NFATc2 Mediates GalR2-Induced Invasion and Proliferation

Understanding the critical signaling cascades in HNSCC will facilitate the development of targeted therapeutics. Nuclear Factor of activated T-cells, Cytoplasmic-2 (NFATc2) was identified as a potential biomarker of Head and Neck Squamous Cell Carcinoma (HNSCC) in an immunomics screen. NFATc2, a transcription factor that is induced by extracellular signal-regulated kinase (ERK), promotes prostaglandin-2 (PGE2) release in breast cancer, but has an unknown role in HNSCC. In a previous study we showed that galanin receptor 2 (GalR2) induces extracellular ERK activation and promotes tumor progression.

Objectives: To investigate whether NFATc2 mediates GalR2-induced proliferation and invasion in HNSCC.

Methods: Expression of NFATc2 in HNSCC was evaluated by immunoblot analysis of HNSCC cell lines and by immunohistochemical staining of HNSCC tissue. Nuclear translocation of NFATc2 was determined following galanin treatment in GalR2 transfected cells. Proliferation, invasion and PGE2 secretion were quantified in HNSCC cell lines overexpressing GalR2 with siNFATc2 or non target siRNA.

Results: NFATc2 is expressed in HNSCC. GalR2 promotes nuclear translocation of NFATc2 and induces secretion of PGE2 in HNSCC cells. In these cells, knockdown of NFATc2 inhibits PGE2 secretion, proliferation and invasion.

Conclusions: GalR2 induces PGE2 secretion and invasion in HNSCC via NFATc2. Since invasion is essential for tumor progression, the GalR2-NFATc2 signaling cascade may be an important therapeutic target.

This study was supported in part by NIDCR F30-DE021293-02, R01-DE018512, K02-DE019513, R21-DE017977, DE007057-32 (Tissue Engineering and Regeneration at Michigan training grant).