The Mechanisms Of Chemokine CXCL5 Promotes Angiogenesis In Colorectal Cancer

Angiogenesis is now accepted as a hallmark of cancer and related to tumor distance metastasis.Chemokine CXCL5 is strongly associated with angiogenesis and has been implicated in several processes in tumors.However,the function of CXCL5 in colorectal cancer(CRC)has not been fully defined.In our previous study,CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients.Next,the effect of CXCL5 on tumor angiogenesis was examined in CRC.First of all,Immunohistochemistry was used to monitor the expression of CXCL5 and CD31 in CRC patients' tissues.Secondly,HUVEC cell lines stably transfected with sh CXCR2,sh FOXD1 and FOXD1 lentivirus plasmids were used in an in vitro study.Tube formation assays,proliferation and migration assays were used to evaluate the effect of CXCL5 on tumor angiogenesis.Western blot,q RT-PCR,Ch IP-PCR,luciferase reporter assays were used to further detect the molecular mechanism about the function of CXCL5 on tumor angiogenesis.Additionally,nude mice were used to verify the influence of CXCL5 on tumor angiogenesis in vivo.Based on these experiments,this paper found that CXCL5 was upregulated in tumor tissues and that its level positively correlated with the expression of CD31.In our in vitro study,recombinant human CXCL5(rh CXCL5)was used to stimulate HUVECs.And then,this paper found that their tube formation ability,proliferation and migration were enhanced by the activation of the AKT/NF-?B/FOXD1/VEGF-A pathway in a CXCR2-dependent manner.However,silencing of CXCR2 and FOXD1 or inhibition of the AKT and NF-?B pathways could attenuate the tube formation ability,proliferation and migration of rh CXCL5-stimulated HUVECs in vitro.rh CXCL5 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,which can promote colorectal cell metastasis through tumor angiogenesis by the activation of the AKT/NF-?B/FOXD1/VEGF-A pathway in a CXCR2-dependent manner in CRC.Furthermore,this paper proposes that FOXD1 is a novel regulator of VEGF-A.These observations open new avenues for therapeutic application in tumor anti-angiogenesis.