matsumura Yumiko、Yagi Hiroshi、Asanoma Kazuo、Yahata Hideaki、Itakura Atsuo、Takeda Satoru、Kato Kiyoko
  • Journal Title: International Journal of Cancer Volume: - Issue: 7 Pages: 1987-1999
  • DOI: 10.1002/ijc.32965
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Contribution of senescence in human endometrial stromal cells during proliferative phase to embryo receptivity (2020)
  • Author(s): Tomari H, Kawamura T, Asanoma K, Egashira K, Kawamura K, Honjo K, Nagata Y, Kato K
  • Journal Title: Biology of Reproduction Volume: - Issue: 1 Pages: 104-113
  • DOI: 10.1093/biolre/ioaa044
  • NAID: 120007044566
  • Peer Reviewed
• [Journal Article] Mutual suppression between BHLHE40/BHLHE41 and the MIR301B-MIR130B cluster is involved in epithelial-to-mesenchymal transition of endometrial cancer cells (2019)
  • Author(s): Asanoma K, Hori E, Yoshida S, Yagi H, Onoyama I, Kodama K, Yasunaga M, Ohgami T, Kaneki E, Okugawa K, Yahata H, Kato K,
  • Journal Title: Oncotarget Volume: 10 Issue: 45 Pages: 4640-4654
  • DOI: 10.18632/oncotarget.27061
  • Peer Reviewed / Open Access
• [Journal Article] Survey of the desire to have children and engage in sexual activity after trachelectomy among young Japanese women with early-stage cervical cancer. (2019)
  • Author(s): 3.Yahata H, Sonoda K, Okugawa K, Yagi H, Yasunaga M, Ohgami T, Onoyama I, Kaneki E, Asanoma K, Kato K.
  • Journal Title: J Obstet Gynaecol Res. Volume: 45 Issue: 11 Pages: 2255-2259
  • DOI: 10.1111/jog.14099
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gα13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer (2019)
  • Author(s): Yagi Hiroshi、Onoyama Ichiro、Asanoma Kazuo、Hori Emiko、Yasunaga Masafumi、Kodama Keisuke、Kijima Masako、Ohgami Tatsuhiro、Kaneki Eisuke、Okugawa Kaoru、Yahata Hideaki、Kato Kiyoko
  • Journal Title: The FASEB Journal Volume: 33 Issue: 12 Pages: 13683-13694
  • DOI: 10.1096/fj.201901278r
  • Peer Reviewed / Open Access
• [Journal Article] Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-β1 Signaling Pathway. (2018)
  • Author(s): Ohmaru-Nakanishi Takako, Asanoma Kazuo, Fujikawa Mai, Fujita Yasuyuki, Yagi Hiroshi, Onoyama Ichiro, Hidaka Nobuhiro, Sonoda Kenzo, Kato Kiyoko.
  • Journal Title: American Journal of Pathology Volume: 188 Pages: 683-695
  • Peer Reviewed
• [Presentation] Mutual regulation between MIR301B-MIR130B and BHLHE40-BHLHE41 is involved in epithelial-to-mesenchymal transition of uterine endometrial cancer cells (2019)
  • Author(s): ASANOMA kazuo, YAGI hiroshi, ONOYAMA ichiro, SONODA kenzo, KATO kiyoko
  • Organizer: 第71回日本産科婦人科学会学術講演会
• [Presentation] Mutual regulation between MIR301B-MIR130B and BHLHE40-BHLHE41 is involved in epithelial-to-mesenchymal transition of uterine endometrial cancer cells (2018)
  • Author(s): Kazuo Asanoma
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] The MIR130 families suppress epithelial-to-mesenchymal transition of uterine endometrial cancer cells by inhibiting the expression of BHLHE40 and BHLHE41. (2017)
  • Author(s): ASANOMA kazuo, Ohmaru takako, SONODA kenzo, WAKE norio, KATO kiyoko
  • Organizer: 69th Annual Congress of the Japan Society of OB/GY
• [Presentation] The MIR130 families enhance epithelial-to-mesenchymal transition of uterine endometrial cancer cells by inhibiting the expression of BHLHE40 and BHLHE41. (2017)
  • Author(s): ASANOMA kazuo, SONODA kenzo, KATO kiyoko
  • Organizer: The 59th Meeting of the Japan Society of Gynecologic Oncology