Department of Urology, Wan Fang Hospital, Taipei, Taiwan, R.O.C.
Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.
Anticancer Res. 2020 Nov;40(11):6093-6099. doi: 10.21873/anticanres.14630.
BACKGROUND/AIM: Bruton's tyrosine kinase (BTK) has been discovered to serve a critical role in the survival and infiltration of B-cell lymphoma. Recently, it was reported that BTK inhibitors exerted potential beneficial effects against numerous types of solid tumor, including glioblastoma multiforme and breast cancer; however, whether BTK is crucial for the progression of bladder cancer (BLCA) remains unclear. The present study investigated the in vitro function of BTK in stemness properties of BLCA cells. Furthermore, the therapeutic effects of a standard chemotherapeutic drug, carboplatin in combination with the BTK inhibitor, ibrutinib were also investigated.
The association between BTK and BLCA progression was evaluated using free databases. The in vitro stemness and metastatic properties of BLCA cells were also investigated. Finally, the cytotoxicity of carboplatin in combination with ibrutinib was determined.
The meta-survival analysis of the association between BTK and BLCA progression revealed that the expression levels of BTK were associated with a higher risk of BLCA progression. The CD133-side population of BLCA cells formed spheroids when cultured in serum-free conditioned medium. In addition, expression levels of BTK and activated mTOR signaling in side population cells was up-regulated compared with the parental BLCA cells. Furthermore, the transfection of short hairpin RNA targeting BTK into BLCA cells markedly reduced cell migratory ability. More importantly, in advanced BLCA cells, which were more resistant to carboplatin, it was discovered that the cell viability was significantly reduced in the presence of ibrutinib (p<0.05).
The findings of the present study suggested that BTK may have a critical role in the progression of BLCA; however, the underlying mechanisms and potential therapeutic strategies involved require further investigations.
背景/目的：布鲁顿酪氨酸激酶（BTK）已被发现对 B 细胞淋巴瘤的存活和浸润起着关键作用。最近有报道称，BTK 抑制剂对多种实体瘤，包括多形性胶质母细胞瘤和乳腺癌，具有潜在的有益作用；然而，BTK 是否对膀胱癌（BLCA）的进展至关重要尚不清楚。本研究旨在探讨 BTK 在 BLCA 细胞干性特性中的体外功能。此外，还研究了标准化疗药物卡铂联合 BTK 抑制剂伊布替尼的治疗效果。
使用免费数据库评估 BTK 与 BLCA 进展之间的关联。还研究了 BLCA 细胞的体外干性和转移特性。最后，测定了卡铂联合伊布替尼的细胞毒性。
BTK 与 BLCA 进展之间关联的荟萃生存分析表明，BTK 的表达水平与 BLCA 进展的风险较高相关。BLCA 细胞的 CD133 侧群在无血清条件培养基中培养时形成球体。此外，侧群细胞中 BTK 和激活的 mTOR 信号的表达水平较亲本 BLCA 细胞上调。此外，将靶向 BTK 的短发夹 RNA 转染到 BLCA 细胞中可显著降低细胞迁移能力。更重要的是，在对卡铂更耐药的晚期 BLCA 细胞中，发现伊布替尼存在时细胞活力明显降低（p<0.05）。
本研究的结果表明，BTK 可能在 BLCA 的进展中起关键作用；然而，尚需进一步研究其潜在的机制和治疗策略。
