title: miR-29b Mediates NF-κB Signaling in KRAS-Induced Non-Small Cell Lung Cancers.
abstract: A global understanding of miRNA function in EGFR signaling pathways may provide insights into improving the management of KRAS-mutant lung cancers, which remain relatively recalcitrant to treatment. To identify miRNAs implicated in EGFR signaling, we transduced bronchial epithelial BEAS-2B cells with retroviral vectors expressing KRAS(G12V) and monitored miRNA expression patterns by microarray analysis. Through this approach, we defined miR-29b as an important target for upregulation by mutant KRAS in non-small cell lung cancers. Cell biologic analyses showed that pharmacologic inhibition of EGFR or MEK was sufficient to reduce levels of miR-29b, while PI3K inhibition had no effect. In KRAS(G12V)-transduced BEAS-2B cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis, arguing that miR-29b mediated apoptotic resistance conferred by mutant KRAS. Mechanistic investigations traced this effect to the ability of miR-29b to target TNFAIP3/A20, a negative regulator of NF-κB signaling. Accordingly, overexpression of an miR-29b-refractory isoform of TNFAIP3 restored NF-κB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b. We also noted that miR-29b could confer sensitivity to intrinsic apoptosis triggered by exposure to cisplatin, a drug used widely in lung cancer treatment. Thus, miR-29b expression may tilt cells from extrinsic to intrinsic mechanisms of apoptosis. Overall, our results reveal a complexity in cancer for miR-29b, which can act as either an oncogene or tumor suppressor gene depending on signaling context. Cancer Res; 76(14); 4160-9. ©2016 AACR.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Langsch
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumgartner
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haemmig
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlup
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schäfer
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Berezowska
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Gregor
authors.initials: G
authors.lastname: Rieger
authors.affiliation: Universitätsklinik für Thoraxchirurgie, Inselspital Bern, Bern, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dorn
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland. erik.vassella@pathology.unibe.ch.
authors.forename: Erik
authors.initials: E
authors.lastname: Vassella
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D066246:ErbB Receptors; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D016283:Proto-Oncogene Proteins p21(ras)