CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-κB pathway in colorectal cancer

Abstract

The mechanisms underlying the role of CXCL5 in tumor angiogenesis have not been fully defined. Here, we examined the effect of CXCL5 on tumor angiogenesis in colorectal cancer (CRC). Immunohistochemistry was used to monitor the expression of CXCL5 and CD31 in CRC patients’ tissues. HUVEC cell lines stably transfected with shCXCR2 and shFOXD1 lentivirus plasmids were used in an in vitro study. Based on some molecular biological experiments in vitro and in vivo, we found that CXCL5 was upregulated in tumor tissues and that its level positively correlated with the expression of CD31. Next, we used recombinant human CXCL5 (rhCXCL5) to stimulate HUVECs and found that their tube formation ability, proliferation, and migration were enhanced by the activation of the AKT/NF-κB/FOXD1/VEGF-A pathway in a CXCR2-dependent manner. However, silencing of CXCR2 and FOXD1 or inhibition of the AKT and NF-κB pathways could attenuate the tube formation ability, proliferation, and migration of rhCXCL5-stimulated HUVECs in vitro. rhCXCL5 can promote angiogenesis in vivo in Matrigel plugs, and the overexpression of CXCL5 can also increase microvessel density in vivo in a subcutaneous xenotransplanted tumor model in nude mice. Taken together, our findings support CXCL5 as an angiogenic factor that can promote cell metastasis through tumor angiogenesis in CRC. Furthermore, we propose that FOXD1 is a novel regulator of VEGF-A. These observations open new avenues for therapeutic application of CXCL5 in tumor anti-angiogenesis.

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

“…In renal cell carcinoma and bladder cancer, CXCL5 is secreted by tumor cells and induces a strong synergistic effect on the proliferation and recruitment of endothelial cells in the pathway of CXCL5/CXCR2 axis [51,52]. Recombinant human CXCL5 activates CXCR2 to promote angiogenesis and tube formation of blood vessels, and involves in the process of proliferation and migration of human umbilical vein endothelial cells via the CXCR2/ AKT/NF-B/Forkhead Box D1 (FOXD1)/VEGF-A signaling pathway [53]. Overexpression of CXCL5 in the subcutaneous xenograft tumor model increased the distribution density of F I G U R E 2 The contributions of CXCL5 to tumor progression.…”

“…These cells play an essential role in the development of tumors via CXCL5/CXCR2 axis. In addition, CXCL5 promotes tumor-associated angiogenesis and lymphangiogenesis, creating a more conducive environment for tumor growth and metastasis micro vessels in vivo [53]. CXCL5/CXCR2 axis plays an important role in tumor angiogenesis.…”

“…Inhibit the establishment of early metastatic microenvironment [40] Restrain tumor progression [7,47,69] Reduce resistance to targeted drugs [47,70,71] Inhibit tumor angiogenesis [53,68] Enhance drug utility [68,72,73] assisting paclitaxel is considered to be safe and has no mutual pharmacokinetic effects (NCT02001974) [75]. Relevant clinical applications are should be conducted to improve the survival time of patients (Table 3).…”

CXCL5 Modified Nanoparticle Surface Improves CXCR2+ Cell Selective Internalization

“…It is released by several type of tissues, including endothelial cells and human skin cells after UV radiation [28]. It is also involved in cancer proliferation in different tissues [29][30][31]. Its clinical value for cancer prognosis is also recently becoming very significant [32,33].…”

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

“…Significant breakthroughs have been made in the early diagnosis and treatment of CRC in recent decades (4). Unfortunately, the overall survival (OS) rate of patients with CRC remains poor, especially in the advanced stage, mainly due to recurrence and metastasis (5).…”