Mechanism of CCL21/CCL19-CCR7 as a Key Regulatory Signaling Cassette for Non-Small Cell Lung Cancer Patients with Brain Metastasis

Abstract

To elucidate the molecular mechanism underlying the high metastasis rate of brain for non-small cell lung cancer patients and to establish a comprehensive differential gene profile for non-small cell lung cancer brain metastasis. The differentially expressed genes for non-small cell lung cancer brain metastasis patients were systematically investigated. The enriched biological processes and signaling pathways were explored. The protein-protein interaction network was constructed. Compared with primary non-small cell lung cancer, the brain metastasis patients demonstrated 352 differentially expressed genes with the majority as down-regulated ones (342) and 10 up-regulated ones. Meanwhile, C-C motif chemokine ligand 21, C-C motif chemokine ligand 19, deleted in malignant brain tumors 1 gene, tryptase alpha/beta 1, lactotransferrin, complement component 4 binding protein alpha, C-C motif chemokine ligand 14, C-X-C motif chemokine ligand 9, cluster of differentiation 79A as well as membrane spanning 4-domains A1 were significant and differentially expressed (all down-regulated). The genes of cluster including C-C motif chemokine ligand 21, C-C motif chemokine ligand 19 played a pivotal role in non-small cell lung cancer brain metastasis. The cytokines C-C motif chemokine ligand 19 and C-C motif chemokine ligand 21 as well as their closely associated receptors, C-C chemokine receptor 7 could be detected as high expression levels in non-small cell lung cancer cell line (A549). Inhibition of C-C motif chemokine ligand 19 and C-C motif chemokine ligand 21 as well as C-C chemokine receptor 7 using small interfering ribonucleic acid obviously repressed the cell invasion and metastasis but not for cell proliferation and apoptosis. Meanwhile, the procedure was independent of micro ribonucleic acid lethal-7a regulation. This study hypothesized an innovative signaling axis (C-C motif chemokine ligand 21/C-C motif chemokine ligand 19-C-C chemokine receptor 7) for non-small cell lung cancer brain metastasis and provided a beneficial strategy for better understanding the lung metastases in clinic.