| 5-Fluorouracil(5-Fu)is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer,but many patients still suffer from treatment failure due to 5-Fu resistance.Emerging observations revealed the important role of chemokine(C-X-C motif)ligand 13(CXCL-13)in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer.Purpose:This study was designed to reveal the important role of CXCL 13 in causing colorectal cancer resistance to 5-Fu and explore potential clinical therapeutic targets.Methods:CXCL-13 levels of patient' s serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay(ELISA).In cell assays,cell viability was detected by CCK08.Overall survival(OS)and disease-free survival(DFS)were used to assess the prognosis of patients with 5-Fu resistant and sensitive colorectal cancer.Therefore,the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.Results:In this study,we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and non-resistant cells.Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu-resistant patients.High levels of serum CXCL-13 also predicted a worse clinical outcome.The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance,while its antibody overcame 5-Fu resistance,and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance,which can be saved by added recombination CXCL-13.Furthermore,we verified that the increased expression of CXCL-13 was closely related to the stimulation of 5-Fu by patient-derived xenografts(PDX)model.Conclusion:These results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu-resistant colorectal cancer in prevention and treatment strategies. |
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