A potential role of aberrant DNA methylation in the chemoresistance in bladder cancer cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K11017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Sapporo Medical University
• Principal Investigator: Masumori Naoya 札幌医科大学, 医学部, 教授 (20295356)
• Co-Investigator(Kenkyū-buntansha): 西山 直隆 富山大学, 大学院医学薬学研究部(医学), 講師 (70619030) ; 進藤 哲哉 札幌医科大学, 医学部, 助教 (80749292) ; 新海 信雄 札幌医科大学, 医学部, 研究員 (40772398)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 転移性尿路上皮癌 / 化学療法抵抗性 / エピジェネティック治療 / 予後予測マーカー

Outline of Final Research Achievements

We found that the treatment with 5-Aza-CdR strikingly suppressed tumor formation by CDDP-resistant BCa cells in nude mice . Because 5-Aza-CdR alone was sufficient to completely block the xenograft formation, no synergistic effect of 5-Aza-CdR plus CDDP was observed.
miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. T

Free Research Field

尿路上皮癌

Academic Significance and Societal Importance of the Research Achievements

予後不良である転移性膀胱癌に対して5-Aza-CdRを組み合わせた2次治療が臨床応用されることで、新たな治療法の開発につながり、多くの膀胱癌患者の予後延長効果が期待される。5-Aza-CdRが有効な患者を選択するためのコンパニオン診断マーカー候補を同定、2次治療に対する新たな分子標的薬の開発が期待できる。