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Gonzalez-Vallinas, M.* ; Rodriguez-Paredes, M.* ; Albrecht, M.* ; Sticht, C.* ; Stichel, D.* ; Gutekunst, J.* ; Pitea, A. ; Sass, S. ; Sánchez-Rivera, F.J.* ; Bermejo, J.L.* ; Schmitt, J.* ; De La Torre, C.* ; Warth, A.* ; Theis, F.J. ; Müller, N.S. ; Gretz, N.* ; Muley, T.* ; Meister, M.* ; Tschaharganeh, D.F.* ; Schirmacher, P.* ; Matthäus, F.* ; Breuhahn, K.*

Epigenetically regulated chromosome 14q32 miRNA cluster induces metastasis and predicts poor prognosis in lung adenocarcinoma patients.

Mol. Cancer Res. 16, 390-402 (2018)

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Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify miRNAs involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis- associated miRNAs were identified in The Cancer Genome Atlas lung adenocarcinoma patient cohort (sequencing data; n = 449) and subsequently validated by qRT-PCR in an independent clinical cohort (n = 108). Overexpression of miRNAs located on chromosome 14q32 was associated with metastasis in lung adenocarcinoma patients. Importantly, Kaplan-Meier analysis and log-rank test revealed that higher expression levels of individual 14q32 miRNAs (mir-539, mir-323b, and mir- 487a) associated with worse disease-free survival of never-smoker patients. Epigenetic analysis including DNA methylation microarray data and bisulfite sequencing validation demonstrated that the induction of 14q32 cluster correlated with genomic hypomethylation of the 14q32 locus. CRISPR activation technology, applied for the first time to functionally study the increase of clustered miRNA levels in a coordinated manner, showed that simultaneous overexpression of 14q32 miRNAs promoted tumor cell migratory and invasive properties. Analysis of individual miRNAs by mimic transfection further illustrated that miR-323b-3p, miR-487a-3p, and miR-539-5p significantly contributed to the invasive phenotype through the indirect regulation of different target genes. In conclusion, overexpression of 14q32 miRNAs, associated with the respective genomic hypomethylation, promotes metastasis and correlates with poor patient prognosis in lung adenocarcinoma. Implications: This study points to chromosome 14q32miRNAs as promising targets to inhibit tumor cell dissemination and to predict patient prognosis in lung adenocarcinoma. Mol Cancer Res; 16(3); 390-402.

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