Department of Urology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
BMC Cancer. 2023 Feb 20;23(1):170. doi: 10.1186/s12885-023-10638-3.
Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC.
The correlation between FGFR4 CN determined via real-time PCR and protein expression evaluated using western blotting and immunohistochemistry was assessed in ccRCC cell lines (A498, A704, and 769-P), a papillary RCC cell line (ACHN), and clinical ccRCC specimens. The effect of FGFR4 inhibition on ccRCC cell proliferation and survival was assessed via either RNA interference or using the selective FGFR4 inhibitor BLU9931, followed by MTS assays, western blotting, and flow cytometry. To investigate whether FGFR4 is a potential therapeutic target, a xenograft mouse model was administered BLU9931.
60% of ccRCC surgical specimens harboured an FGFR4 CN amplification. FGFR4 CN was positively correlated with its protein expression. All ccRCC cell lines harboured FGFR4 CN amplifications, whereas ACHN did not. FGFR4 silencing or inhibition attenuated intracellular signal transduction pathways, resulting in apoptosis and suppressed proliferation in ccRCC cell lines. BLU9931 suppressed tumours at a tolerable dose in the mouse model.
FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC.
一些透明细胞肾细胞癌 (ccRCC) 病例存在成纤维细胞生长因子受体 4 (FGFR4) 基因拷贝数 (CN) 增益。在这项研究中，我们研究了 FGFR4 CN 扩增在 ccRCC 中的功能贡献。
通过实时 PCR 确定的 FGFR4 CN 与使用 Western blot 和免疫组化评估的蛋白表达之间的相关性在 ccRCC 细胞系 (A498、A704 和 769-P)、乳头状 RCC 细胞系 (ACHN) 和临床 ccRCC 标本中进行了评估。通过 RNA 干扰或使用选择性 FGFR4 抑制剂 BLU9931 评估 FGFR4 抑制对 ccRCC 细胞增殖和存活的影响，然后进行 MTS 测定、Western blot 和流式细胞术。为了研究 FGFR4 是否是一个潜在的治疗靶点，在异种移植小鼠模型中给予 BLU9931。
60%的 ccRCC 手术标本存在 FGFR4 CN 扩增。FGFR4 CN 与其蛋白表达呈正相关。所有 ccRCC 细胞系均存在 FGFR4 CN 扩增，而 ACHN 则没有。FGFR4 沉默或抑制减弱了细胞内信号转导通路，导致 ccRCC 细胞系中的细胞凋亡和增殖受到抑制。BLU9931 以可耐受的剂量抑制了小鼠模型中的肿瘤。
FGFR4 扩增后促进 ccRCC 细胞增殖和存活，使其成为 ccRCC 的潜在治疗靶点。
