Nuclear translocation of hypoxia related factors and examination of its inhibitory effect: individualization from the therapeutic viewpoint

• Project/Area Number: 15K08355
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Saitama Medical University
• Principal Investigator: Yasuda Masanori 埼玉医科大学, 医学部, 教授 (50242508)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 低酸素誘導因子 / ヒストン脱アセチル化酵素 / 卵巣癌 / 卵巣明細胞癌 / ARID1A / HDAC / HIF-1a / 低酸素環境 / HIF-1α / 治療標的 / シリマリン

Outline of Final Research Achievements

In ovarian clear cell carcinomas, the single-nucleotide polymorphisms (C1772T) of hypoxia inducible factor (HIF)-1α is more frequent than in healthy group and other carcinomas, but it does not affect patient prognosis or its protein expression. Immunohistochemical expression of HIF-1α and its regulator histone deacetylase (HDAC)6 do not correlate with prognosis in ovarian clear cell canrcioma patients without ARID1A mutation, but with ARID1A mutation Significantly reduced survival time. In clear cell ovarian carcinomas, we found that HIF-1α and HDAC6 could be prognostic factors and therapeutic targets, and that ARID1A could be a biomarker.

Academic Significance and Societal Importance of the Research Achievements

卵巣癌の中でも、卵巣明細胞癌は既存の化学療法に抵抗性とされ、有効な化学療法の開発が望まれている。我々の研究は卵巣明細胞癌の主要な遺伝子変異であるARID1Aをバイオマーカーとして、HIF-1αやHDAC6が予後予測因子や治療標的となりえることを見出した。卵巣癌においても組織型や遺伝子変異に応じて治療を個別化するべきと考えられる。

Research Products

• [Journal Article] Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma (2019)
  • Author(s): Yano Mitsutake、Katoh Tomomi、Miyazawa Mariko、Miyazawa Masaki、Ogane Naoki、Miwa Maiko、Hasegawa Kosei、Narahara Hisashi、Yasuda Masanori
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2397-2397
  • DOI: 10.1038/s41598-019-38653-0
  • Peer Reviewed / Open Access
• [Journal Article] Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma (2019)
  • Author(s): Suzuki Hiroyuki、Yano Mitsutake、Miyazawa Mariko、Miyazawa Masaki、Ogane Naoki、Hasegawa Kosei、Tsuda Hitoshi、Yoshida Masayuki、Okagaki Ryugo、Ishihara Osamu、Yasuda Masanori
  • Journal Title: Journal of Ovarian Research Volume: 12 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s13048-019-0481-9
  • Peer Reviewed / Open Access
• [Journal Article] Association of histone deacetylase expression with histology and prognosis of ovarian cancer (2018)
  • Author(s): Yano Mitsutake、Yasuda Masanori、Sakaki Mika、Nagata Koji、Fujino Takashi、Arai Eiichi、Hasebe Takahiro、Miyazawa Masaki、Miyazawa Mariko、Ogane Naoki、Hasegawa Kosei、Narahara Hisashi
  • Journal Title: Oncology Letters Volume: 15 Pages: 3524-3531
  • DOI: 10.3892/ol.2018.7726
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint inhibitors of CTLA4 and PD-1 for malignant melanoma arising in ovarian cystic teratoma (2018)
  • Author(s): Yano Mitsutake、Asami Yuri、Nishikawa Tadaaki、Yoshida Saori、Kamada Kouichi、Katoh Tomomi、Teramoto Yukiko、Nakamura Yasuhiro、Yasuda Masanori
  • Journal Title: Medicine Volume: 97 Issue: 43 Pages: e12937-e12937
  • DOI: 10.1097/md.0000000000012937
  • Peer Reviewed / Open Access
• [Journal Article] Cleaved caspase-3 expression is a potential prognostic factor for endometrial cancer with positive peritoneal cytology (2018)
  • Author(s): Ogane Naoki、Yasuda Masanori、Kato Hisamori、Kato Tomomi、Yano Mitsutake、Kameda Yoichi、Kamoshida Shingo
  • Journal Title: Cytopathology Volume: in press Issue: 3 Pages: 254-261
  • DOI: 10.1111/cyt.12550
  • NAID: 120006517726
  • Peer Reviewed
• [Journal Article] Advanced Mucinous Adenocarcinoma Arising from a Mature Cystic Teratoma: A Case Report and Literature Review． (2016)
  • Author(s): Miyasaka A, Nishikawa T, Kozawa E, Yasuda M, Fujiwara K, Hasegawa K.
  • Journal Title: Case Rep Oncol. Volume: 27 Issue: 2 Pages: 331-337
  • DOI: 10.1159/000447258
  • Peer Reviewed / Open Access
• [Journal Article] Possible role of thymidine phosphorylase in gynecological tumors as an individualized treatment strategy. (2016)
  • Author(s): Shida M, Yasuda M, Fujita M, Miyazawa M, Kajiwara H, Hirasawa T, Ikeda M, Matsui N, Muramatsu T, Mikami M
  • Journal Title: Oncol Lett. Volume: 12 Pages: 3215-3223
  • Peer Reviewed / Open Access
• [Journal Article] Utility of histogram analysis of apparent diffusion coefficient maps obtained using 3.0T MRI for distinguishing uterine carcinosarcoma from endometrial carcinoma. (2016)
  • Author(s): Takahashi M, Kozawa E, Tanisaka M, Hasegawa K, Yasuda M, Sakai F.
  • Journal Title: J Magn Reson Imaging. Volume: 43 Issue: 6 Pages: 1301-7
  • DOI: 10.1002/jmri.25103
  • Peer Reviewed / Open Access
• [Journal Article] Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression. (2016)
  • Author(s): Kurosaki A, Hasegawa K, Kato T, Abe K, Hanaoka T, Miyara A, O'Shannessy DJ, Somers EB, Yasuda M, Sekino T, Fujiwara K.
  • Journal Title: Int J Cancer. Volume: 138 Issue: 8 Pages: 1994-2002
  • DOI: 10.1002/ijc.29937
  • Peer Reviewed / Open Access
• [Journal Article] Synchronous mucinous metaplasia and neoplasia of the female genital tract with external urethral meatus neoplasm: A case report. (2015)
  • Author(s): Ikeda Y, Yasuda M, Kato T, Yano Y, Kurosaki A, Hasegawa K
  • Journal Title: Gynecol Oncol Rep. Volume: 12 Pages: 27-30
  • Peer Reviewed / Open Access
• [Presentation] Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma (2019)
  • Author(s): Mitsutake Yano, Tomomi Katoh, Mariko Miyazawa, Masaki Miyazawa, Naoki Ogane, Maiko Miwa, Kosei Hasegawa, Hisashi Narahara, Masanori Yasuda
  • Organizer: The 108th Annual Meeting of United States and Canadian Academy of Pathology (USCAP)
  • Int'l Joint Research
• [Presentation] 進行卵巣癌における HDACの発現と化学療法感受性の相関 (2018)
  • Author(s): 矢野光剛, 榊美佳, 永田耕治, 藤野節, 新井栄一, 長谷部孝裕, 小笠原仁子, 宮澤麻里子, 宮澤昌樹, 安田政実
  • Organizer: 第107回病理学会総会
• [Presentation] 明細胞癌の治療標的としてHDAC6の可能性～ARID1A に着目して～ (2018)
  • Author(s): Mitsutake Yano, Mariko Miyazawa, Masaki Miyazawa, Maiko Miwa, Kosei Hasegawa, Hisashi Narahara, Masanori Yasuda
  • Organizer: 第15回病理学会カンファレンス
• [Presentation] HDAC6 as a therapeutic target for ovarian clear cell carcinoma, in association with ARID1A loss (2018)
  • Author(s): Mitsutake Yano, Mariko Miyazawa, Masaki Miyazawa, Maiko Miwa, Kosei Hasegawa, Hisashi Narahara, Masanori Yasuda
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] SilibininによるHIF-1阻害の検討：卵巣癌化学療法における補助的意義 (2018)
  • Author(s): 宮澤麻里子, 安田政実, 宮澤昌樹, 矢野光剛, 加藤智美, 大金直樹, 平澤猛, 松井成明, 林優, 三上幹男
  • Organizer: 第107回病理学会総会
• [Presentation] 卵巣癌におけるHDACの免疫組織化学的発現の検討 (2017)
  • Author(s): 矢野 光剛, 加藤 智美, 長谷川 幸清, 榊 美佳, 永田 耕治, 新井 栄一, 長谷部 孝裕, 宮澤 麻里子, 宮澤 昌樹, 楢原 久司, 安田 政実
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
• [Presentation] 卵巣上皮性腫瘍における上皮と間質の解析【第2報】 (2017)
  • Author(s): 成清 羊佳, 周東 真代, 渡辺 宏志, 加藤 智美, 鎌田 孝一, 矢野 光剛, 長谷川 幸清, 新井 栄一, 長谷部 孝裕, 安田 政実
  • Organizer: 第106回日本病理学会総会
• [Presentation] 卵巣癌におけるHDACの免疫組織化学的発現の検討 (2017)
  • Author(s): 矢野 光剛, 加藤 智美, 鎌田 孝一, 長谷川 幸清, 榊 美佳, 永田 耕治, 藤野 節, 新井 栄一, 長谷部 孝裕, 安田 政実
  • Organizer: 第106回日本病理学会総会
• [Presentation] SilibininによるHIF-1阻害の検討；卵巣癌化学療法における補助的意義 (2017)
  • Author(s): 宮澤 麻里子, 安田 政実, 平澤 猛, 宮澤 昌樹, 林 優, 加藤 智美, 松井 成明, 梶原 博, 信田 政子, 池田 仁恵, 村松 俊成, 三上 幹男
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
• [Presentation] 細胞診から考える境界病変 WHO分類改定の影響 (2016)
  • Author(s): 安田政実
  • Organizer: 第55回日本臨床細胞学会秋期大会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-11-18
• [Presentation] 細胞学の基礎 形態と機能 病理形態の基礎と、病理診断における機能的洞察 (2016)
  • Author(s): 安田政実
  • Organizer: 第58回日本婦人科腫瘍学会
  • Place of Presentation: 米子コンベンションセンター（鳥取県米子市）
  • Year and Date: 2016-07-08
• [Presentation] 腹膜悪性中皮腫の2例 (2016)
  • Author(s): 安田政実、菊地 淳
  • Organizer: 第44回日本婦人科病理学会学術集会
  • Place of Presentation: 東京慈恵会医科大学（東京都港区）
  • Year and Date: 2016-06-11
• [Presentation] 最近のWHO婦人科病理分類と細胞診（像）の対比 (2016)
  • Author(s): 安田政実
  • Organizer: 第57回日本臨床細胞学会総会春期大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-05-28
• [Presentation] 「WHO2014準拠卵巣腫瘍取扱い規約」の改訂で現場の対応はどう変わるか (2016)
  • Author(s): 安田政実
  • 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
• [Presentation] 子宮体癌の初期病変･前駆病変の実際―WHO分類の考え方― (2015)
  • Author(s): 安田政実
  • Organizer: 第43回日本婦人科病理学会学術集会
  • Place of Presentation: 東京女子医科大学（新宿区、東京）
  • Year and Date: 2015-12-20
• [Presentation] 女性生殖器と外尿道口に同時に発生した粘液性腫瘍の一例 (2015)
  • Author(s): 成清羊佳，加藤智美，細沼沙紀，鎌倉靖夫，周東真代，渡辺宏志，矢野友梨，小澤栄人，永田耕治，安田政実
  • Organizer: 第54回日本臨床細胞学会秋期大会
  • Place of Presentation: 名古屋国際会議場（名古屋市、愛知県）
  • Year and Date: 2015-11-21
• [Presentation] 子宮内膜ポリープ由来癌の細胞像および臨床病理学的背景 (2015)
  • Author(s): 加藤智美，佐瀬智子，鎌倉靖夫，菊地淳，大金直樹，小澤栄人，今井雄一，長谷川幸清，梶原博，安田政実
  • Organizer: 第56回日本臨床細胞学会総会（春期大会）
  • Place of Presentation: くにびきメッセ・松江テルサ（松江市、島根県）
  • Year and Date: 2015-06-12
• [Presentation] Germ cell tumour of the ovary (2015)
  • Author(s): Yasuda M
  • Organizer: The 19th Korea Taiwan Japan Joint Meeting for Gynecological Pathology
  • Place of Presentation: 名古屋市立大学（名古屋市、愛知県）
  • Year and Date: 2015-06-06
  • Int'l Joint Research