Jiangxi Clinical Research Center for Respiratory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Center for Experimental Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
Cell Oncol (Dordr). 2024 Aug;47(4):1405-1423. doi: 10.1007/s13402-024-00938-6. Epub 2024 Apr 3.
The hyperactivation of epidermal growth factor receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC). Hedgehog (Hh) signaling has been implicated in the tumorigenesis and progression of various cancers, however, its function in NSCLC cells remains controversial. Herein, we present a novel finding that challenges the current understanding of Hh signaling in tumor growth.
Expression of Hh ligands and receptor were assessed using TCGA datasets, immunoblotting and immunohistochemical. Biological function of Hh ligands and receptor in NSCLC were tested using colony formation, cell count kit-8 (CCK-8) and xenograft assays. Biochemical effect of Hh ligands and receptor on regulating EGFR stability and activity were checked via immunoblotting.
Expression of Hh ligands and receptor was suppressed in NSCLC tissues, and the lower expression levels of these genes were associated with poor prognosis. Ptch1 binds to EGFR and facilitates its poly-ubiquitylation and degradation independent of downstream transcriptional signaling. Moreover, Hh ligands cooperate with Ptch1 to regulate the protein stability and activity of EGFR. This unique mechanism leads to a suppressive effect on NSCLC tumor growth.
Non-canonical Hh signaling pathway, involving cooperation between Hh ligands and their receptor Ptch1, facilitates the degradation of EGFR and attenuates its activity in NSCLC. These findings provide novel insights into the regulation of EGFR protein stability and activity, offer new diagnostic indicators for molecular typing of NSCLC and identify potential targets for targeted therapy of this challenging disease.
表皮生长因子受体（EGFR）的过度激活在非小细胞肺癌（NSCLC）中起着关键作用。Hedgehog（Hh）信号转导已被牵涉到各种癌症的肿瘤发生和进展中，但它在 NSCLC 细胞中的功能仍存在争议。在此，我们提出了一个新的发现，挑战了目前对 Hh 信号在肿瘤生长中的作用的理解。
使用 TCGA 数据集、免疫印迹和免疫组织化学评估 Hh 配体和受体的表达。使用集落形成、细胞计数试剂盒-8（CCK-8）和异种移植实验测试 Hh 配体和受体在 NSCLC 中的生物学功能。通过免疫印迹检查 Hh 配体和受体对调节 EGFR 稳定性和活性的生化作用。
Hh 配体和受体的表达在 NSCLC 组织中受到抑制，这些基因的低表达水平与预后不良相关。Ptch1 与 EGFR 结合，并独立于下游转录信号促进其多泛素化和降解。此外，Hh 配体与 Ptch1 合作调节 EGFR 的蛋白稳定性和活性。这种独特的机制导致对 NSCLC 肿瘤生长的抑制作用。
涉及 Hh 配体及其受体 Ptch1 之间合作的非经典 Hh 信号通路促进了 EGFR 的降解，并减弱了其在 NSCLC 中的活性。这些发现为 EGFR 蛋白稳定性和活性的调节提供了新的见解，为 NSCLC 的分子分型提供了新的诊断指标，并确定了针对这种具有挑战性疾病的靶向治疗的潜在靶点。
