Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis
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 o...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2019-11-01
|
Series: | BMC Cancer |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s12885-019-6229-5 |
id |
doaj-752cf73173a3466ba1380b7768a58e94 |
---|---|
record_format |
Article |
spelling |
doaj-752cf73173a3466ba1380b7768a58e942020-11-25T04:08:31ZengBMCBMC Cancer1471-24072019-11-0119111210.1186/s12885-019-6229-5Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosisYu-Wei Lin0Shih-Tsung Huang1Jian-Ching Wu2Tian-Huei Chu3Shih-Chung Huang4Ching-Chih Lee5Ming-Hong Tai6Department of Radiation Oncology, Chi Mei Medical CenterDoctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen UniversityDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineCenter for Neuroscience, National Sun Yat-sen UniversityInstitute of Biomedical Science, National Sun Yat-sen UniversityDepartment of Otolaryngology, Head and Neck Surgery, Kaohsiung Veterans General HospitalInstitute of Biomedical Science, National Sun Yat-sen UniversityAbstract 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.http://link.springer.com/article/10.1186/s12885-019-6229-5Oral CancerHepatoma-derived growth factor (HDGF)Vascular endothelial growth factor (VEGF)Hypoxia-inducible factor 1-α (HIF-1α)Nucleolin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yu-Wei Lin Shih-Tsung Huang Jian-Ching Wu Tian-Huei Chu Shih-Chung Huang Ching-Chih Lee Ming-Hong Tai |
spellingShingle |
Yu-Wei Lin Shih-Tsung Huang Jian-Ching Wu Tian-Huei Chu Shih-Chung Huang Ching-Chih Lee Ming-Hong Tai Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis BMC Cancer Oral Cancer Hepatoma-derived growth factor (HDGF) Vascular endothelial growth factor (VEGF) Hypoxia-inducible factor 1-α (HIF-1α) Nucleolin |
author_facet |
Yu-Wei Lin Shih-Tsung Huang Jian-Ching Wu Tian-Huei Chu Shih-Chung Huang Ching-Chih Lee Ming-Hong Tai |
author_sort |
Yu-Wei Lin |
title |
Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis |
title_short |
Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis |
title_full |
Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis |
title_fullStr |
Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis |
title_full_unstemmed |
Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis |
title_sort |
novel hdgf/hif-1α/vegf axis in oral cancer impacts disease prognosis |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2019-11-01 |
description |
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. |
topic |
Oral Cancer Hepatoma-derived growth factor (HDGF) Vascular endothelial growth factor (VEGF) Hypoxia-inducible factor 1-α (HIF-1α) Nucleolin |
url |
http://link.springer.com/article/10.1186/s12885-019-6229-5 |
work_keys_str_mv |
AT yuweilin novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT shihtsunghuang novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT jianchingwu novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT tianhueichu novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT shihchunghuang novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT chingchihlee novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis AT minghongtai novelhdgfhif1avegfaxisinoralcancerimpactsdiseaseprognosis |
_version_ |
1724425337516851200 |