Mechanism of inhibitory effect of Carbonyl reductase on cancers aiming to gene therapy

• Project/Area Number: 26462508
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Hirosaki University
• Principal Investigator: Yokoyama Yoshihito 弘前大学, 医学研究科, 教授 (90261453)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: Carbonyl reductase / Ovarian cancer / アポトーシス / 腫瘍縮小 / 遺伝子治療 / 卵巣癌 / Carbonyl reductase DNA / デンドリマー / TNFα受容体 / Caspase-8 / NF-κB / c-jun

Outline of Final Research Achievements

Tumor growth was significantly suppressed in mice injected with CR1-overexpressing cells. Tumor volume in the CR1 induction group decreased temporarily until 2 weeks. Tumor cell membranes in both CR1 induction and control groups were positive for TNFR1 expression; however, total protein levels did not differ between the two groups. TNFR-2 expression was comparatively weak in both groups. The expression of NF-κB and c-Jun was weaker in the CR1 induction group than in control. In contrast, caspase-8 and caspase-3 expression was higher in the CR1 induction group. Furthermore, the number of apoptotic cells was significantly greater in tumors that appeared after injections of both types of CR1-overexpressing cells than in those of control cancer cells. These results suggest that CR1 induces apoptosis by activating the caspase pathway via binding to TNFR1.

Research Products

• [Journal Article] Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences. (2017)
  • Author(s): Yokoyama Y, Shigeto T, Miura R, Kobayashi A, Mizunuma M, Yamauchi A, Futagami M, Mizunuma H.
  • Journal Title: Oncol Lett Volume: 13 Issue: 6 Pages: 4933-4938
  • DOI: 10.3892/ol.2017.6095
  • NAID: 120006576906
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Contributions of the Japanese Gynecologic Oncology Group (JGOG) in Improving the Quality of Life in Women With Gynecological Malignancies. (2017)
  • Author(s): Futagami F, Yokoyama Y, Shimada M, Sato S, Miyagi E, Tozawa-Ono A, Suzuki N, Fujimura M, Aoki Y, Sagae S, Sugiyama T
  • Journal Title: Curr Oncol Rep Volume: 19 Issue: 4
  • DOI: 10.1007/s11912-017-0580-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Palliative care for patients with gynecologic cancer in Japan: a Japan Society of Gynecologic Palliative Medicine (JSGPM). (2016)
  • Author(s): Futagami M, Yokoyama Y, Sato T, Hirota K, Shimada K, Miyagi E, Suzuki N, Fujiwara M.
  • Journal Title: Asia Pac J Cancer Prev Volume: 17 Pages: 4637-4622
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A case of para-ovarian serous cystadenofibroma that showed a malignant potential in image inspection. (2016)
  • Author(s): Miura R, Fukui A, Funamizu A, Shigeto T, Yokoyama Y, Mizunuma H
  • Journal Title: Gynecol Minimal Inv Ther Volume: 5 Pages: 96-98
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A strategy using photodynamic therapy and clofibric acid to treat peritoneal dissemination of ovarian cancer. (2016)
  • Author(s): Yokoyama Y, Shigeto T, Miura R, Kobayashi A, Mizunuma M, Yamauchi A, Futagami M, Mizunuma H.
  • Journal Title: Asia Pac J Cancer Prev Volume: 17 Issue: 2 Pages: 775-779
  • DOI: 10.7314/apjcp.2016.17.2.775
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The advantage of incorporating liquid-based cytology (TACASTM) in mass screening for cervical cancer. (2016)
  • Author(s): Yokoyama Y, Futagami M, Watanabe J, Sakuraba A, Nagasawa K, Maruyama H, Sato S.
  • Journal Title: Hum Cell Volume: 29 Issue: 2 Pages: 83-90
  • DOI: 10.1007/s13577-015-0130-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The randomized phase 3 trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG Trial. (2016)
  • Author(s): Sugiyama T, Okamoto A, Enomoto T, Hamano T, Aotani E, Terao Y, Suzuki N, Mikami M, Yaegashi N, Kato K, Yoshikawa H, Yokoyama Y, Tanabe H, Nishino K, Nomura H, Kim JW, Kim BG, Pignata S, Alexandre J, Green J, Isonishi S, Terauchi F, Fujiwara K, Aoki D.
  • Journal Title: J Clin Oncol Volume: 34 Issue: 24 Pages: 2881-2887
  • DOI: 10.1200/jco.2016.66.9010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Passage of irinotecan and its active metabolite, SN-38, into human milk. (2016)
  • Author(s): Nakagawa J, Terui K, Hosoi K, Ueno K, Yokoyama Y, Hayakari M.
  • Journal Title: J Clin Pharm Ther Volume: 41 Issue: 5 Pages: 579-582
  • DOI: 10.1111/jcpt.12428
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FOXP1 forkhead transcription factor is associated with the pathogenesis of endometrial cancer. (2016)
  • Author(s): Mizunuma M, Yokoyama Y, Futagami M, Horie K, Watanabe J, Mizunuma H
  • Journal Title: Heliyon Volume: 2 Issue: 5 Pages: e00116-e00116
  • DOI: 10.1016/j.heliyon.2016.e00116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Streptococcal Toxic Shock Syndrome: Life Saving Role of Peritoneal Lavage and Drainage. (2016)
  • Author(s): Yokoyama M, Oyama F, Ito A, Yokota M, Matsukura D, Tsutsumi S, Kasai T, Nitobe Y, Morikawa A, Ozaki T, Yokoyama Y.
  • Journal Title: Clin Med Insight Case Rep Volume: 9 Pages: 75-77
  • DOI: 10.4137/ccrep.s40217
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A case of ovarian small cell carcinoma of the pulmonary type that was observed as it developed. (2016)
  • Author(s): Kumasaka R, Yokoyama Y, Fuchinoue K, Mizunuma H, Taniguchi R, Hashimoto T, Oda T, Kusumi T
  • Journal Title: Eur J Gynaecol Oncol Volume: 37 Pages: 710-713
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical efficacy of nedaplatin-based concurrent chemoradiotherapy for uterine cervical cancer: A Tohoku Gynecologic Cancer Unit Study. (2016)
  • Author(s): Kagabu M, Shoji T, Omi H, Honda T, Miura T, Yokoyama Y, Tokunaga H, Takano T, Ohta T, Sato N, Watanabe T, Yamada H, Mizunuma H, Yaegashi N, Nagase S, Terada Y, Fujimori K, Tase T, Sugiyama T.
  • Journal Title: Int J Clin Oncol Volume: 21 Pages: 735-740
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dysgerminoma developing from an ectopic ovary in a patient with WAGR syndrome: A case report. (2016)
  • Author(s): Miura R, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H, Kurose A, Tsuruga K, Sasaki S, Terui K, Ito E.
  • Journal Title: Mol Clin Oncol Volume: 5 Issue: 5 Pages: 503-506
  • DOI: 10.3892/mco.2016.1004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gene therapy for ovarian cancer using carbonyl reductase 1 DNA with a polyamidoamine dendrimer in mouse models. (2016)
  • Author(s): Kobayashi A, Yokoyama Y, Osawa Y, Miura R, Mizunuma H.
  • Journal Title: Cancer Gene Therapy Volume: 23 Issue: 1 Pages: 24-28
  • DOI: 10.1038/cgt.2015.61
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] How do Japanese gynecologists view hormone replacement therapy for survivors of endometrial cancer? Japanese Gynecologic Oncology Group (JGOG) survey. (2015)
  • Author(s): Yokoyama Y, Ito K, Takamatsu K, Takehara K, Nakanishi T, Harano K, Watari H, Susumu N, Aoki D, Saito T.
  • Journal Title: International Journal of Clinical Oncology Volume: 20 Issue: 5 Pages: 997-1004
  • DOI: 10.1007/s10147-015-0808-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer. (2015)
  • Author(s): Mizunuma M, Yokoyama Y, Futagami M, Aoki M, Takai Y, Mizunuma H.
  • Journal Title: International Journal of Clinical Oncology Volume: 20 Issue: 5 Pages: 989-996
  • DOI: 10.1007/s10147-015-0807-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor signaling. (2015)
  • Author(s): Miura R, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H.
  • Journal Title: International Journal of Oncology Volume: 47 Issue: 6 Pages: 2173-2180
  • DOI: 10.3892/ijo.2015.3205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis. (2015)
  • Author(s): Luchini C, Veronese N, Solmi M, Cho H, Kim JH, Chou A, Gill AJ, Faraj SF, Chaux A, Netto GJ, Nakayama K, Kyo S, Lee SY, Kim DW, Yousef GM, Scorilas A, Nelson GS, Köbel M, Kalloger SE, Schaeffer DF, Yan HB, Liu F, Yokoyama Y, Zhang X, Pang D, Lichner Z, Sergi G, Manzato E, Capelli P, Wood LD, Scarpa A, Correll CU.
  • Journal Title: Oncotarget Volume: 36 Issue: 36 Pages: 39088-39097
  • DOI: 10.18632/oncotarget.5142
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation (2015)
  • Author(s): Osawa Y, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H.
  • Journal Title: International Journal of Oncology Volume: 46 Issue: 3 Pages: 1252-1258
  • DOI: 10.3892/ijo.2014.2810
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The level of RECQL1 expression is a prognostic factor for epithelial ovarian cancer. (2014)
  • Author(s): Matsushita Y, Yokoyama Y, Yoshida H, Osawa Y, Mizunuma M, Shigeto T, Futagami M, Imaizumi T, Mizunuma H.
  • Journal Title: Journal of Ovarian Research Volume: 7 Issue: 1 Pages: 107-107
  • DOI: 10.1186/s13048-014-0107-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression. (2014)
  • Author(s): Tamura Y, Yokoyama Y, Yoshida H, Imaizumi T, Mizunuma H.
  • Journal Title: Journal of Ovarian Research Volume: 7 Issue: 1 Pages: 94-94
  • DOI: 10.1186/s13048-014-0094-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action. (2014)
  • Author(s): Matsumura Y, Yokoyama Y, Shigeto T, Fuatagami M, Mizunuma H.
  • Journal Title: Molecular Pain Volume: 10 Pages: 61-61
  • DOI: 10.1186/1744-8069-10-61
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] L-type Amino Acid Transporter 1 (LAT1) Expression Increases in Well-differentiated but Decreases in Poorly Differentiated Endometrial Endometrioid Adenocarcinoma, and Shows an Inverse Correlation With p53 Expression. (2014)
  • Author(s): Watanabe J, Yokoyama Y, Futagami M, Mizunuma, H, Yoshioka H, Washiya K, Hana K Endou H, Okayasu I.
  • Journal Title: International Journal of Gynecological Cancer Volume: 24 Issue: 4 Pages: 659-663
  • DOI: 10.1097/igc.0000000000000123
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] カルボニル還元酵素１DNAとデンドリマー複合体を用いた卵巣癌マウスモデルの遺伝子治療 (2016)
  • Author(s): 小林麻美、横山良仁
  • 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（米子）
  • Year and Date: 2016-07-08
• [Presentation] 卵巣癌細胞における微小管結合蛋白質Tau発現の臨床的意義 (2016)
  • Author(s): 山内愛紗、横山良仁
  • 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（米子）
  • Year and Date: 2016-07-08
• [Presentation] エイジング：上皮性卵巣がん (2016)
  • Author(s): 横山良仁
  • Organizer: 第16回日本抗加齢学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-06-10
  • Invited
• [Presentation] 子宮体癌とFOXP1遺伝子発現の関連性 (2016)
  • Author(s): 水沼槙人、横山良仁
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2016-04-21
• [Presentation] 母乳へのイリノテカンおよび活性代謝物SN-38の移行性 (2016)
  • Author(s): 横山良仁
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2016-04-21
• [Presentation] 婦人科術後患者のヘルスケア (2015)
  • Author(s): 横山良仁
  • Organizer: 第53回日本癌治療学会
  • Place of Presentation: 国立京都国際会議場（京都府京都市）
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] 卵巣がん・卵管がん・腹膜がんの予防・診断 (2015)
  • Author(s): 横山良仁
  • Organizer: 第57回日本婦人科腫瘍学会
  • Place of Presentation: マリオス盛岡地域交流センター（岩手県盛岡市）
  • Year and Date: 2015-08-07
  • Invited
• [Presentation] エストロゲン応答性転写因子FOXP1は卵巣がんの予後因子になり得るか？ (2015)
  • Author(s): 横山良仁
  • Organizer: 第67回日本産科婦人科学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-07
• [Presentation] Carbonyl reductase1の発現低下は卵巣癌の増殖を促進する (2015)
  • Author(s): 大澤有姫、横山良仁、小林麻美、重藤龍比古、二神真行、水沼英樹
  • Organizer: 第67回日本産科婦人科学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-07
• [Presentation] 腫瘍壊死因子受容体を介したクロフィブリン酸による卵巣悪性腫瘍増殖抑制効果の機序の解明 (2015)
  • Author(s): 三浦理絵、横山良仁、水沼英樹
  • Organizer: 第67回日本産科婦人科学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-07
• [Presentation] 子宮がん集団検診における液状化検体細胞診導入の取り組み (2014)
  • Author(s): 横山良仁
  • Organizer: 第23回日本婦人科がん検診学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-11-23
  • Invited
• [Presentation] Decreased ARID1A expression is correlated with chemo-resistance in epithelial ovarian cancer (2014)
  • Author(s): Yoshihito Yokoyama
  • Organizer: 15th Biennial Meeting of the International Gynecologic Cancer Society
  • Place of Presentation: メルボルン
  • Year and Date: 2014-11-08 – 2014-11-11
• [Presentation] Pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response of radiation therapy and concurrent chemoradiation therapy in cervical carcinoma (2014)
  • Author(s): Makito Mizunuma, Yoshihito Yokoyama
  • Organizer: 15th Biennial Meeting of the International Gynecologic Cancer Society
  • Place of Presentation: メルボルン
  • Year and Date: 2014-11-08 – 2014-11-11
• [Presentation] 類内膜腺癌G1に対する高用量MPA療法の治療成績 (2014)
  • Author(s): 松村由紀子 二神真行 重藤龍比古 横山良仁 水沼英樹
  • Organizer: 第56回日本婦人科腫瘍学会
  • Place of Presentation: 宇都宮
  • Year and Date: 2014-07-17 – 2014-07-19
• [Presentation] 上皮性卵巣癌におけるARID1A発現の低下は化学療法抵抗性と相関する (2014)
  • Author(s): 横山良仁
  • Organizer: 第66回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-18 – 2014-04-20