Neuregulin-induced HER3 activation drives migration in head and neck squamous cell carcinoma via HER2 and FAK signaling pathways.

IF 4.8 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2025-08-01 Epub Date: 2025-05-12 DOI:10.1007/s13402-025-01069-2

Eun Jin Lim, Yu Jeong Yoon, Jeonghoon Heo, Seungwon Kim, Yung-Hyun Choi, Young-Ho Kim

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Abstract

Purpose: To investigate the role of neuregulin (NRG) signaling in promoting head and neck squamous cell carcinoma (HNSCC) migration through HER3-dependent pathways and to assess the therapeutic potential of targeting the NRG/HER3 axis in mitigating perineural invasion.

Methods: NRG-driven migration was studied using DRG co-culture, wound healing assays, and HER3 inhibition (shRNA, AV-203). The biological function and biochemical effects of the HER3/HER2/FAK axis in response to NRG were analyzed via phosphorylation assays, knockdown, western blotting, and cell staining for protein expression.

Results: NRG promoted directional migration of FaDu and TU138 HNSCC cells through HER3/HER2 and HER3/PI3K interactions. HER3 inhibition (shRNA or AV-203) abolished HER3 phosphorylation, disrupted HER3-HER2 interactions, and suppressed AKT and ERK signaling. Wound healing assays confirmed that NRG enhances migration via HER3 activation. NRG also induced HER3-dependent FAK phosphorylation, and FAK knockdown or inhibition with PF228 significantly reduced NRG-driven migration, highlighting the critical role of HER3-FAK signaling.

Conclusion: NRG promotes HNSCC cell migration by activating HER3, forming HER3-HER2 and HER3-FAK complexes, and driving downstream AKT, ERK, and FAK signaling. Targeting the NRG/HER3 axis holds potential as a therapeutic strategy to address perineural invasion and associated clinical challenges in HNC.

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神经调节蛋白诱导的HER3激活通过HER2和FAK信号通路驱动头颈部鳞状细胞癌的迁移。

目的：探讨神经调节蛋白（NRG）信号通路在促进头颈部鳞状细胞癌（HNSCC）通过HER3依赖通路迁移中的作用，并评估靶向NRG/HER3轴减轻神经周围侵袭的治疗潜力。方法：通过DRG共培养、伤口愈合试验和HER3抑制（shRNA, AV-203）研究nrg驱动的迁移。通过磷酸化、敲低、western blotting和细胞染色分析HER3/HER2/FAK轴对NRG的生物学功能和生化效应。结果：NRG通过HER3/HER2和HER3/PI3K相互作用促进FaDu和TU138 HNSCC细胞的定向迁移。HER3抑制（shRNA或AV-203）消除了HER3磷酸化，破坏了HER3- her2相互作用，抑制了AKT和ERK信号传导。伤口愈合实验证实NRG通过HER3激活促进迁移。NRG还诱导her3依赖性FAK磷酸化，PF228敲低或抑制FAK可显著降低NRG驱动的迁移，突出了HER3-FAK信号传导的关键作用。结论：NRG通过激活HER3，形成HER3- her2和HER3-FAK复合物，并驱动下游AKT、ERK和FAK信号传导，促进HNSCC细胞迁移。靶向NRG/HER3轴具有解决HNC神经周围侵袭和相关临床挑战的治疗策略的潜力。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.