Abstract
BackgroundMetastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood.MethodsHerein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo.ResultsWe found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3β/β-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and β-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model.ConclusionIn conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients.
Highlights
Metastasis is a major cause of death in human colorectal cancer patients
We revealed that CXCL5 secreted by tumor cells was able to promote Colorectal cancer (CRC) migration through ERK/Elk-1/Snail-mediated epithelial-mesenchymal transition (EMT) (Epithelial mesenchymal transition) and invasion via the AKT/GSK3β/β-catenin/MMP7 pathway in a CXCR2dependent manner
We further found that, CXCL5 staining was observed in the tumor mesenchyme, CXCL5 was primarily expressed in the tumor lesions rather than the fibroblasts, which were visualized with the fibroblast marker α-smooth muscle actin (Fig. 3a and b)
Summary
Metastasis is a major cause of death in human colorectal cancer patients. the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood. As the major cause of death for most cancer patients, tumor metastasis is an important adverse factor in the treatment and prognosis of CRC patients [3]. Despite an increase in our understanding of cell biology and the identification of many metastasis-related molecules [6], the chemokinerelated alterations in the tumor microenvironment that promote CRC metastasis remain largely unknown. Recent studies have reported that TNF-α-induced mesenchymal stromal cells (MSCs) can secrete CXCL5 to recruit CXCR2+ neutrophils that promote breast cancer metastasis [9]. These findings indicate that CXCL5 can act as a protumoral molecule in a paracrine way through recruiting immune cells. The mechanisms underlying the role of CXCL5 on CRC remain unknown
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