Functional role and regulatory mechanism of iASPP in cervical cancer

• Project/Area Number: 15K10697
• 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: DONG PEIXIN 北海道大学, 医学研究院, 助教 (50602504)
• Co-Investigator(Kenkyū-buntansha): 櫻木 範明 北海道大学, 医学研究院, 特任教授 (70153963)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 子宮頸癌 / microRNA / EMT / 癌幹細胞 / p53 / iASPP / 癌 / 遺伝子

Outline of Final Research Achievements

Derepression of wild-type p53 by suppressing its negative inhibitor iASPP represents a potential therapeutic option for cervical cancer. We investigated whether targeting iASPP can restore p53 tumor suppressor functions and how epigenetic mechanisms, such as aberrant microRNA (miRNA) expression, regulate iASPP expression in this cancer. We found that iASPP acts as a key promoter of CC cell proliferation, EMT, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and to reduce p53-responsive microRNA-34a levels. microRNA-124 directly targets iASPP to reduce the expression of iASPP and attenuate cervical cancer cell growth and invasiveness. iASPP also promotes EMT and confers cisplatin resistance in cervical cancer via p53-miR-20a-FBXL5/BTG3 signaling. Altogether, reducing iASPP expression leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated cervical cancer.

Research Products

• [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)
• [Int'l Joint Research] University of Tennessee(米国)
• [Int'l Joint Research] Sun Yat-sen University Cancer Center(中国)
• [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
• [Journal Article] HPV self-sampling in Japanese women: A feasibility study in a population with limited experience of tampon use (2016)
  • Author(s): 2.Hanley SJ, Fujita H, Yokoyama S, Kunisawa S, Tamakoshi A, Dong P, Kobayashi N, Watari H, Kudo M, Sakuragi N
  • Journal Title: J Med Screen Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression (2016)
  • Author(s): 3.Dong P, Ihira K, Xiong Y, Watari H, Hanley SJ, Yamada T, Hosaka M, Kudo M, Yue J, Sakuragi N
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 15 Pages: 20260-20270
  • DOI: 10.18632/oncotarget.7754
  • NAID: 120005752853
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors (2015)
  • Author(s): 1.Dong P, Ihira K, Hamada J, Watari H, Yamada T, Hosaka M, Hanley SJ, Kudo M, Sakuragi N
  • Journal Title: Oncotarget Volume: 6 Issue: 24 Pages: 19968-19975
  • DOI: 10.18632/oncotarget.4847
  • NAID: 120005690905
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Presentation] EZH2 Stimulates Twist Expression by Epigenetic Silencing of Its Suppressor miR-361 through an YY1-dependent Mechanism (2015)
  • Author(s): Dong P, Sakuragi N
  • Organizer: The 8th World Congress of Regenerative Medicine & Stem Cell (RMSC-2015)
  • Place of Presentation: Shanghai (China)
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells (2015)
  • Author(s): Dong P, Sakuragi N
  • Organizer: The European Cancer Congress (ECC 2015)
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] MicroRNA-101はEZH2，MCL-1，FOSを制御して高悪性度子宮体癌細胞の増殖，浸潤，がん幹細胞様形質を抑制する (2015)
  • Author(s): 金野 陽輔, 董 培新, 渡利 英道, 鈴木 史彦, 櫻木 範明
  • Organizer: 第14回日本婦人科がん分子標的研究会学術集会
  • Place of Presentation: 美ヶ原温泉のホテル翔峰(長野県松本市)
  • Year and Date: 2015-07-17
• [Presentation] EZH2 stimulates Twist expression by epigenetic silencing of its suppressor miR-361 through an YY1-dependent mechanism (2015)
  • Author(s): Dong P, Sakuragi N
  • Organizer: 第17回日本RNA学会年会
  • Place of Presentation: ホテルライフォート札幌(北海道札幌市)
  • Year and Date: 2015-07-15
• [Presentation] MicroRNA-101 attenuates Twist1 expression by induction of its negative regulator miR-361-5p through an EZH2-dependent mechanism (2015)
  • Author(s): Dong P, Sakuragi N
  • Organizer: 第67回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜国際平和会議場(神奈川県横浜市)
  • Year and Date: 2015-04-09
• [Presentation] MicroRNA-101は高悪性度子宮体癌細胞の増殖，浸潤，がん幹細胞様形質を抑制する (2015)
  • Author(s): 金野 陽輔, 董 培新, 鈴木 史彦, 櫻木 範明
  • Organizer: 第67回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜国際平和会議場(神奈川県横浜市)
  • Year and Date: 2015-04-09
• [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
• [Remarks] http://researchmap.jp/2853/
• [Remarks] https://www.researchgate.net/profile/Peixin_Dong