Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature

Abstract

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer

“…MiR-335-5p and miR-34b-3p were identified as unique to NSCLC brain metastasis, with others such as miR-330-3p having a diagnostic potential [125,126]. Comparative studies identified specific miRNAs upregulated and downregulated in brain metastases compared to primary NSCLC tumors, highlighting the role of miRNAs in controlling tumor cell proliferation, migration, and invasion [127]. Notable findings include miR-596-3p's role in inhibiting brain metastases by modulating YAP1 and IL-8 and the significant downregulation of microRNA-375 in patients with brain metastases [128,129].…”

Advances in Brain Metastases Diagnosis: Non-coding RNAs As Potential Biomarkers

“…Regarding NSCLC brain metastases, Tsakonas et al studied microRNA expression in patients with NSCLC primary tumors with metastatic brain NSCLC [ 18 , 19 ]. They found that compared to primary NSCLC tumor samples, there are five microRNAs upregulated (microRNA-219a-5p, microRNA-9-5p, microRNA-124-3P, microRNA-219a-2-3p, and microRNA-129-2-3p) in brain metastases, while six microRNAs are found to be downregulated (microRNA-199a-5p, microRNA-199b-5p, microRNA-142-3p, microRNA-199b-5p, microRNA-199a-3p, and microRNA-150-5p) [ 18 , 19 ].…”

“…Regarding NSCLC brain metastases, Tsakonas et al studied microRNA expression in patients with NSCLC primary tumors with metastatic brain NSCLC [ 18 , 19 ]. They found that compared to primary NSCLC tumor samples, there are five microRNAs upregulated (microRNA-219a-5p, microRNA-9-5p, microRNA-124-3P, microRNA-219a-2-3p, and microRNA-129-2-3p) in brain metastases, while six microRNAs are found to be downregulated (microRNA-199a-5p, microRNA-199b-5p, microRNA-142-3p, microRNA-199b-5p, microRNA-199a-3p, and microRNA-150-5p) [ 18 , 19 ]. In adenocarcinoma metastases, Zhao et al found that five microRNAs are upregulated ( microRNAs-9*, microRNA-1471, microRNA-718, microRNA-3656, microRNA-720) compared to primary lung adenocarcinoma, while three microRNAs were found to be downregulated (microRNAs-214, microRNA-145, microRNA-23a) [ 20 ].…”