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Purpose <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月12日

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

摘要

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.