RNA-binding protein-regulated fibronectin is essential for EGFR-activated metastasis of head and neck squamous cell carcinoma.

Abstract

There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.

• Authors: Jiunn-Min Shieh, Ting-Wei Chang, Jing-He Wang, Song-Ping Liang, Pei-Lu Kao, Liang-Yi Chen, Chia-Jui Yen, Yun-Ju Chen, Wen-Chang Chang, Ben-Kuen Chen
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 37 Issue 10 Pg. e23206 (10 2023) ISSN: 1530-6860 [Electronic] United States
• PMID: 37718485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Fibronectins
• Epidermal Growth Factor
• ErbB Receptors
• 5' Untranslated Regions
• Integrins
• EGFR protein, human

Topics

• Humans
• Squamous Cell Carcinoma of Head and Neck (genetics)
• Fibronectins (genetics)
• Endothelial Cells
• Epidermal Growth Factor
• ErbB Receptors (genetics)
• 5' Untranslated Regions
• Integrins
• Head and Neck Neoplasms (genetics)