RT info:eu-repo/semantics/article
T1 Epigenetically regulated chromosome 14q32 miRNA cluster induces metastasis and predicts poor prognosis in lung adenocarcinoma patients
A1 González-Vallinas Garrachón, Margarita
A1 Rodríguez Paredes, Manuel
A1 Albrecht, Marco
A1 Sticht, Carsten
A1 Stichel, Damian
A1 Gutekunst, Julian
A1 Pitea, Adriana
A1 Sass, Steffen
A1 Sánchez Rivera, Francisco J.
A1 Lorenzo Bermejo, Justo
A1 Schmitt, Jennifer
A1 Torre, Carolina de la
A1 Warth, Arne
A1 Theis, Fabian J.
A1 Müller, Nikola S.
A1 Gretz, Norbert
A1 Muley, Thomas
A1 Meister, Michael
A1 Tschaharganeh, Darjus F.
A1 Schirmacher, Peter
A1 Matthäus, Franziska
A1 Breuhahn, Kai
K1 Cáncer
K1 miARN
K1 3207.13 Oncología
AB 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 ¼ 449) and subsequently validated by qRT-PCR in an independentclinical cohort (n ¼ 108). Overexpression of miRNAs locatedon chromosome 14q32 was associated with metastasis in lungadenocarcinoma patients. Importantly, Kaplan–Meier analysisand log-rank test revealed that higher expression levels ofindividual 14q32 miRNAs (mir-539, mir-323b, and mir487a) associated with worse disease-free survival of never-smoker patients. Epigenetic analysis including DNA methylationmicroarray data and bisulfite sequencing validation demonstrated that the induction of 14q32 cluster correlated with genomichypomethylation of the 14q32 locus. CRISPR activation technology, applied for the first time to functionally study theincrease of clustered miRNA levels in a coordinated manner,showed that simultaneous overexpression of 14q32 miRNAspromoted tumor cell migratory and invasive properties. Analysisof individual miRNAs by mimic transfection further illustratedthat miR-323b-3p, miR-487a-3p, and miR-539-5p significantlycontributed to the invasive phenotype through the indirectregulation of different target genes. In conclusion, overexpression of 14q32 miRNAs, associated with the respective genomichypomethylation, promotes metastasis and correlates with poorpatient prognosis in lung adenocarcinoma
PB American Association for Cancer Research
SN 1541-7786
YR 2018
FD 2018
LK http://uvadoc.uva.es/handle/10324/42586
UL http://uvadoc.uva.es/handle/10324/42586
LA eng
NO Molecular Cancer Research, 2018, vol. 16, n. 3, p. 390-402
NO Producción Científica
DS UVaDOC
RD 22-nov-2024