Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Cell Death Dis. 2022 Jan 10;13(1):39. doi: 10.1038/s41419-021-04479-w.
Bladder cancer is a highly heterogeneous and aggressive malignancy with a poor prognosis. EGF/EGFR activation causes the detachment of SHC-binding protein 1 (SHCBP1) from SHC adapter protein 1 (SHC1), which subsequently translocates into the nucleus and promotes cancer development via multiple signaling pathways. However, the role of the EGF-SHCBP1 axis in bladder cancer progression remains unexplored. Herein, we report that SHCBP1 is upregulated in bladder cancer tissues and cells, with cytoplasmic or nuclear localization. Released SHCBP1 responds to EGF stimulation by translocating into the nucleus following Ser273 phosphorylation. Depletion of SHCBP1 reduces EGF-induced cell migration and invasiveness of bladder cancer cells. Mechanistically, SHCBP1 binds to RACGAP1 via its N-terminal domain of amino acids 1 ~ 428, and this interaction is enhanced following EGF treatment. Furthermore, SHCBP1 facilitates cell migration by inhibiting RACGAP-mediated GTP-RAC1 inactivation, whose activity is indispensable for cell movement. Collectively, we demonstrate that the EGF-SHCBP1-RACGAP1-RAC1 axis acts as a novel regulatory mechanism of bladder cancer progression, which offers a new clinical therapeutic strategy to combat bladder cancer.
膀胱癌是一种高度异质性和侵袭性的恶性肿瘤，预后不良。EGF/EGFR 激活导致 SHC 结合蛋白 1（SHCBP1）与 SHC 衔接蛋白 1（SHC1）分离，随后 SHCBP1 转位到细胞核，并通过多种信号通路促进癌症发展。然而，EGF-SHCBP1 轴在膀胱癌进展中的作用仍未被探索。在此，我们报告 SHCBP1 在膀胱癌组织和细胞中上调，存在于细胞质或细胞核中。释放的 SHCBP1 在 Ser273 磷酸化后，响应 EGF 刺激，发生核转位。SHCBP1 的耗竭会降低 EGF 诱导的膀胱癌细胞迁移和侵袭。在机制上，SHCBP1 通过其氨基末端的氨基酸 1~428 与 RACGAP1 结合，并且这种相互作用在 EGF 处理后增强。此外，SHCBP1 通过抑制 RACGAP 介导的 GTP-RAC1 失活来促进细胞迁移，而 RACGAP 介导的 GTP-RAC1 失活对于细胞运动是必不可少的。总之，我们证明了 EGF-SHCBP1-RACGAP1-RAC1 轴作为膀胱癌进展的新的调节机制，为治疗膀胱癌提供了新的临床治疗策略。
