title: MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma.
abstract: The c-Src kinase regulates cancer cell invasion through inhibitor of DNA binding/differentiation 1 (ID1). Src and ID1 are frequently overexpressed in human lung adenocarcinoma. The current study aimed at identifying microRNAs (miRNAs) involved in the Src-ID1 signaling in lung cancer. Incubation of lung cancer cells with the Src inhibitor saracatinib led to the upregulation of several miRNAs including miR-29b, which was the most highly upregulated miRNA with predicted binding to the ID1 3'-untranslated region (UTR). Luciferase reporter assays confirmed direct binding of miR-29b to the ID1 3'-UTR. Expression of miR-29b suppressed ID1 levels and significantly reduced migration and invasion. Expression of antisense-miR-29b (anti-miR-29b), on the other hand, enhanced ID1 mRNA and protein levels, and significantly increased lung cancer cell migration and invasion, a hallmark of the Src-ID1 pathway. The ectopic expression of ID1 in miR-29b-overexpressing cells was able to rescue the migratory potential of these cells. Both, anti-miR-29b and ID1 overexpression diminished the effects of the Src inhibitors saracatinib and dasatinib on migration and invasion. Saracatinib and dasatinib decreased c-Myc transcriptional repression on miR-29b and led to increased ID1 protein levels, whereas forced expression of c-Myc repressed miR-29b and induced ID1. In agreement, we showed direct recruitment of c-Myc to the miR-29b promoter. miR-29b was significantly downregulated in primary lung adenocarcinoma samples compared with matched alveolar lung tissue, and miR-29b expression was a significant prognostic factor for patient outcome. These results suggest that miR-29b is involved in the Src-ID1 signaling pathway, is dysregulated in lung adenocarcinoma and is a potential predictive marker for Src kinase inhibitors.
authors.affiliation: Department of Clinical Research, University of Bern, and Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: S I
authors.initials: SI
authors.lastname: Rothschild
authors.forename: M P
authors.initials: MP
authors.lastname: Tschan
authors.forename: E A
authors.initials: EA
authors.lastname: Federzoni
authors.forename: R
authors.initials: R
authors.lastname: Jaggi
authors.forename: M F
authors.initials: MF
authors.lastname: Fey
authors.forename: M
authors.initials: M
authors.lastname: Gugger
authors.forename: O
authors.initials: O
authors.lastname: Gautschi
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051798:Inhibitor of Differentiation Protein 1; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D019061:src-Family Kinases