Study to overcome the inherent chemoresistance of ovarian clear cell adenocarcinoma based on the functional analyses of ANXA4 molecular subtypes

• Project/Area Number: 25462602
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Yokohama City University
• Principal Investigator: MIYAGI Etsuko 横浜市立大学, 医学(系)研究科(研究院), 教授 (40275053)
• Co-Investigator(Kenkyū-buntansha): MIYAGI Yohei 地方独立行政法人神奈川県立がんセンター(臨床研究所), がん分子病態学部, 総括部長 (00254194) ; YAMADA Roppei 地方独立行政法人神奈川県立がんセンター(臨床研究所), がん生物学部, 技幹 (30404974)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 卵巣がん / パクリタキセル / ANXA4 / 卵巣明細胞腺癌 / パクリタキセル耐性 / annexinA4 / 卵巣明細胞腺がん / 卵巣癌 / 浸潤 / 転移 / アネキシンA4

Outline of Final Research Achievements

Clear cell adenocarcinoma (CCA) is the frequent histologic subtype of the epithelial ovarian cancer in Japanese population. Because it shows resistance to chemotherapy resulted in poor prognosis, the improvement of the treatment is really needed. The group of the principal investigator of this research found annexin A4 (ANXA4) as a highly enriched protein in CCA. Although ANXA4 has been known as a protein involved in chemoresistance in other types of cancers, precise mechanisms of the resistance is still unclear.
The present study disclosed that there are two different molecular types of ANXA4, and each type is involved in Paclitaxel and Carboplatin resistance respectively, which are usually used in ovarian cancer chemotherapy. We further demonstrated a possibility that the chaperon-mediated autophagy through LAMP-2 protein could be involved in the chemoresistance mechanism.

Research Products

• [Journal Article] High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors (2016)
  • Author(s): Koizume S, Ito S, Yoshioka Y, Kanayama T, Nakamura Y, Yoshihara M, Yamada R, Ochiya T, Ruf W, Miyagi E, Hirahara F, Miyagi Y
  • Journal Title: Thromb Haemost Volume: 115 Issue: 02 Pages: 299-310
  • DOI: 10.1160/th15-03-0213
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phase II study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel in patients with locally advanced uterine cervical cancer: The JACCRO GY-01 trial. (2016)
  • Author(s): Umayahara K, Takekuma M, Hirashima Y, Noda SE, Ohno T, Miyagi E, Hirahara F, Hirata E, Kondo E, Tabata T, Nagai Y, Aoki Y, Wakatsuki M, Takeuchi M, Toita T, Takeshima N, Takizawa K.
  • Journal Title: Gynecol Oncol. Volume: 140 Issue: 2 Pages: 253-258
  • DOI: 10.1016/j.ygyno.2015.12.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aberrant Expression of the Cell Polarity Regulator aPKCλ/ι is Associated With Disease Progression in Cer (2016)
  • Author(s): Mizushima T, Asai-Sato M, Akimoto K, Nagashima Y, Taguri M, Sasaki K, Nakaya MA, Asano R, Tokinaga A, Kiyono T, Hirahara F, Ohno S, Miyagi E.
  • Journal Title: Int J Gynecol Pathol. Volume: 35 Issue: 2 Pages: 106-17
  • DOI: 10.1097/pgp.0000000000000228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth (2015)
  • Author(s): Ryoko Asano, Mikiko Asai-Sato, Yohei Miyagi, Taichi Mizushima, Makiko Koyama-Sato, Yoji Nagashima, Masataka Taguri, Hideya Sakakibara, Fumiki Hirahara, Etsuko Miyagi
  • Journal Title: American Journal of Obstetrics and Gynecology Volume: 212 Issue: 2 Pages: 1-9
  • DOI: 10.1016/j.ajog.2015.02.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Radiation Therapy for Para-Aortic Lymph Node Metastasis from Uterine Cervical Cance (2015)
  • Author(s): Hata M，Miyagi E，Koike I，Numazaki R，Asai-Sato M，Kasuya T，Kaizu H，Mukai Y，Hirahara F，Inoue T
  • Journal Title: Anticancer Res Volume: 35 Pages: 4849-4854
  • Peer Reviewed
• [Journal Article] Three-year questionnaire survey on human papillomavirus vaccination targeting new female college students (2015)
  • Author(s): Sukegawa A, Ohshige K, Arai S, Sakanashi K, Usui M, Hirahara F, Miyagi E
  • Journal Title: J Obstet Gynaecol Res Volume: 41 Issue: 1 Pages: 99-106
  • DOI: 10.1111/jog.12500
  • Peer Reviewed
• [Journal Article] Postoperative radiation therapy for extramammary Paget's disease (2015)
  • Author(s): Hata M, Koike I, Wada H, Miyagi E, Kasuya T, Kaizu H, Mukai Y, Inoue T
  • Journal Title: Br J Dermatology Volume: 172 Issue: 4 Pages: 1014-1020
  • DOI: 10.1111/bjd.13357
  • Peer Reviewed
• [Journal Article] Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer (2015)
  • Author(s): Koizume S, Ito S, Nakamura Y et al.
  • Journal Title: Mol Cancer Volume: 14 Issue: 1 Pages: 77-77
  • DOI: 10.1186/s12943-015-0351-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increasing trends in cervical cancer mortality among young Japanese women below the age of 50 years: an analysis using the Kanagawa population-based Cancer Registry, 1975-2012. (2015)
  • Author(s): Motoki Y, Mizushima S, Taguri M, Takahashi K, Asano R, Kato H, Asai-Sato M, Katayama K, Okamoto N, Hirahara F, Miyagi E.
  • Journal Title: Cancer Epidemiol Volume: 39 Issue: 5 Pages: 700-706
  • DOI: 10.1016/j.canep.2015.08.001
  • Peer Reviewed / Open Access
• [Journal Article] Attitudes toward cervical cancer screening among women receiving human papillomavirus vaccination in a university-hospital-based community: Interim 2-year follow-up results (2014)
  • Author(s): Miyagi E, Sukegawa A, Motoki Y, Kaneko T, Maruyama Y, Asai-Sato M, Numazaki R, Mizushima S, Hirahara F
  • Journal Title: J Obstet Gynaecol Res Volume: 40 Issue: 4 Pages: 1105-1113
  • DOI: 10.1111/jog.12288
  • Peer Reviewed
• [Journal Article] Amino acid profile index for early detection of endometrial cancer: verification as a novel diagnostic marker (2014)
  • Author(s): Ihata Y, Miyagi E, Numazaki R, Muramatsu T, Imaizumi A, Yamamoto H, Yamakado M, Okamoto N, Hirahara F
  • Journal Title: Int J Clin Oncol Volume: 19 Issue: 2 Pages: 364-372
  • DOI: 10.1007/s10147-013-0565-2
  • Peer Reviewed
• [Journal Article] Annexin A4 is involved in proliferation, chemoresistance and migration and invasion in ovarian clear cell adenocarcinoma cells. (2013)
  • Author(s): Mogami T, Yokota N, Asai-sato M, Yamada R, Koizume S, Sakuma Y, Yoshihara M, Nakamura Y, Takano Y, Hirahara F, Miyagi Y, and Miyagi E.
  • Journal Title: PLOS ONE Volume: 8 Issue: 11 Pages: 1-8
  • DOI: 10.1371/journal.pone.0080359
  • Peer Reviewed
• [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] Radiation therapy for pelvic lymph node metastasis from uterine cervical cancer (2013)
  • Author(s): Hata M, Koike I, Miyagi E, Numazaki R, Asai-Sato M, Kasuya T, Kaizu H, Matsui T, Hirahara F, Inoue T
  • Journal Title: Gynecol Oncol Volume: 131 Issue: 1 Pages: 99-102
  • DOI: 10.1016/j.ygyno.2013.07.085
  • Peer Reviewed
• [Presentation] 日本の子宮頸がん予防の将来を考える～横浜・神奈川子宮頸がん予防プロジェクトから見えてきた意識と行動の課題～ (2015)
  • Author(s): 宮城悦子
  • Organizer: 第34回神奈川県臨床細胞学会学術集会
  • Place of Presentation: 相模原南メディカルセンター（神奈川県相模原市）
  • Year and Date: 2015-10-03
  • Invited
• [Presentation] International comparison of background to the success or failure of HPV vaccination programmes (2015)
  • Author(s): Konnno R, Miyagi E, Hanley S
  • Organizer: HPV2015 (30th International Papillomavirus Conference & Clinical Workshop)
  • Place of Presentation: Lisbon (Portugal)
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] The long and winding road to explore ovarian cancer biomarkers (2014)
  • Author(s): Miyagi E
  • Organizer: International Symposium for Life Design and Engineering 2014
  • Place of Presentation: Pacifico Yokohama (神奈川県横浜市)
• [Presentation] Women against cervical cancer in Japan; Local activities in Yokohama City (2013)
  • Author(s): Miyagi E, Motoki Y, Sato MA, Sukegawa A, Numazaki R, Iwata M, Mizushima S, Ohshige K, Nakayama H, Kato H, Hirahara F
  • Organizer: EUROGIN2013
  • Place of Presentation: Florence, Italy
• [Presentation] Trends in incidence of cervical cancer from 1985 to 2009 in Kanagawa, Japan (2013)
  • Author(s): Motoki Y, Mizushima S, Kaneko T, Kato H, Sato AM, Numazaki R, Okamoto N, Hirahara F, Miyagi E
  • Organizer: EUROGIN2013
  • Place of Presentation: Florence, Italy
• [Presentation] Inhibition of synergistic ICAM1 induction suppresses growth of ovarian clear cell carcinoma (2013)
  • Author(s): Koizume S, Itoh S, Yoshihara M, Nakamura Y, Miyagi E, Hirahara F, Takano Y, Miyagi Y
  • Organizer: 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Increase of cervical cancer risk among young Japanese women; Analyses of Kanagawa cancer registry data 1985-2011 (2013)
  • Author(s): Motoki Y, Kaneko T, Mizushima S, Asai-Sato M, Numazaki R, Kato H, Okamoto N, Hirahara F, Miyagi E
  • Organizer: The 3rd Biennial Meeting of ASGO/The 55th Meeting of JSGO
  • Place of Presentation: ウェスティン都ホテル京都（京都府京都市）
• [Presentation] How can we overcome adverse reactions in HPV vaccination in Japan? (2013)
  • Author(s): Miyagi E
  • Organizer: The 3rd Biennial Meeting of ASGO/The 55th Meeting of JSGO
  • Place of Presentation: ウェスティン都ホテル京都（京都府京都市）
• [Book] がん化学療法クリティカルポイント対応マニュアル (2013)
  • Author(s): 監修・編集 宮城悦子
  • Total Pages: 337
  • Publisher: 株式会社じほう