Blood expression mechanism and function of TFPI2: a new biomarker for ovarian cancer

• Project/Area Number: 25460695
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: National Institute of Health Sciences (2016); Yokohama City University (2013-2015)
• Principal Investigator: ARAKAWA Noriaki 国立医薬品食品衛生研究所, 医薬安全科学部, 主任研究官 (60398394)
• Co-Investigator(Renkei-kenkyūsha): MIYAGI Etsuko 横浜市立大学, 医学部産婦人科, 教授 (40275053) ; MIYAGI Etsuko 福島県立医科大学, 医学部衛生学・予防医学講座, 助教 (20626767)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 卵巣がん / 明細胞がん / TFPI2 / バイオマーカー / 診断 / 卵巣癌 / 明細胞癌 / 診断マーカー / 明細胞腺癌 / 遺伝子発現 / プロモーターメチル化 / 組織因子経路インヒビター２

Outline of Final Research Achievements

In this study, we examined relationship between TFPI2 and OCCC by investigating mechanisms underlying blood expression of TFPI2 in OCCC patients, and sought to evaluate the serum biomarker performance of TFPI2 in preoperative prediction of OCCC. TFPI2 gene was highly expressed in tumor tissues from OCCC patients. Unlike other cancer cell lines, and hypermethylation of TFPI2 promoter was undetected in OCCC-derived cell lines. Gene knockdown experiments showed that p53 is a more likely candidate for transcription factor involved in the characteristic expression of TFPI2 in OCCC. Serum TFPI2 was specifically elevated in OCCC patients, consistent with the gene expression level in the tumor tissues. These results suggest that TFPI2 is a useful serum biomarker for clinical diagnosis of OCCC.

Research Products

• [Journal Article] Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma. (2016)
  • Author(s): Arakawa N, Kobayashi H, Yonemoto N, Masuishi Y, Ino Y, Shigetomi H, Furukawa N, Ohtake N, Miyagi Y, Hirahara F, Hirano H, Miyagi E.
  • Journal Title: PLoS One. Volume: 11 Issue: 10 Pages: e0165609-e0165609
  • DOI: 10.1371/journal.pone.0165609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphoproteome analysis demonstrates the potential role of THRAP3 phosphorylation in androgen-independent prostate cancer cell growth. (2016)
  • Author(s): Ino Y, Arakawa N, Ishiguro H, Uemura H, Kubota Y, Hirano H, Toda T
  • Journal Title: Proteomics Volume: 16 Issue: 7 Pages: 1069-1078
  • DOI: 10.1002/pmic.201500365
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of glycosylphosphatidylinositol-anchored proteins and ω-sites using TiO2-based affinity purification followed by hydrogen fluoride treatment. (2016)
  • Author(s): Masuishi Y, Kimura Y, Arakawa N, Hirano H.
  • Journal Title: J Proteomics Volume: 139 Pages: 77-83
  • DOI: 10.1016/j.jprot.2016.03.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mass spectrometric analysis of the phosphorylation levels of the SWI/SNF chromatin remodeling/tumor suppressor proteins ARID1A and Brg1 in ovarian clear cell adenocarcinoma cell lines. (2014)
  • Author(s): Kimura, A., Arakawa, N., and Hirano, H.
  • Journal Title: J Proteome Res. Volume: 13(11) Issue: 11 Pages: 4959-4969
  • DOI: 10.1021/pr500470h
  • Peer Reviewed / Open Access
• [Journal Article] Secretome-based identification of TFPI2, a novel serum biomarker for detection of ovarian clear cell adenocarcinoma. (2013)
  • Author(s): Arakawa N, Miyagi E, Nomura A, Morita E, Ino Y, Ohtake N, Miyagi Y, Hirahara F, Hirano H.
  • Journal Title: J. Proteome Res. Volume: 12(10) Issue: 10 Pages: 4340-4350
  • DOI: 10.1021/pr400282j
  • Peer Reviewed
• [Journal Article] Mass spectrometric identification of glycosylphosphatidylinositol-anchored peptides (2013)
  • Author(s): Masuishi Y, Nomura A, Okayama A, Kimura Y, Arakawa N, Hirano H.
  • Journal Title: J. Proteome Res. Volume: 12(10) Issue: 10 Pages: 4617-4626
  • DOI: 10.1021/pr4004807
  • Peer Reviewed
• [Journal Article] The novel PAR-1-binding protein MTCL1 has crucial roles in organizing microtubules in polarizing epithelial cells. (2013)
  • Author(s): Sato Y, Akitsu M, Amano Y, Yamashita K, Ide M, Shimada K, Yamashita A, Hirano H, Arakawa N, Maki T, Hayashi I, Ohno S, Suzuki A.
  • Journal Title: J Cell Sci. Volume: 126(Pt 20) Pages: 4671-83
  • DOI: 10.1242/jcs.127845
  • Peer Reviewed / Open Access
• [Presentation] Identification of a new biomarker for castration resistant prostate cancer by secretome analysis (2016)
  • Author(s): Arakawa N, Uemura H, Ito Y, Ino Y, Myoba S, Ohtake N, Yao M, Hirano H.
  • Organizer: HUPO2016
  • Place of Presentation: 台北
  • Year and Date: 2016-09-19
  • Int'l Joint Research
• [Presentation] MRM-based quantifications of blood biomarkers using a quantification peptide-tagged fusion protein. (2015)
  • Author(s): Arakawa, N., Masuishi, Y., Myoba, S., Ohtake, N., and Hirano, H.
  • Organizer: HUPO 14th Annual World Congress
  • Place of Presentation: バンクーバー
  • Year and Date: 2015-09-27
  • Int'l Joint Research / Invited
• [Presentation] 卵巣がんの新しい血清診断マーカーTFPI-2の同定と臨床的有用性 (2015)
  • Author(s): 荒川憲昭
  • Organizer: 日本病態プロテアーゼ学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-08-21
  • Invited
• [Presentation] 培養細胞を起点としたバイオマーカー探索と診断応用 (2015)
  • Author(s): 荒川憲昭
  • Organizer: 日本プロテオーム学会
  • Place of Presentation: 熊本
  • Year and Date: 2015-07-23
  • Invited
• [Presentation] Secretome-based identification of PGE2-regulated proteins in human abdominal aortic aneusysm (2015)
  • Author(s): Ishiwata, R., Yokoyama, U., Arakawa, N., and Ishikawa, Y.
  • Organizer: 6th International conference on phospholipase A2 and lipid mediators.
  • Place of Presentation: 東京京王プラザホテル
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] 培養細胞を利用した新規卵巣がん血清診断マーカー候補蛋白質の同定 (2014)
  • Author(s): 荒川憲昭
  • Organizer: 日本プロテオーム学会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2014-07-17 – 2014-07-18
  • Invited
• [Presentation] MRM法による卵巣明細胞腺癌細胞株特異的なSWI/SNFクロマチン再構成複合体因子Brg1のリン酸化レベル低下の解析 (2014)
  • Author(s): 木村鮎子, 荒川憲昭, 平野久
  • Organizer: 日本ヒトプロテオーム学会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2014-07-17 – 2014-07-18
• [Presentation] アンドロゲン非依存性前立腺癌細胞におけるリン酸化タンパク質の網羅的解析 (2014)
  • Author(s): 井野洋子、荒川憲昭、石黒斉、上村博司、窪田吉信、平野久
  • Organizer: 日本プロテオーム学会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2014-07-17 – 2014-07-18
• [Presentation] Secretome-Based Identification of Novel Serum Biomarkers for Ovarian Clear Cell Adenocarcinoma (2013)
  • Author(s): Noriaki Arakawa, Etsuko Miyagi, Ayako Nomura, Erina Morita, Yusuke Masuishi, Yoko Ino, Norihisa Ohtake, Shohei Myoba, Yohei Miyagi, Fumiki Hirahara, Hisashi Hirano
  • Organizer: HUPO2013
  • Place of Presentation: 横浜市・パシフィコ横浜
• [Presentation] Quantitative Variation of Protein Components and Their Phosphorylations in the SWI/SNF Chromatin Remodeling Complex Associated with High Malignancy of Ovarian Clear Cell Adenocarcinoma (2013)
  • Author(s): Ayuko Kimura, Ayako Nomura, Takao Kawakami, Noriaki Arakawa, Hisashi Hirano
  • Organizer: HUPO2013
  • Place of Presentation: 横浜市・パシフィコ横浜
• [Remarks] プロテオーム科学研究室
  • URL: http://www.tsurumi.yokohama-cu.ac.jp/lab/proteome.html
• [Remarks] 広報誌innovation vol.14 特集: 産学連携 革新的バイオマーカーの開発
  • URL: http://www-user.yokohama-cu.ac.jp/~kyotenpr/pr
• [Remarks] 先端医科学研究センター市民講座「たんぱく質の異常で病気を診（み）る～早期発見・早期治療に向けて～」
  • URL: http://www.u-presscenter.jp/modules/bulletin/index.php?page=article&storyid=7456
• [Remarks] 難治性卵巣がん 診断マーカーを特定、横浜市大先端研／神奈川
  • URL: http://www.kanaloco.jp/article/59934/cms_id/59725
• [Remarks] プロテオーム科学研究室
  • URL: http://www-mls.tsurumi.yokohama-cu.ac.jp/lab/proteome.html
• [Remarks] 学術院国際総合科学群 平野久教授・荒川憲昭助教らの研究成果が特許として成立しました！
  • URL: http://www.yokohama-cu.ac.jp/res_pro/patent/20130426_tokyoken_hirano_arakawa.html