Nerve growth factor (NGF)-TrkA axis in head and neck squamous cell carcinoma triggers EMT and confers resistance to the EGFR inhibitor erlotinib
Nerve growth factor (NGF)-TrkA axis in head and neck squamous cell carcinoma triggers EMT and confers resistance to the EGFR inhibitor erlotinib
复制标题
头颈鳞状细胞癌中的神经生长因子 (NGF)-TrkA 轴触发 EMT 并赋予对 EGFR 抑制剂厄洛替尼的耐药性
DOI：
10.1016/j.canlet.2019.12.015
复制
发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Ji, Tong
中科院分区：
文献类型：
--
作者：
Lin, Chengzhong;Ren, Zhenhu;Ji, Tong
了解调节肿瘤传播和治疗耐药的分子机制对于有效的癌症治疗至关重要。在此，我们报道神经生长因子（NGF）及其受体 TrkA 通过头颈鳞状细胞癌（HNSCC）中 STAT3 的激活促进上皮间质转化（EMT）和 EGFR 抑制剂耐药性。 HNSCC 中 NGF 和 TrkA 表达均升高，表明临床结果较差。 NGF在神经周围微环境的癌细胞和神经中高表达，而TrkA在神经周围侵袭的癌细胞中表达较高。 NGF/TrkA 轴可以促进 HNSCC 细胞扩散并通过 STAT3 激活触发 EMT。此外，我们发现 NGF/TrkA 轴通过 HNSCC 细胞的 EMT 过程赋予对 EGFR 抑制剂厄洛替尼的耐药性。在体外和体内模型中，阻断 TrkA 信号传导可显着逆转 EMT 并使 HNSCC 细胞对厄洛替尼敏感。总的来说，我们的结果证明了旁分泌 NGF/TrkA 轴有利于 EMT 并赋予 HNSCC EGFR 靶向治疗耐药性的新证据。
Understanding the molecular mechanisms regulating tumor dissemination and therapeutic resistance is of central importance for effective cancer therapies. Here, we report that nerve growth factor (NGF) and its receptor TrkA facilitate epithelial-mesenchymal transition (EMT) and EGFR inhibitor resistance via STAT3 activation in head and neck squamous cell carcinoma (HNSCC). Both NGF and TrkA expression were elevated in HNSCC, indicating poor clinical outcomes. NGF was highly expressed in cancer cells and nerves in perineural niche, whereas TrkA expression was higher in cancer cells with perineural invasion. The NGF/TrkA axis could promote HNSCC cell dissemination and trigger EMT via STAT3 activation. Moreover, we discovered that the NGF/TrkA axis conferred resistance to the EGFR inhibitor erlotinib via EMT processes in HNSCC cells. Blocking TrkA signaling markedly reversed EMT and sensitized HNSCC cells to erlotinib in both in vitro and in vivo models. Overall, our results demonstrate novel evidence that the paracrine NGF/TrkA axis favors EMT and confers EGFR-targeted therapeutic resistance in HNSCC.