C-C Motif Ligand 21/C-C Motif Chemokine Receptor 7 Modulated Tumor Properties for Non-Small Cell Lung Cancer Brain Metastasis Patients

Abstract

The non-small cell lung cancer is a common malignancy with high metastasis capacity. The brain is the primary site for non-small cell lung cancer patients with unclear mechanism. Here, in this study, we hypothesized an innovative signaling cascade for the disorder and systematically investigated the underlying mechanism. Their differentially gene expression analysis was based on 13 conventional nonsmall cell lung cancer and 15 non-small cell lung cancer brain metastasis patients respectively. The nonsmall cell lung cancer cell line, adenocarcinomic human alveolar basal epithelial cells-A549 and human bronchial epithelial cell line-BEAS-2B were established for in vitro study. The syngeneic mouse tumor models injected with 5×105 cells of control, C-C motif ligand 21 overexpressing, C-C motif chemokine receptor 7 overexpressing A549 cells were generated for in vivo analysis. Compared with conventional non-small cell lung cancer patients, the non-small cell lung cancer brain metastasis patients showed 352 differentially expressed genes, as 212 down-regulated ones and 140 up-regulated ones. Moreover, the C-C motif ligand 21 and C-C motif chemokine receptor 7 were prominently inhibited in non-small cell lung cancer brain metastasis patients. In A549 cells, C-C motif ligand 21 overexpressing could inhibit epithelial-mesenchymal transition progression. C-C motif ligand 21 modulated epithelial-mesenchymal transition and migration plus invasion ability but not proliferation capacity of non-small cell lung cancer cells through C-C motif chemokine receptor 7 dependent signaling pathway, as Janus kinase 2/signal transducer and activator of transcription 3 was a potential downstream signaling pathway. Moreover, C-C motif ligand 21/C-C motif chemokine receptor 7 signaling axis could modulate tumor growth and survival time in vivo. Collectively, these data initiated a C-C motif ligand 21/C-C motif chemokine receptor 7-Janus kinase 2/signal transducer and activator of transcription 3 signaling for non-small cell lung cancer patients with brain metastasis, which shed various beneficial insights for future study.