Identification of LEFTY as a molecular marker for ovarian clear cell carcinoma

• Project/Area Number: 16K15250
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Kitasato University
• Principal Investigator: Kajita Sajiine 北里大学, 医学部, 講師 (60194734)
• Co-Investigator(Kenkyū-buntansha): 三枝 信 北里大学, 医学部, 教授 (00265711)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 卵巣明細胞癌 / LEFTY / TGF-beta / 細胞増殖 / アポトーシス / Lefty遺伝子 / 卵巣明細胞 / Lefty / Smad2 / バイオマーカー / エキソソーム

Outline of Final Research Achievements

To identify proteins involved in ovarian clear cell carcinoma (OCCCa), shotgun proteomics analysis was applied. Of the highly expressed proteins in OCCCa, we focused on left-right determination factor (LEFTY). In 143 cases of ovarian carcinoma, LEFTY expression was significantly higher in OCCCas compared with non-OCCCas. OCCCa cells stably overexpressing LEFTY1 showed reduced cell proliferation, along with decreased pSmad2 expression, and also either displayed an activated p53/p21waf1 pathway or increased p27kip1 expression, directly or indirectly. Moreover, the treatment of stable cell lines with cisplatin led to increased apoptotic cells, together with the inhibition of protein expression of a pSmad2-mediated X-linked inhibitor of apoptosis and a decreased bcl2/bax ratio. These findings suggest that LEFTY may be an excellent OCCCa-specific molecular marker, which has anti-tumor effects in altering cell proliferation and cellular susceptibility to apoptosis.

Academic Significance and Societal Importance of the Research Achievements

日本人に多い卵巣の明細胞癌の新規バイオマーカーとしてLEFTYを見出した。LEFTYは卵巣明細胞癌で特異的に高発現し、癌細胞の増殖を抑制するとともに、細胞死（アポトーシス）促進に関与する。これらの制御機構を介して卵巣明細胞癌に対して抗腫瘍効果を示す。今後、LEFTY分子を用いた卵巣明細胞癌の早期診断ツールの開発や分子標的薬としての活用が期待できる。

Research Products

• [Journal Article] Nodal induces apoptosis and inhibits proliferation in ovarian endometriosis-clear cell carcinoma lesions. (2019)
  • Author(s): Mirura R, Yokoi A, Matsumoto T, Oguri Y, Hashimura M, Tochimoto M, Kajita S, Saegusa M
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 308-308
  • DOI: 10.1186/s12885-019-5539-y
  • Peer Reviewed / Open Access
• [Journal Article] Identification of LEFTY as a molecular marker for ovarian clear cell carcinoma. (2017)
  • Author(s): Akiya M, Yamazaki M, Matsumoto T, Kawashima Y, Oguri Y, Kajita S, Kijima D, Chiba R, Yokoi A, Takahashi H, Kodera Y, Saegusa M.
  • Journal Title: Oncotarget Volume: 8 Issue: 38 Pages: 63646-63664
  • DOI: 10.18632/oncotarget.18882
  • Peer Reviewed / Open Access
• [Presentation] 卵巣明細胞腺癌の発癌・進展過程におけるLeftyの機能解析 (2016)
  • Author(s): 秋谷昌史、山崎真瑛、松本俊英、梶田咲美乃、三枝信
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12