Elucidation of the miRNA-EZH2 feedback loop regulating endometrial cancer microenvironment

• Project/Area Number: 16K11123
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Hokkaido University
• Principal Investigator: Konno Yosuke 北海道大学, 医学研究院, 助教 (10572703)
• Co-Investigator(Kenkyū-buntansha): 董 培新 北海道大学, 医学研究院, 助教 (50602504) ; 櫻木 範明 北海道大学, 医学研究院, 名誉教授 (70153963)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: microRNA / 子宮体癌 / EZH2 / EMT / 癌 / 遺伝子

Outline of Final Research Achievements

In this study, we aimed to clarify whether the miRNA-EZH2 feedback loop contributes to EZH2 overexpression in endometrial cancer and whether EZH2 induces the expression of IL-6/8 through miRNAs-mediated signaling pathways. We found that EZH2 and tumor suppressor miRNAs mutually form a negative feedback loop, resulting in enhanced expression of EZH2 and decreased expression of tumor suppressor miRNAs and that EZH2 induces the overproduction of IL-6/8 via miRNAs-mediated pathways in endometrial cancer cells. These findings suggest that targeting and inhibition of EZH2 represents a potential therapeutic strategy for endometrial cancer.

Academic Significance and Societal Importance of the Research Achievements

EZH2と癌抑制miRNA群が相互に負のフィードバックループを形成して、EZH2の発現亢進及びlet-7bなどのmiRNAの発現低下を招き、下流にあるTwist、Snail、STAT3経路、NF-κB経路及びWnt/β-catenin経路の活発化を介して、IL-6/8過剰産生及び体癌の悪性化を導くという重要な成果が得られている。本研究により得られた知見は、今後体癌の根絶を目指す基層研究の発展及び新しい治療法の開発に大きく貢献していると考えられる。

Research Products

• [Int'l Joint Research] University of Tennessee(米国)
• [Int'l Joint Research] Sun Yat-sen University(中国)
• [Int'l Joint Research] University of Tennessee(米国)
• [Int'l Joint Research] Sun Yat-sen University Cancer Center(中国)
• [Int'l Joint Research] University of Tennessee(米国)
• [Int'l Joint Research] Sun Yat-sen University Cancer Center(中国)
• [Journal Article] B7H3 As a Promoter of Metastasis and Promising Therapeutic Target (2018)
  • Author(s): Dong Peixin、Xiong Ying、Yue Junming、Hanley Sharon J. B.、Watari Hidemichi
  • Journal Title: Frontiers in Oncology Volume: 8 Pages: 264-268
  • DOI: 10.3389/fonc.2018.00264
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion (2018)
  • Author(s): Dong Peixin、Xiong Ying、Yue Junming、Hanley Sharon J. B.、Watari Hidemichi
  • Journal Title: Frontiers in Oncology Volume: 8 Pages: 386-396
  • DOI: 10.3389/fonc.2018.00386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long Non-coding RNA NEAT1: A Novel Target for Diagnosis and Therapy in Human Tumors (2018)
  • Author(s): Dong Peixin、Xiong Ying、Yue Junming、Hanley Sharon J. B.、Kobayashi Noriko、Todo Yukiharu、Watari Hidemichi
  • Journal Title: Frontiers in Genetics Volume: 9 Pages: 471-451
  • DOI: 10.3389/fgene.2018.00471
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lentiviral vector mediated-ASAP1 expression promotes epithelial to mesenchymal transition in ovarian cancer cells (2018)
  • Author(s): Zhang Tao、Zhao Guannan、Yang Chuanhe、Dong Peixin、Watari Hidemichi、Zeng Lin、Pfeffer Lawrence、Yue Junming
  • Journal Title: Oncology Letters Volume: 15 Pages: 4432-4438
  • DOI: 10.3892/ol.2018.7834
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of human papillomavirus genotyping and cytology triage, COMPACT Study: Design, methods and baseline results in 14 642 women (2018)
  • Author(s): Aoyama-Kikawa Satomi、Fujita Hiromasa、Hanley Sharon J.B.、Kasamo Mitsunori、Kikuchi Kokichi、Torigoe Toshihiko、Matsuno Yoshihiro、Tamakoshi Akiko、Sasaki Takayuki、Matsuura Motoki、Kato Yasuhito、Dong Peixin、Watari Hidemichi、Saito Tsuyoshi、Sengoku Kazuo、Sakuragi Noriaki
  • Journal Title: Cancer Science Volume: 109 Issue: 6 Pages: 2003-2012
  • DOI: 10.1111/cas.13608
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation (2018)
  • Author(s): Dong Peixin、Xiong Ying、Yue Junming、Hanley Sharon J.B.、Watari Hidemichi
  • Journal Title: Oncotarget Volume: 9 Issue: 33 Pages: 23253-23263
  • DOI: 10.18632/oncotarget.25298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4?miR-18a pathway in cervical cancer (2018)
  • Author(s): Dong Peixin、Xiong Ying、Yu Jiehai、Chen Lin、Tao Tang、Yi Song、Hanley Sharon J. B.、Yue Junming、Watari Hidemichi、Sakuragi Noriaki
  • Journal Title: Oncogene Volume: 37 Issue: 39 Pages: 5257-5268
  • DOI: 10.1038/s41388-018-0347-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miR-203 inhibits ovarian tumor metastasis by targeting BIRC5 and attenuating the TGFβ pathway (2018)
  • Author(s): Wang Baojin、Li Xia、Zhao Guannan、Yan Huan、Dong Peixin、Watari Hidemichi、Sims Michelle、Li Wei、Pfeffer Lawrence M、Guo Yuqi、Yue Junming
  • Journal Title: Journal of Experimental & Clinical Cancer Research Volume: 37 Issue: 1 Pages: 235-240
  • DOI: 10.1186/s13046-018-0906-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Knockout of MTF1 Inhibits the Epithelial to Mesenchymal Transition in Ovarian Cancer Cells (2018)
  • Author(s): Ji Liang、Zhao Guannan、Zhang Peng、Huo Wenying、Dong Peixin、Watari Hidemichi、Jia Limin、Pfeffer Lawrence M、Yue Junming、Zheng Jinhua
  • Journal Title: Journal of Cancer Volume: 9 Issue: 24 Pages: 4578-4585
  • DOI: 10.7150/jca.28040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. (2017)
  • Author(s): Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley S-JB, Noguchi M, Hirata N, Suizu F, Yamada T, Kudo M, and Sakuragi N.
  • Journal Title: Oncotarget Volume: 8 (8) Issue: 8 Pages: 13509-13520
  • DOI: 10.18632/oncotarget.14586
  • NAID: 120005972933
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling (2017)
  • Author(s): Xiong Ying、Sun Fei、Dong Peixin、Watari Hidemichi、Yue Junming、Yu Min-fei、Lan Chun-yan、Wang Yin、Ma Ze-biao
  • Journal Title: J Exp Clin Cancer Res Volume: 36 Issue: 1 Pages: 48-55
  • DOI: 10.1186/s13046-017-0520-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis (2017)
  • Author(s): Zhang Qi、Dong Peixin、Liu Xishi、Sakuragi Noriaki、Guo Sun-Wei
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 6804-6814
  • DOI: 10.1038/s41598-017-06920-7
  • NAID: 120006331863
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lentiviral CRISPR/Cas9 nickase vector mediated BIRC5 editing inhibits epithelial to mesenchymal transition in ovarian cancer cells (2017)
  • Author(s): Zhao Guannan、Wang Qinghui、Gu Qingqing、Qiang Wenan、Wei Jian-Jun、Dong Peixin、Watari Hidemichi、Li Wei、Yue Junming
  • Journal Title: Oncotarget Volume: 8 Issue: 55 Pages: 94666-94680
  • DOI: 10.18632/oncotarget.21863
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced miR-143 and miR-107 activation (2017)
  • Author(s): Dong Peixin、Xiong Ying、Hanley Sharon J. B.、Yue Junming、Watari Hidemichi
  • Journal Title: J Exp Clin Cancer Res Volume: 36 Issue: 1 Pages: 150-156
  • DOI: 10.1186/s13046-017-0617-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KLF4 expression enhances the efficacy of chemotherapy drugs in ovarian cancer cells (2017)
  • Author(s): Wang B, Shen A, Ouyang X, Zhao G, Du Z, Huo W, Zhang T, Wang Y, Yang C, Dong P, Watari H, Pfeffer LM, Yue J
  • Journal Title: Biochem Biophys Res Commun Volume: 484 Issue: 3 Pages: 486-492
  • DOI: 10.1016/j.bbrc.2017.01.062
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells (2017)
  • Author(s): Huo W, Zhao G, Yin J, Ouyang X, Wang Y, Yang C, Wang B, Dong P, Wang Z, Watari H, Chaum E, Pfeffer LM, Yue J
  • Journal Title: J Cancer Volume: 8 Issue: 1 Pages: 57-64
  • DOI: 10.7150/jca.16723
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells (2016)
  • Author(s): Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K, Yamada T, Kudo M, Yue J, Sakuragi N
  • Journal Title: J Exp Clin Cancer Res Volume: 5 Issue: 1 Pages: 132-141
  • DOI: 10.1186/s13046-016-0415-y
  • NAID: 120005837941
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124 (2016)
  • Author(s): Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K, Suzuki F, Yamada T, Kudo M, Yue J, Sakuragi N
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 35480-35491
  • DOI: 10.1038/srep35480
  • NAID: 120005851099
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 高悪性度体がんのジェネティック・エピジェネティック研究 (2018)
  • Author(s): 董 培新
  • Organizer: 「総合女性医療システム学分野」記念シンポジウム, 京王プラザホテル札幌(北海道札幌市)
• [Presentation] 高悪性度子宮体癌細胞に対するEZH2特異的阻害剤の抗腫瘍効果とその分子機構 (2018)
  • Author(s): 董 培新
  • Organizer: 第27回日本癌病態治療研究会, ホテルポートプラザ千葉(千葉県千葉市
• [Presentation] Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced (2018)
  • Author(s): Dong Peixin
  • Organizer: IGCS 2018, Kyoto (Japan)
  • Int'l Joint Research
• [Presentation] Evaluation of partial genotyping with HPV 16/18 for triage of HPV positive cytology negative Japanese women: Baseline results of the COMPACT study (2018)
  • Author(s): Aoyama-Kikawa S, Fujita H, Hanley SJB, Kasamo M, Kikuchi K, Torigoe T, Matsuno Y, Tamakoshi A, Sasaki T, Matsuura M, Kato Y,Dong P, Watari H, Saito T, Sengoku K, Sakuragi N
  • Organizer: The 32nd International Papillomavirus Conference, Sydney (Australia)
  • Int'l Joint Research
• [Presentation] Comparison of HPV genotyping and cytology triage, COMPACT-Study: Design, methods and baseline results in 14,642 women (2018)
  • Author(s): 3.Aoyama-Kikawa S, Fujita H, Hanley SJB, Kasamo M, Kikuchi K, Torigoe T, Matsuno Y, Tamakoshi A, Sasaki T, Matsuura M, Kato Y, Dong P, Watari H, Saito T, Sengoku K, Sakuragi N
  • Organizer: The 32nd International Papillomavirus Conference, Sydney (Australia)
  • Int'l Joint Research
• [Presentation] miR-137 and miR-34a directly target snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells (2018)
  • Author(s): Dong Peixin
  • Organizer: The 12th World Congress of Regenerative Medicine & Stem Cell-2018, Xian (China)
  • Int'l Joint Research / Invited
• [Presentation] Epigenetic aspects of endometrial cancer progression: Insights into interactions of EZH2 and microRNAs (2017)
  • Author(s): Dong Peixin
  • Organizer: The 4th International Obstetrics & Gynecology Summit; The Red House Forum, Shanghai (China)
  • Int'l Joint Research / Invited
• [Presentation] Reactivating the expression of silenced miR-124 for endometrial cancer treatment (2016)
  • Author(s): Dong P, Konno Y, Sakuragi N
  • Organizer: The 7th Annual World Gene Convention
  • Place of Presentation: Shanghai(China)
  • Year and Date: 2016-11-03
  • Int'l Joint Research / Invited
• [Presentation] Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124 (2016)
  • Author(s): 董 培新, 井平 圭, 金野 陽輔, 渡利 英道, 櫻木 範明
  • Organizer: 第15回日本婦人科がん分子標的研究会
  • Place of Presentation: ホテルニューオータニイン札幌(北海道札幌市)
  • Year and Date: 2016-08-19
• [Presentation] Targeting EZH2-miR-361-Twist axis in endometrial cancer (2016)
  • Author(s): Dong P, Ihira K, Konno Y, Sakuragi N
  • Organizer: The 6th Annual World Congress of Molecular & Cell Biology
  • Place of Presentation: Dalian(China)
  • Year and Date: 2016-04-25
  • Int'l Joint Research / Invited
• [Presentation] EZH2 stimulates Twist expression by epigenetic silencing of its suppressor miR-361 through an YY1-dependent mechanismEZH2 stimulates Twist expression by epigenetic silencing of its suppressor miR-361 through an YY1-dependent mechanism (2016)
  • Author(s): Ihira K, Dong P, Hanley SJ, Yamada T, Sakuragi N
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2016-04-21
• [Remarks] https://www.hokudai.ac.jp/
• [Remarks] Peixin Dong, M.D., Ph.D.
  • URL: https://scholar.google.com/citations?user=Ze3zls4AAAAJ
• [Remarks]
  • URL: http://scholar.google.com/citations?user=Ze3zls4AAAAJ
• [Remarks]
  • URL: https://www.researchgate.net/profile/Peixin_Dong