Elucidating mechanism of peritoneal metastasis in mutant p53 ovarian cancer based on cell-to-cell communication

• Project/Area Number: 17H06753
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya University
• Principal Investigator: Yoshikawa Nobuhisa 名古屋大学, 医学部附属病院, 病院助教 (60804747)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); 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)
• Keywords: 卵巣癌 / 腹膜播種 / 微小環境 / miRNA / エクソソーム / 変異型p53 / PRIMA1-MET / オミックス解析 / がん抑制遺伝子 / TP53

Outline of Final Research Achievements

To evaluate the effects of exogenous mutant p53 protein on endogenous miRNAs expression, two different mutant p53 protein, R248W and R248Q, were expressed in ovarian cancer cell lines haboring p53-null. We identified eight miRNAs that showed 1.5-fold or more increase in expression and two miRNAs that had two-third or more expression reduction in two forced expression strains of mutant p53.
As a part of elucidation of the mechanism of peritoneal metastasis, we conducted comprehensive analysis of cancer-related miRNAs using FFPE between patients with mature teratomas and malignant transformations, and identified multiple miRNAs. We also elucidated and reported a novel mechanism by which PAI-1, which is abundantly present in cancerous ascites fluid, promotes changes in peritoneal mesothelial cells to promote the tumor-promoting environment.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は難治性卵巣癌の腹膜微小環境におけるケモカインの意義の一端を明らかにするとともに、非常に稀な成熟奇形腫の悪性転化の発生に関与するmiRNA群を同定することを通して、卵巣癌の病態解明に寄与することになった。本研究の成果のみで現在の患者の治療を革新的に変化させたりできるものではないが、今後本研究を含む様々な知見の集積を通して卵巣癌の発生および難治性の克服につながっていくものと考えられる。本研究で得られた成果を継続して研究していくことがより一層のメカニズム解明に必要である。

Research Products

• [Journal Article] PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination. (2019)
  • Author(s): Peng Y, Kajiyama H, Yuan H, Nakamura K, Yoshihara M, Yokoi A, Fujikake K, Yasui H, Yoshikawa N, Suzuki S, Senga T, Shibata K, Kikkawa F.
  • Journal Title: Cancer Lett Volume: 442 Pages: 181-192
  • DOI: 10.1016/j.canlet.2018.10.027
  • NAID: 120006623836
  • Peer Reviewed
• [Journal Article] The upregulated expression of vascular endothelial growth factor in surgically treated patients with recurrent/radioresistant cervical cancer of the uterus. (2018)
  • Author(s): Yoshida K, Suzuki S, Sakata J, Utsumi F, Niimi K, Yoshikawa N, Nishino K, Shibata K, Kikkawa F, Kajiyama H.
  • Journal Title: Oncol Lett Volume: 16(1) Pages: 515-521
  • DOI: 10.3892/ol.2018.8610
  • Peer Reviewed / Open Access
• [Journal Article] Fertility-sparing surgery of malignant transformation arising from mature cystic teratoma of the ovary (2018)
  • Author(s): Yoshikawa Nobuhisa、Teshigawara Toshiya、Ikeda Yoshiki、Nishino Kimihiro、Sakata Jun、Utsumi Fumi、Niimi Kaoru、Sekiya Ryuichiro、Suzuki Shiro、Kawai Michiyasu、Shibata Kiyosumi、Kikkawa Fumitaka、Kajiyama Hiroaki
  • Journal Title: Oncotarget Volume: 9 Issue: 44 Pages: 27564-27573
  • DOI: 10.18632/oncotarget.25548
  • Peer Reviewed
• [Journal Article] Reproductive outcomes of 105 malignant ovarian germ cell tumor survivors: a multicenter study (2018)
  • Author(s): Tamauchi Satoshi、Kajiyama Hiroaki、Yoshihara Masato、Ikeda Yoshiki、Yoshikawa Nobuhisa、Nishino Kimihiro、Utsumi Fumi、Niimi Kaoru、Suzuki Shiro、Kikkawa Fumitaka
  • Journal Title: American Journal of Obstetrics and Gynecology Volume: 219 Issue: 4 Pages: 385.e1-385.e7
  • DOI: 10.1016/j.ajog.2018.07.021
  • Peer Reviewed