Elevated expression of CXCL3 in colon cancer promotes malignant behaviors of tumor cells in an ERK-dependent manner

Abstract

Background: CXCL3 is a member of CXC-type chemokine family that is identified as a major regulator in immune and inflammation responses. Recently, numerous evidence indicated that CXCL3 is broadly expressed in various human tumor types, and it is also known to play a critical role in mediating tumor development and progression. However, the expression profile of CXCL3 and the exact molecular mechanism behind the role of CXCL3 in colon adenocarcinoma (COAD) has not been fully elucidated. Methods: The expression and clinical significance of CXCL3 mRNA and protein in the tissues from COAD patients were estimated using bioinformatics and immunohistochemistry assays. The expression and roles of exogenous administration or overexpression of CXCL3 in HT-29 and SW480 COAD cells were determined using ELISA, CCK-8 and Transwell assays. Mechanically, CXCL3-induced malignant behaviors were elucidated using western blotting assay and ERk1/2 inhibitor PD98059. Results: TCGA-COAD data analysis revealed that CXCL3 mRNA is highly expressed and has high clinical diagnostic accuracy in COAD. Increased expression of CXCL3 mRNA was associated with patient’s clinical stage, race, gender, age, histological subtype, nodal mestastasis and TP53 mutation status. Similarly, immunohistochemistry assay also exhibited that CXCL3 protein in COAD tissues was significantly up-regulated. Gene expression associated assay implied that CXCL1 and CXCL2 were markedly correlated with CXCL3 in COAD. PPI analysis revealed that CCNB1, MAD2L1, H2AFZ and CXCL2 may be the important molecules involved in CXCL3-related tumor biology. GSEA analysis revealed that CXCL3 was mainly enriched in the cell cycle, DNA replication, NOD-like receptors, NOTCH and TGF-β Signal pathways. In vitro, exogenous administration or overexpression of CXCL3 resulted in increased malignant behaviors of HT-29 and SW480 cells, and overexpression of CXCL3 affected the expression of genes related to extracellular signal regulated kinase (ERK) pathway, including ERK1/2, p-ERK, Bcl-2, Bax and Cyclin D1. In addition, CXCL3-induced malignant behaviors in HT-29 and SW480 cells were obviously attenuated following treatment with ERK inhibitor PD98059. Conclusion: CXCL3 is upregulated in COAD and plays a crucial role in the control of malignant behaviors of tumor cells, which indicated its involvement in the pathogenesis of COAD.