As a result, we identified candidate chemokines by bioinformatics analysis and identified that this CXCL2 was notably up-regulated in platinum-resistant EOC

As a result, we identified candidate chemokines by bioinformatics analysis and identified that this CXCL2 was notably up-regulated in platinum-resistant EOC. a significant role in malignancy chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian malignancy (EOC). Differently expressed (DE) genes were screen out based on analysis of “type”:”entrez-geo”,”attrs”:”text”:”GSE114206″,”term_id”:”114206″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 functions of CXCL2 in TFIIH EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results ORM-15341 showed, CXCL2 was recognized 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 managed cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further exhibited 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 recognized a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-021-00864-3. strong class=”kwd-title” Keywords: Epithelial ovarian malignancy (EOC), Platinum-resistance, Chemokine, CXCL2 Backgrounds Epithelial ovarian malignancy (EOC) is the first cause of gynecological malignancy-related death [1]. At present, platinum-based chemotherapies were recommended as the first-line?chemotherapeutic regimens for EOC. Even though tremendous progress has made in comprehensive therapies, the survival rate of EOC patients with advanced tumor remains poor even in high\resource countries such as the United States and Canada [2]. Though?initial response rates of platinum-based regimens are 60C80%, majority of EOC patients acquire platinum resistance during treatment. Platinum resistance is one of the main causes of subsequent relapses and metastasis [3]. Thus, platinum resistance remains an urgent challenge for EOC patients, but the mechanism remains unidentified. There is a lack of effective approach to against platinum resistance in malignancies. Therefore, exposing the molecular mechanism contributing to platinum resistance in EOC and exploring therapeutic?targets are clinical significances. Chemokines contain a group of about 50 small (8C 14?kDa) secreted proteins. These molecules regulate cell biological?processes, including in malignancies initiation and progression [4, 5]. These secreted proteins work by interacting with the corresponding receptors, a family of about 20 seven-transmembrane G-protein-coupled receptors [6]. Previous studies have suggested chemokines and their corresponding receptors were involved in malignancies progression mainly in the three mechanisms: attracting malignancy cells for metastasis; mobilization of hematopoietic cell populations from your 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]. Increasing evidences have supported that using immune checkpoint inhibitors that targeting chemokines and their receptors becomes a novel approach of malignancy therapy [8C10]. The anti-CCR4 monoclonal antibody and the CXCR4 receptor inhibitor are already in the clinical practice for hematological malignancies ORM-15341 [11C15]. CXCL10 was suggested as an immune checkpoint molecule in malignancy, displaying a positive autocrine effect and directly suppressing tumor growth[16]. CXCL17 expression was that associated with lung malignancy and hepatic?malignancy[17]. In addition, recently studies also proved chemokines and their receptors participate in the malignancy chemoresistance. Ren et al. exhibited CXCR3-mediated AMPK signaling pathway contributed to metabolic alteration during the chemoresistance to agent-sorafenib in hepatocellular carcinoma [18]. Zhang et al. recognized?CXCL13 was involved in 5-Fu resistance in colorectal?malignancy [19]. These studies suggested that chemokines and their receptors might be potential novel therapeutic?targets of malignancy chemoresistance. Thus, 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. Currently, gene expression profiles have been progressively used to identify candidate significant genes in various diseases, especially in malignancies [20]. General public genomics data repositories provided powerful systems biology approaches to detect the association between genes and malignancy. In the present study, we devoted to exploring the role of chemokines in platinum-resistant EOC. We used bioinformatics methods to screen our differentially expressed (DE) chemokines by comparing gene expression profiles based on platinum sensitivity status and ADP-ribose polymerase (PARP) levels. Candidate DE chemokines were next validated in platinum-resistant and sensitive EOC samples and cells. Materials and Methods Differentially expressed genes (DEGs) screening in EOC with platinum resistance The gene expression profile was obtained from ORM-15341 “type”:”entrez-geo”,”attrs”:”text”:”GSE114206″,”term_id”:”114206″GSE114206 dataset of GEO database. “type”:”entrez-geo”,”attrs”:”text”:”GSE114206″,”term_id”:”114206″GSE114206 dataset contained 6 low PARP and platinum-resistant EOC samples and 6 ORM-15341 high PARP and platinum-sensitive EOC samples. We use the limma R package to screen the.