Exploring the mechanism by which BUB1 confers malignant potential in utothelial carcinoma

• Project/Area Number: 17K16821
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Osaka Medical College
• Principal Investigator: Komua Kazumasa 大阪医科大学, 医学部, 助教 (10789853)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 膀胱癌 / DNAダメージ / 膀胱がん

Outline of Final Research Achievements

TMT-based quantification analysis between treatment-naive and chemo-radiation resistant tumors identified 1640 proteins. We confirmed that GO term analysis of UniProtKB key words for upregulated proteins exhibited significantly upregulated DNA damage repair pathways and revealed that BUB1 (budding uninhibited by benzimidazoles 1) is the most significantly upregulated protein in chemo-resistant clones compared to treatment-naive tumor. We next developed experimental model to analyze the function of aberrant BUB1 expression upon DNA damage using digital droplet PCR and CRISPR-Cas9 system and revealed that upregulation of BUB1 activated alternative non-homologous end joining repair creating deletion and insertion sites at double strand break. In dataset analysis, upregulation of BUB1 is associated with poor outcome and notably, there was a significant correlation between increased BUB1 expression and tumor mutation burden suggesting the link to the effect of immune-checkpoint inhibition.

Academic Significance and Societal Importance of the Research Achievements

現在国内で行われているゲノム医療の普及促進の一つの課題として、解析後のアウトプットとなる臨床治験を含む治療選択肢の拡充が挙げられると考えている。癌治療、研究において特定のKey Moleculeによる多彩な形質変化を明らかにすることは、患者様の発現差異による層別化を可能にし、さらにその変化に伴う治療ターゲットの発見がテーラーメード医療を可能にする。本研究においてもBUB1 inhibitorによる治療効果予測因子を明らかにすることにより、個別化医療Precision Medicineへの発展を目指すとともに、来るべきゲノム医療で加療選択され得る治療オプションの一つとなる可能性を明らかにしたい。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Dana Farber Cancer Institute(米国)
• [Journal Article] hibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D. (2018)
  • Author(s): Komura K、Yoshikawa Y, Shimamura T, Chakraborty G, Gerke TA, Hinohara K, Chadalavada K, Jeong SH, Armenia J, Du SY, Mazzu YZ, Taniguchi K, Ibuki N, Meyer CA, Nanjangud GJ, Inamoto T, Lee GM, Mucci LA, Azuma H, Sweeney CJ, Kantoff PW.
  • Journal Title: Journal of Clinical Investigation Volume: 128(7) Issue: 7 Pages: 2979-95
  • DOI: 10.1172/jci96769
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells. (2018)
  • Author(s): Kuranaga Y, Sugito N, Shinohara H, Tsujino T, Taniguchi K, Komura K, Ito Y, Soga T, Akao Y.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 10 Pages: 3012-3012
  • DOI: 10.3390/ijms19103012
  • Peer Reviewed / Open Access
• [Journal Article] A Panel of MicroRNA Signature as a Tool for Predicting Survival of Patients with Urothelial Carcinoma of the Bladder (2018)
  • Author(s): Inamoto Teruo、Uehara Hirofumi、Akao Yukihiro、Ibuki Naokazu、Komura Kazumasa、Takahara Kiyoshi、Takai Tomoaki、Uchimoto Taizo、Saito Kenkichi、Tanda Naoki、Yoshikawa Yuki、Minami Koichiro、Hirano Hajime、Nomi Hayahito、Kato Ryuji、Hayashi Tetsuya、Azuma Haruhito
  • Journal Title: Disease Markers Volume: 2018 Pages: 1-6
  • DOI: 10.1155/2018/5468672
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of lncRNA MIR222HG co-transcribed from the miR-221/222 gene promoter facilitates the development of castration-resistant prostate cancer (2018)
  • Author(s): Sun Tong、Du Shin-Yi、Armenia Joshua、Qu Fangfang、Fan Jingyu、Wang Xiaodong、Fei Teng、Komura Kazumasa、Liu Shirley X.、Lee Gwo-Shu Mary、Kantoff Philip W
  • Journal Title: Oncogenesis Volume: 7 Issue: 3 Pages: 30-30
  • DOI: 10.1038/s41389-018-0039-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preoperative Measurement of the Modified Glasgow Prognostic Score Predicts Patient Survival in Non-Metastatic Renal Cell Carcinoma Prior to Nephrectomy. (2017)
  • Author(s): Tsujino T,Komura K, Matsunaga T, Yoshikawa Y, Takai T, Uchimoto T, Saito K, Tanda N, Oide R, Minami K, Uehara H, Jeong SH, Taniguchi K, Hirano H, Nomi H, Ibuki N, Takahara K, Inamoto T, Azuma H.
  • Journal Title: Ann Surg Oncol. Volume: 24(9) Issue: 9 Pages: 2787-93
  • DOI: 10.1245/s10434-017-5948-6
  • Peer Reviewed
• [Journal Article] The combination of preoperative platelet count and neutrophil lymphocyte ratio as a prognostic indicator in localized renal cell carcinoma. (2017)
  • Author(s): Takuya Tsujino,Kazumasa Komura, Atsushi Ichihashi, Takeshi Tsutsumi,Tomohisa Matsunaga, Yuki Yoshikawa, Ryoichi Maenosono, Kyohei Okita,Tomoaki Takai, Rintaro Oide, Koichiro Minami, Hirofumi Uehara, Kohei Taniguchi, Hajime Hirano, Hayahito Nomi, Naokazu Ibuki, Kiyoshi Takahara,Teruo Inamoto, Haruhito Azuma.
  • Journal Title: Oncotarget Volume: 8 Issue: 66 Pages: 110311-25
  • DOI: 10.18632/oncotarget.22688
  • Peer Reviewed
• [Journal Article] The systemic inflammation-based Glasgow Prognostic Score as a powerful prognostic factor in patients with upper tract urothelial carcinoma. (2017)
  • Author(s): Inamoto T,Matsuyama H, Sakano S, Ibuki N, Takahara K, Komura K, Takai T, Tsujino T, Yoshikawa Y, Minami K, Nagao K, Inoue R, Azuma H.
  • Journal Title: Oncotarget Volume: 8(68) Issue: 68 Pages: 113248-57
  • DOI: 10.18632/oncotarget.22641
  • Peer Reviewed
• [Presentation] Aberrant Error-Prone DNA Damage Repair as a Potential Therapeutic Target in Advanced Urothelial Carcinoma (2019)
  • Author(s): Komura K,Inamoto T, Uehara H, Ibuki , Minami K, Tsujino T, Azuma H.
  • Organizer: the 34rd Annual European Association of Urology (EAU) Congress 2019
  • Int'l Joint Research
• [Presentation] 放射線化学療法耐性尿路上皮がんにおけるError-Prone DNA Repairの異常亢進と臨床への治療応用 (2019)
  • Author(s): 小村 和正
  • Organizer: 日本泌尿器科学会総会
• [Presentation] combination of platelet count and neutrophil to lymphocyte ratio (COP-NLR) for prediction of treatment outcome for patients with localized renal cell carcinoma. (2018)
  • Author(s): Kazumasa Komura,Takuya Tsujino,Naokazu Ibuki,Teruo Inamoto,Haruhito Azuma.
  • Organizer: 2018 Genitourinary Cancers Symposium
  • Int'l Joint Research
• [Presentation] Aggressive prostate cancer by the loss of male specific histone demethylase ‘KDM5D’. (2018)
  • Author(s): Komura K,Inamoto T, Ibuki N, Sweeney C, Azuma H, Kantoff P.
  • Organizer: EAU 2018
  • Int'l Joint Research
• [Presentation] Decreased Expression of Male Specific Histone Demethylase “KDM5D” is Prognostic for Development of Castration-Resistant Prostate Cancer. (2017)
  • Author(s): Kazumasa Komura,Seong Ho Jeong, Kunihiko Hinohara, Gwo-Shu Mary Lee, Christopher J. Sweeney, Haruhito Azuma, and Philip W. Kantoff。
  • Organizer: AUA 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] 限局性前立腺癌の高密度焦点式超音波療法でのPSA Flareの意義の検討. (2017)
  • Author(s): 小村 和正,伊夫貴 直和、稲元 輝生、東 治人.
  • Organizer: 第31回日本泌尿器内視鏡学会総会