CXCR5 and TLR4 signals synergistically enhance non‐small cell lung cancer progression

Abstract

Dear Editor, Chemokines and their receptors play essential roles in neoplastic transformation, tumour cell growth and survival, and organ-specific metastasis during carcinogenesism. [1][2][3] Of various CXC chemokines, CXCL13 and its related receptor CXCR5 have been implicated in lung cancer progression. 2 However, the molecular and cellular mechanisms by which the CXCR5-CXCL13 signal axis is functionally regulated in lung cancer progression are still poorly understood. Through clinical microarray data analysis of primary non-small cell lung cancer (NSCLC; n = 42) patients, we found that the up-regulation of CXCR5 and CXCL13 or CXCR5 and TLR4 in lung tumour tissues versus matched lung normal tissues was significantly associated with gene sets related to cancer module, lung fibrosis, VEGF, chemokine, cytokine and TLR signalling pathway. Through functional analysis with CXCR5knockout (CXCR5-KO) human lung cancer cells generated by CRISPR/Cas9 gene editing method, we found that the CXCR5-CXCL13 axis was functionally linked to TLR4 signalling through activation of NF-κB for lung cancer progression, strongly suggesting that our clinically comparative results and functional investigations of TLR4-CXCR5 signalling network in lung cancer could potentially contribute to translational approaches for the development of lung cancer therapeutic agents.Gene expression profiling interactive analysis (http:// gepia.cancer-pku.cn/detail.php?gene = CXCR5) revealed a positive correlation between CXCR5 and CXCL13 expression in lung adenocarcinoma (LUAD) (Figure S1A; p = 3.8e−08, R = 0.25). The expression of CXCL13 was significantly enhanced in LUAD and lung squamous cell carcinoma (Figures S1B and C). To clinically get insight into the role of the CXCR5-CXCL13 axis, we utilised microarray data of primary NSCLC patients' lung tumour tissues (n = 42; Table S1) and their matched lung normal tissues (n = 42). We performed a gene Ji Hye Shin, Mi-Jeong Kim and Ji Young Kim contributed equally to this work.