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Open Access 01-12-2019 | Oral Cancer | Research article

Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis

Authors: Yu-Wei Lin, Shih-Tsung Huang, Jian-Ching Wu, Tian-Huei Chu, Shih-Chung Huang, Ching-Chih Lee, Ming-Hong Tai

Published in: BMC Cancer | Issue 1/2019

Abstract

Background

Hepatoma-derived growth factor (HDGF) participates in angiogenesis and represents a negative prognostic factor in oral cancer. The current study was designed to elucidate the regulatory mechanism between HDGF and vascular endothelial growth factor (VEGF) and the clinical impact of oral cancer.

Methods

TCGA data and surgical samples from oral cancer patients were used for the clinicopathological parameter and survival analysis. Human oral cancer SCC4 and SAS cells were treated with recombinant HDGF protein. VEGF gene expression and protein level were analyzed by RT-PCR, Western blotting, and enzyme-linked immunosorbent assay. The signaling pathways for regulating VEGF expression were investigated. The nucleolin neutralizing antibody and HIF-1α inhibitor were applied to SCC4 cells to investigate their effects on the HDGF-stimulated VEGF pathways.

Results

TCGA and immunohistochemical analysis revealed a positive correlation between HDGF and VEGF expression in oral cancer tissues. Recombinant HDGF significantly increased VEGF gene and protein expression in oral cancer SCC4 cells in a dose-dependent manner. HDGF enhanced the phosphorylation levels of AKT and IkB and the protein level of HIF-1α and NF-κB. The nucleolin-neutralizing antibody abolished HDGF-stimulated HIF-1α, NF-κB and VEGF protein expression in SCC4 cells. The HIF-1α inhibitor antagonized the HDGF-induced VEGF gene expression. High VEGF expression was strongly correlated with HDGF expression, advanced disease, and poor survival.

Conclusion

This study postulated a new pathway in which HDGF activated HIF-1α and then induced VEGF expression through binding to membrane nucleolin under normoxic conditions, leading to poor disease control. The HDGF/HIF-1α/VEGF axis is important for developing future therapeutic strategies.

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Title: Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis
Authors: Yu-Wei Lin
Shih-Tsung Huang
Jian-Ching Wu
Tian-Huei Chu
Shih-Chung Huang
Ching-Chih Lee
Ming-Hong Tai
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Oral Cancer
Oral Cavity Carcinoma
Published in: BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-019-6229-5

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