Abstract
Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC). Differently expressed (DE) genes were screen out based on analysis of GSE114206 dataset in GEO database. The expression of DE chemokines was further validated in platinum- resistant and sensitive EOC. Cell viability assay and cell apoptosis assay were performed to explore the roles of CXCL2 in EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results showed, CXCL2 was identified up-regulated in platinum-resistant EOC. The functional assays showed overexpressing CXCL2 or co-culturing with recombinant human CXCL2 promoted cell resistance to cisplatin. Conversely, knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2 increased cell response to cisplatin. CXCL2 overexpressing maintained cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further demonstrated that CXCL2-mediated resistance to cisplatin could be saved by SB225002, the inhibitor of CXCL2 receptor, as well as be rescued by SAR-020106, the inhibitor of ATR/CHK1 signaling pathway. This study identified a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC.
Highlights
Tumor microenvironment and chemokines play a significant role in cancer chemoresistance
CXCL2 is up‐regulated in platinum‐resistant Epithelial ovarian cancer (EOC) By analyzing the gene expression profiles of GSE114206 dataset, we identified 1269 up-regulated Differentially expressed genes (DEGs) and 1140 down-regulated DEGs (P < 0.05, |log2FC > 1)
By further validating mRNA expression level of CXCL2, CXCL11 and CXCL13, we found CXCL2 was up-regulated in platinum-resistant EOC samples (Fig. 1B) and cisplatinresistant EOC cells (Fig. 1C-F)
Summary
Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. Chemokines contain a group of about 50 small (8– 14 kDa) secreted proteins These molecules regulate cell biological processes, including in malignancies initiation and progression [4, 5]. Previous studies have suggested chemokines and their corresponding receptors were involved in malignancies progression mainly in the three mechanisms: attracting cancer cells for metastasis; mobilization of hematopoietic cell populations from the bone marrow to colonize at the tumor site and regulate tumor processes; acting as growth factors and supporting tumor growth through an autocrine pathway [6, 7]. Zhang et al identified CXCL13 was involved in 5-Fu resistance in colorectal cancer [19] These studies suggested that chemokines and their receptors might be potential novel therapeutic targets of cancer chemoresistance. The present study devoted to exploring the role of chemokines in platinum-resistant EOC and investigate the biological function and underlying regulation mechanism of the candidate chemokine. Candidate DE chemokines were validated in platinum-resistant and sensitive EOC samples and cells
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