Research Paper|Volume 15, Issue 11|pp 4774—4793

Visfatin upregulates VEGF-C expression and lymphangiogenesis in esophageal cancer by activating MEK1/2-ERK and NF-κB signaling

Chang-Lun Huang^1,², David Achudhan¹, Po-I Liu^3,⁴, Yen-You Lin⁵, Shan-Chi Liu⁶, Jeng-Hung Guo^1,⁷, Chun-Lin Liu^1,⁷, Chih-Ying Wu^7,^8,⁹, Shih-Wei Wang^10,¹¹, Chih-Hsin Tang^1,^5,^12,^13,¹⁴

¹Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan
²Department of Surgery, Division of Thoracic Surgery, Changhua Christian Hospital, Changhua 500, Taiwan
³Department of General Thoracic Surgery, Asia University Hospital, Taichung 41354, Taiwan
⁴Department of Physical Therapy, Asia University, Taichung 41354, Taiwan
⁵Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan
⁶Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin 65152, Taiwan
⁷Department of Neurosurgery, China Medical University Hospital, Taichung 404327, Taiwan
⁸Graduate Institute of Integrated Medicine, China Medical University, Taichung 406040, Taiwan
⁹Department of Neurosurgery, China Medical University Hsinchu Hospital, Hsinchu 302, Taiwan
¹⁰Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
¹¹College of Pharmacy, Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
¹²Chinese Medicine Research Center, China Medical University, Taichung 406040, Taiwan
¹³Department of Medical Laboratory Science and Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan
¹⁴Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu 302, Taiwan

Received: March 23, 2023Accepted: May 17, 2023Published: June 7, 2023

https://doi.org/10.18632/aging.204762

Copyright: © 2023 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Lymph node metastasis is a recognized prognostic factor in esophageal cancer. Adipokines, including visfatin, and the molecule vascular endothelial growth factor (VEGF)-C, are implicated in lymphangiogenesis, but whether any association exists between esophageal cancer, adipokines and VEGF-C is unknown. We examined the relevance of adipokines and VEGF-C in esophageal squamous cell carcinoma (ESCC) in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We found significantly higher levels of visfatin and VEGF-C expression in esophageal cancer tissue than in normal tissue. Immunohistochemistry (IHC) staining identified that higher levels of visfatin and VEGF-C expression were correlated with advanced stage ESCC. Visfatin treatment of ESCC cell lines upregulated VEGF-C expression and VEGF-C-dependent lymphangiogenesis in lymphatic endothelial cells. Visfatin induced increases in VEGF-C expression by activating the mitogen-activated protein kinase kinases1/2-extracellular signal-regulated kinase (MEK1/2-ERK) and Nuclear Factor Kappa B (NF-κB) signaling cascades. Transfecting ESCC cells with MEK1/2-ERK and NF-κB inhibitors (PD98059, FR180204, PDTC, and TPCK) and siRNAs inhibited visfatin-induced increases in VEGF-C expression. It appears that visfatin and VEGF-C are promising therapeutic targets in the inhibition of lymphangiogenesis in esophageal cancer.