Tumor microenvironment and ubiquitin system in platinum resistance urothelial carcinoma

• Project/Area Number: 26462429
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Keio University
• Principal Investigator: TANAKA NOBUYUKI 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (60445244)
• Co-Investigator(Kenkyū-buntansha): 小坂 威雄 慶應義塾大学, 医学部(信濃町), 講師 (30445407) ; 大家 基嗣 慶應義塾大学, 医学部(信濃町), 教授 (00213885) ; 松本 一宏 慶應義塾大学, 医学部(信濃町), 助教 (80366153) ; 丹羽 直也 慶應義塾大学, 医学部(信濃町), 助教 (40626743)
• Project Period (FY): 2014-04-01 – 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 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); 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)
• Keywords: 尿路上皮癌 / 上皮間葉転換 / シスプラチン / FBXO32 / 抗がん剤耐性 / ユビキチン

Outline of Final Research Achievements

To identify the molecules involved in epithelial-to-mesenchymal transition (EMT) in tumors post acquired platinum resistance (PR), we examined the changes in gene expression before and after platinum treatment. Four urothelial carcinoma cell lines, T24, 5637, and their PR sublines of T24PR and 5637PR, were assessed by microarray, and FBXO32 was newly identified as a negative regulator of EMT. In vitro study showed an intimate relationship between FBXO32 expression and EMT, demonstrating that FBXO32 knockdown resulted in the EMT acquisition. In contract, FBXO32 overexpression suppressed EMT. The association between FBXO32 expression and EMT was further validated using human specimens. CGH array analysis demonstrated loss of heterozygosity at 8q24.13 in T24PR cells, which harbors FBXO32. In 5637PR cells, decreased nuclear FOXO1/3a expression seemed to affect FBXO32 dysregulation. These results suggest the association between EMT and ubiquitin-proteasome regulation when tumors develop PR.

Research Products

• [Journal Article] Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model. (2016)
  • Author(s): Tanaka N, Mizuno R, Yasumizu Y, Ito K, Shirotake S, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Oya M
  • Journal Title: Urol Oncol Volume: 35(2) Issue: 2 Pages: 19-39
  • DOI: 10.1016/j.urolonc.2016.10.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Acquired platinum resistance involves epithelial-to-mesenchymal transition through ubiquitin ligase FBXO32 dysregulation (2016)
  • Author(s): Tanaka N, Kosaka T, Miyazaki Y, Mikami S, Niwa N, Otsuka Y, Minamishima YA, Mizuno R, Kikuchi E, Miyajima A, Sabe H, Okada Y, Uhlen P, Suematsu M, Oya M
  • Journal Title: JCI insight Volume: 1 Issue: 18
  • DOI: 10.1172/jci.insight.83654
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma (2016)
  • Author(s): Shirotake S, Yasumizu Y, Ito K, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Tanaka N, Mizuno R, Oya M
  • Journal Title: Clin Genitourin Cancer Volume: Epub ahead of print Issue: 6 Pages: e575-e583
  • DOI: 10.1016/j.clgc.2016.03.014
  • Peer Reviewed / Open Access
• [Journal Article] Effect of reclassification of the IMDC model in patients with metastatic renal cell carcinoma treated with targeted therapy in the first-line and second-line settings (2016)
  • Author(s): Tanaka N, Mizuno R, Shirotake S, Ito K, Yasumizu Y, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Oya M
  • Journal Title: Urol Oncol Volume: Epub ahead of print Issue: 7 Pages: 293.e17-293.e25
  • DOI: 10.1016/j.urolonc.2016.02.023
  • Peer Reviewed / Open Access
• [Journal Article] Plasma fibrinogen level: An independent prognostic factor for disease-free survival and cancer-specific survival in patients with localized renal cell carcinoma (2016)
  • Author(s): Obata J, Tanaka N, Mizuno R, Kanao K, Mikami S, Matsumoto K, Kosaka T, Kikuchi E, Jinzaki M, Oya M
  • Journal Title: BJU Int Volume: Epub ahead of print Issue: 4 Pages: 598-603
  • DOI: 10.1111/bju.13414
  • Peer Reviewed / Open Access
• [Journal Article] External Validation of the MSKCC and IMDC Risk Models in Patients Treated with Targeted Therapy as a First-line and Subsequent Second-line Treatment: A Japanese Multi-institutional Study. (2016)
  • Author(s): Nobuyuki Tanaka, Ryuichi Mizuno, Keiichi Ito, Suguru Shirotake, Yota Yasumizu, Ayako Masunaga, Yujiro Ito, Yasumasa Miyazaki, Masayuki Hagiwara, Kent Kanao, Shuji Mikami, Ken Nakagawa, Tetsuo Momma, Takeshi Masuda, Tomohiko Asano, Masafumi Oyama, Mototsugu Oya.
  • Journal Title: European Urology Focus. Volume: 2 Issue: 3 Pages: 303-309
  • DOI: 10.1016/j.euf.2015.11.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of Combined Use of Blood-based Inflammatory Markers on Patients with Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Proposal of a Cumulative Marker Score as a Novel Predictive Tool for Prognosis (2015)
  • Author(s): Nobuyuki Tanaka, Eiji Kikuchi, Kent Kanao, Kazuhiro Matsumoto, Suguru Shirotake, Yasumasa Miyazaki, Hiroaki Kobayashi, Gou Kaneko, Masayuki Hagiwara, Hiroki Ide, Jun Obata, Katsura Hoshino, Nozomi Hayakawa, Takeo Kosaka, Satoshi Hara, Ken Nakagawa, Masahiro Jinzaki, Mototsugu Oya
  • Journal Title: European Urology Focus Volume: 1 Issue: 1 Pages: 54-63
  • DOI: 10.1016/j.euf.2015.02.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of outcomes between ultrasonography and cystoscopy in the surveillance of patients with initially diagnosed TaG1-2 bladder cancers: A matched-pair analysis (2015)
  • Author(s): Naoya Niwa, Kazuhiro Matsumoto, Nozomi Hayakawa, Yujiro Ito, Takahiro Maeda, Seiya Akatsuka, Takeshi Masuda, So Nakamura, Nobuyuki Tanaka
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 33 Issue: 9 Pages: 386.e15-386.e21
  • DOI: 10.1016/j.urolonc.2015.04.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer. (2015)
  • Author(s): Y. Ito, E. Kikuchi, N. Tanaka, T. Kosaki, E. Suzuki, R. Mizuno, T. Shinojima, A. Miyajima, K. Umezawa and M. Oya
  • Journal Title: BMC Cancer Volume: 15 Issue: 1 Pages: 324-324
  • DOI: 10.1186/s12885-015-1315-9
  • Peer Reviewed / Open Access
• [Journal Article] A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio for Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Miyazaki Y, Kobayashi H, Kaneko G, Hagiwara M, Ide H, Obata J, Hoshino K, Hayakawa N, Kosaka T, Hara S, Oyama M, Momma T, Nakajima Y, Jinzaki M, Oya M
  • Journal Title: Ann Surg Oncol Volume: 21(12) Issue: 12 Pages: 4041-8
  • DOI: 10.1245/s10434-014-3830-3
  • Peer Reviewed
• [Presentation] 尿路上皮癌における抗がん剤耐性克服とEMT制御 (2015)
  • Author(s): 田中伸之 小坂威雄 宮﨑保匡 丹羽直也 水野隆一 菊地栄次 宮嶋哲 大家基嗣
  • Organizer: 第24回泌尿器科分子・細胞研究会
  • Place of Presentation: JPタワー（東京都千代田区）
  • Year and Date: 2015-02-27 – 2015-02-28
• [Remarks]
  • URL: http://www.keio-urology.jp/
• [Remarks] 慶應義塾大学医学部泌尿器科学教室
  • URL: http://www.keio-urology.jp/
• [Remarks] 慶應義塾大学医学部 泌尿器科学教室
  • URL: http://www.keio-urology.jp/