Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China.
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Oncogene. 2019 Jan;38(5):747-764. doi: 10.1038/s41388-018-0473-z. Epub 2018 Sep 3.
Aberrant activation of EGFR represents a common event in non-small cell lung carcinoma (NSCLC) and activates various downstream signaling pathways. While EGFR activation of β-catenin signaling was previously reported, the mediating mechanism remains unclear. Our current study found that EGFR activation in NSCLC cells releases SHC-binging protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which subsequently translocates into the nucleus and directly promotes the transactivating activity of β-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes β-catenin activity through enhancing the CBP/β-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/β-catenin binding effectively abrogates the aforementioned biological effects of SHCBP1. Clinically, SHCBP1 level in NSCLC tumors was found to inversely correlate with patient survival. Together, our study establishes a novel convergence between EGFR and β-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.
EGFR 的异常激活是非小细胞肺癌（NSCLC）的常见事件，并激活各种下游信号通路。虽然之前已经报道了 EGFR 对β-catenin 信号的激活，但介导机制尚不清楚。我们的研究发现，NSCLC 细胞中 EGFR 的激活会从 SHC 衔接蛋白 1（SHC1）上释放出 SHC 结合蛋白 1（SHCBP1），随后 SHCBP1 转位到细胞核中，直接促进β-catenin 的转录激活活性，从而导致 NSCLC 细胞干性和恶性进展。此外，SHCBP1 通过增强 CBP/β-catenin 相互作用来促进 β-catenin 活性，更有趣的是，一种候选药物可有效阻断 CBP/β-catenin 结合，从而有效阻断 SHCBP1 的上述生物学效应。临床上，在 NSCLC 肿瘤中发现 SHCBP1 水平与患者生存呈负相关。总之，我们的研究确立了 EGFR 和β-catenin 通路之间的新融合，并强调了 SHCBP1 作为预后生物标志物和治疗靶点的潜在意义。
