Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China.
Department of Pathology and Laboratory of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Cancer Res. 2019 May 1;79(9):2220-2231. doi: 10.1158/0008-5472.CAN-18-2603. Epub 2019 Mar 19.
EGFR regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane. CD317 was upregulated in HCC cells, promoting cell-cycle progression and enhancing tumorigenic potential in a manner dependent on EGFR. Mechanistically, CD317 associated with lipid rafts and released EGFR from these ordered membrane domains, facilitating the activation of EGFR and the initiation of downstream signaling pathways, including the Ras-Raf-MEK-ERK and JAK-STAT pathways. Moreover, in HCC mouse models and patient samples, upregulation of CD317 correlated with EGFR activation. These results reveal a previously unrecognized mode of regulation for EGFR and suggest CD317 as an alternative target for treating EGFR-driven malignancies. SIGNIFICANCE: Activation of EGFR by CD317 in hepatocellular carcinoma cells suggests CD317 as an alternative target for treating EGFR-dependent tumors.
表皮生长因子受体（EGFR）调节多种基本的细胞过程，其组成性激活是癌症的常见驱动因素。抗 EGFR 疗法已在癌症患者中显示出益处，但几乎不可避免地会产生耐药性，这强调了需要更好地理解控制 EGFR 激活的机制。在这里，我们报告称，具有独特拓扑结构的表面分子 CD317 通过调节其在质膜上的定位，在肝癌（HCC）细胞中激活 EGFR。CD317 在 HCC 细胞中上调，以依赖于 EGFR 的方式促进细胞周期进程并增强致瘤潜能。在机制上，CD317 与脂筏相关联，并将 EGFR 从这些有序的膜结构域中释放出来，从而促进 EGFR 的激活和下游信号通路的启动，包括 Ras-Raf-MEK-ERK 和 JAK-STAT 通路。此外，在 HCC 小鼠模型和患者样本中，CD317 的上调与 EGFR 激活相关。这些结果揭示了 EGFR 的一种先前未被识别的调节模式，并提示 CD317 可作为治疗 EGFR 驱动的恶性肿瘤的替代靶标。
CD317 在肝癌细胞中激活 EGFR 表明 CD317 可作为治疗 EGFR 依赖性肿瘤的替代靶标。
