Elucidating anticancer drug resistance in urothelial carcinoma by multi-faceted approach

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09715
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kagoshima University
• Principal Investigator: NAKAGAWA Masayuki 鹿児島大学, 医歯学総合研究科, 客員研究員 (90164144)
• Co-Investigator(Kenkyū-buntansha): 大迫 洋一 鹿児島大学, 鹿児島大学病院, 医員 (60793354) ; 榎田 英樹 鹿児島大学, 医歯学域医学系, 教授 (80347103) ; 吉野 裕史 鹿児島大学, 医歯学域鹿児島大学病院, 助教 (90642611)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 尿路上皮癌 / 薬剤耐性 / マイクロRNA / シスプラチン / ジェムシタビン

Outline of Final Research Achievements

Knocking down PHGDH, a metabolic enzyme on the glycolysis pathway, significantly inhibited proliferation of bladder cancer cell lines and induced cell apoptosis. In in vivo, xenograft growth was significantly suppressed in the combination group of PHGDH inhibitors and GC therapy.
Overexpression of miR-99a-5p was contributed to inhibit cell viability and improve GEM sensitivity in the GEM-resistant cell lines. We focused on SMARCD1 a candidate target gene, and cell viability was suppressed and GEM sensitivity was restored in the loss-of-function experiments. In vivo, overexpression of miR-99a-5p and knockdown of SMARCD1 also suppressed the xenograft growth. The mechanism was found to be acceleration of cell senescence through the induction of p21.

Free Research Field

泌尿器癌

Academic Significance and Societal Importance of the Research Achievements

尿路上皮癌は他の泌尿器癌（前立腺癌や腎癌）に比べて明らかに有効な薬物治療の手段が少なく、薬剤耐性が大きな問題である。治療成績の向上や医療経済のためにも新規治療法の開発は急務である。本研究ではPHGDH遺伝子や、miR-99a-5pとその標的遺伝子であるSMARCD1が核心的なGC耐性機序に関わる可能性があることを明らかにできた。さらに研究を発展させれば臨床応用が可能なKey moleculeとして展開できる可能性が確認できた。