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Updated: May 13, 2025

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

Eun Jin Lim1, Yu Jeong Yoon1, Jeonghoon Heo1

  • 1Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, 49267, Republic of Korea.

Cellular Oncology (Dordrecht, Netherlands)
|May 12, 2025
PubMed
Abstract

Insights

Neuregulin (NRG) signaling drives head and neck cancer (HNSCC) cell migration via HER3 activation. Targeting the NRG/HER3 pathway may offer a new therapy for perineural invasion in HNSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Head and neck squamous cell carcinoma (HNSCC) is a complex disease with significant morbidity.
  • Perineural invasion is a hallmark of aggressive HNSCC, contributing to treatment failure and poor prognosis.
  • Understanding the molecular mechanisms driving HNSCC cell migration is crucial for developing effective therapies.

Purpose of the Study:

  • To elucidate the role of neuregulin (NRG) in promoting HNSCC cell migration.
  • To investigate the involvement of the HER3 receptor and its downstream signaling pathways.
  • To evaluate the therapeutic potential of targeting the NRG/HER3 axis against HNSCC perineural invasion.

Main Methods:

  • NRG-induced HNSCC cell migration was assessed using co-culture and wound healing assays.
  • HER3 signaling was inhibited using short hairpin RNA (shRNA) and the AV-203 inhibitor.
  • Key signaling molecules (HER3, HER2, FAK, AKT, ERK) were analyzed through phosphorylation assays, western blotting, and knockdown experiments.

Main Results:

  • NRG significantly promoted directional migration of HNSCC cells.
  • HER3 inhibition abolished HER3 phosphorylation, disrupted HER3-HER2 interactions, and suppressed AKT and ERK signaling.
  • NRG-induced FAK phosphorylation was critical for migration, as FAK inhibition or knockdown reduced cell movement.

Conclusions:

  • NRG activates HER3, leading to the formation of HER3-HER2 and HER3-FAK complexes and downstream signaling (AKT, ERK, FAK), thereby promoting HNSCC cell migration.
  • Targeting the NRG/HER3 axis presents a promising therapeutic strategy to combat perineural invasion in HNSCC.
  • Further research into the NRG/HER3 pathway could lead to novel treatments for advanced head and neck cancers.
Keywords:
Focal adhesion kinaseHER3Head and neck squamous cell carcinomaMigrationNeuregulin

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