FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells
FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells
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DOI：
10.3892/etm.2019.7672
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发表时间：
2019-08-01
影响因子：
2.7
通讯作者：
Tang, Aifa
中科院分区：
文献类型：
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作者：
Xie, Xina;Lin, Jiatian;Tang, Aifa
成纤维细胞生长因子受体3（Fibroblast growth factor receptor 3，FGFR 3）是膀胱癌（bladder cancer，BCa）中的一个高频率突变基因，由于其参与细胞增殖和迁移，已成为一个有前途的治疗靶点。然而，FGFR 3突变是否以及如何影响BCa细胞的化疗敏感性尚不清楚。本研究旨在阐明FGFR 3（S249 C）突变在BCa细胞耐药性发展中的作用。结果显示，与5637（FGFR 3（WT））和T24（FGFR 3（WT））细胞相比，97-7（FGFR 3（S249 C））细胞对顺铂的敏感性降低。磷酸化Akt/总Akt的比率在97-7（FGFR 3（S249 C））细胞中更高，这通过敲低FGFR 3而逆转。此外，通过GDC 0068或LY 294002抑制Akt信号传导增加了97-7（FGFR 3（S249 C））细胞的顺铂敏感性。GDC 0068或LY 294002也显示出增强顺铂对97-7（FGFR 3（S249 C））细胞增殖和凋亡的作用。本研究的结果表明，FGFR 3（S249 C）突变通过激活Akt信号通路促进BCa细胞的化疗耐药性。因此，FGFR 3（S249 C）突变可用作BCa患者化疗敏感性的预测因子。
Fibroblast growth factor receptor 3 (FGFR3) is a high frequency mutant gene in bladder cancer (BCa) and has become a promising therapeutic target due to its involvement in cell proliferation and migration. However, whether and how FGFR3 mutations affects BCa cell chemosensitivity is unknown. The current study aimed to elucidate the role of the FGFR3(S249C) mutation in the development of chemoresistance in BCa cells. The results revealed that 97-7 (FGFR3(S249C)) cells had decreased sensitivity to cisplatin compared with 5637 (FGFR3(WT)) and T24 (FGFR3(WT)) cells. The ratio of phosphorylated-Akt/total-Akt was higher in 97-7 (FGFR3(S249C)) cells, which was reversed by knockdown of FGFR3. Furthermore, inhibition of Akt signaling by GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 (FGFR3(S249C)) cells. GDC0068 or LY294002 was also revealed to augment the effects of cisplatin on 97-7 (FGFR3(S249C)) cell proliferation and apoptosis. The results of the present study demonstrated that the FGFR3(S249C) mutation promotes chemoresistance in BCa cells by activating the Akt signaling pathway. The FGFR3(S249C) mutation may therefore be used as a predictor of chemosensitivity in patients with BCa.