Analysis of lipid raft via CD24 and drug resistance in gynecologic cancer

• Project/Area Number: 16K11165
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka Medical College
• Principal Investigator: Tanaka Yoshimichi 大阪医科大学, 医学部, 講師 (10625502)
• Co-Investigator(Kenkyū-buntansha): 林 正美 大阪医科大学, 医学部, 准教授 (00551748) ; 大道 正英 大阪医科大学, 医学部, 教授 (10283764) ; 恒遠 啓示 大阪医科大学, 医学部, 講師 (70388255) ; 田辺 晃子 大阪医科大学, 医学部, 非常勤講師 (70454543) ; 佐々木 浩 大阪医科大学, 医学部, 講師 (80432491) ; 寺井 義人 大阪医科大学, 医学部, 非常勤講師 (90278531)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: CD24 / EMT / lipid raft / 化学療法抵抗性 / 卵巣癌 / 子宮内膜癌 / MET / ＣＤ２４ / ＥＭＴ / 婦人科悪性腫瘍 / ＧＰＩアンカー型タンパク質 / ラフト形成 / 婦人科癌 / ＧＰＩアンカー型蛋白質

Outline of Final Research Achievements

CD24 has been reported to be a marker for a poor prognosis in several tumors, and we herein examined the functions of CD24 in human endometrioid adenocarcinoma cell lines and evaluated how it contributes to cancer drug resistance. We demonstrated that CD24 was responsible for the recruitment of phosphorylated Met to the lipid raft domain of the cell membrane, resulting in amplification of the Met signaling cascade, ultimately leading endometrial cancer cells to express higher levels of ATP-binding cassette (ABC) transporters. Our findings suggest that CD24-mediated amplification of the Met cascade may contribute to the drug resistance of endometrial cancer. Moreover, the expression of CD24 was an independent predictor of survival in patients with ovarian cancer.Our findings suggest that CD24 induced the EMT phenomenon in ovarian cancer, and that CD24 amplified cell growth-related intracellular signaling via the PI3K/Akt and MAPK pathways by affecting the EMT signal pathways.

Academic Significance and Societal Importance of the Research Achievements

婦人科悪性腫瘍(卵巣癌、子宮内膜癌）において、細胞膜上に存在するGPIアンカー型タンパク質であるCD24の発現上昇が上皮間葉系転換や化学療法抵抗性、予後と強く相関していることを見出した。またCD24がいかにして化学療法抵抗性を獲得しているかを解明した。本経路を阻害することができれば化学療法抵抗性を解除し、治療成績の向上へとつなげることが可能となる。今までとは異なる機序での治療につながることから本研究結果は有意義なものと考える。

Research Products

• [Journal Article] Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer. (2018)
  • Author(s): Kogata Y, Tanaka T,Ono Y, Hayashi M, Terai Y, Ohmichi M.
  • Journal Title: Oncotarget Volume: 9 Issue: 32 Pages: 22769-22784
  • DOI: 10.18632/oncotarget.25232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of matrix metalloproteinase?9 and decorin expression with the infiltration of cervical cancer (2018)
  • Author(s): Tanaka Tomohito、Terai Yoshito、Ohmichi Masahide
  • Journal Title: Oncology Letters Volume: 17 Pages: 130601312-130601312
  • DOI: 10.3892/ol.2018.9713
  • Peer Reviewed / Open Access
• [Journal Article] A case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma (2018)
  • Author(s): Maeda Kazuya、Terai Yoshito、Terada Shinichi、Maruoka Hiroshi、Kogata Yuhei、Ashihara Keisuke、Tanaka Yoshimichi、Tanaka Tomohito、Sasaki Hiroshi、Tsunetoh Satoshi、Yamada Takashi、Ohmichi Masahide
  • Journal Title: Journal of Ovarian Research Volume: 11 Issue: 1 Pages: 74-74
  • DOI: 10.1186/s13048-018-0446-4
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency ? The leading cause of preeclampsia (2018)
  • Author(s): Sano Takumi、Terai Yoshito、Daimon Atsushi、Nunode Misa、Nagayasu Yoko、Okamoto Atsuko、Fujita Daisuke、Hayashi Masami、Ohmichi Masahide
  • Journal Title: Placenta Volume: 65 Pages: 1-6
  • DOI: 10.1016/j.placenta.2018.03.006
  • Peer Reviewed / Open Access
• [Journal Article] CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways. (2017)
  • Author(s): Nakamura K, Terai Y, Tanabe A, Ono YJ, Hayashi M, Maeda K, Fujiwara S, Ashihara K, Nakamura M, Tanaka Y, Tanaka T, Tsunetoh S, Sasaki H, Ohmichi M.
  • Journal Title: Oncol Rep Volume: - Issue: 6 Pages: 3189-3200
  • DOI: 10.3892/or.2017.5583
  • Peer Reviewed / Open Access / Int'l Joint Research