表皮生长因子受体（EGFR）是最早和最明显的驱动基因之一，已知其可以促进恶性肺癌的发展。研究EGFR信号激活的调控机制，除了配体-受体结合、磷酸化和受体激酶的活化外，对于改进EGFR靶向治疗非常重要。在这里，我们报告了Laminin-5γ-2 (LAMC2) 在肺癌中保留着较高的致癌能力，沉默LAMC2抑制了EGFR诱导的细胞增殖和体内肿瘤生长。删除突变实验证明了LAMC2的EGFR受体结合需要EGF-Lam和LamB两个区域同时存在，且LAMC2和EGFR在内质网（ER）膜处共定位。此外，LAMC2过表达增强了EGFR的膜沉积，并促进了EGFR从ER转运。此外，LAMC2对于阻止EGFR蛋白通过泛素化进行降解也是必需的。最后，我们的研究显示，高表达LAMC2与吉非替尼（EGFR酪氨酸激酶抑制剂）治疗的反应呈正相关。总的来说，我们的研究揭示了LAMC2在促进EGFR蛋白表达和稳定性方面的新的调控机制，通过促进ER转运和阻止蛋白通过泛素化降解。此外，LAMC2可能作为一个筛选患者适合接受EGFR-TKI治疗的生物标志物。© 2023. 作者。

The epidermal growth factor receptor (EGFR) is one of the first and most prominent driver genes known to promote malignant lung cancer. Investigating regulatory mechanisms beyond ligand-receptor binding, phosphorylation, and receptor kinase activation as means of EGFR signaling activation is important for improving EGFR-targeted therapy. Here, we report that Laminin-5γ-2 (LAMC2) retained high oncogenic capacity in lung cancer, silencing LAMC2 inhibited EGFR-induced cell proliferation and tumor growth in vivo. Deletion mutation experiments showed that both the EGF-Lam and LamB regions of LAMC2 are necessary for EGFR receptor binding, and that LAMC2 and EGFR were found to co-localize at the endoplasmic reticulum (ER) membrane. In addition, LAMC2 overexpression enhanced EGFR membrane deposition and promoted EGFR transport from the ER. Moreover, LAMC2 was necessary for preventing EGFR protein degradation via ubiquitination. Lastly, our study showed that high LAMC2 expression is positively associated with response to gefitinib (EGFR tyrosine kinase inhibitor) treatment. Overall, our study revealed a new regulatory mechanism of LAMC2 in promoting EGFR protein expression and stability by facilitating ER transport and preventing protein degradation via ubiquitination. Moreover, LAMC2 may serve as a stratifying biomarker for patients suitable for EGFR-TKI treatment.© 2023. The Author(s).