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

2018 Fiscal Year Final Research Report

• 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
• Keywords: 膀胱癌 / DNAダメージ

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.

Free Research Field

泌尿器科

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。