miR-29b Mediates NF-κB Signaling in KRAS-Induced Non-Small Cell Lung Cancers

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 14; pp. 4160 - 4169
• Main Authors: Langsch, Stephanie, Baumgartner, Ulrich, Haemmig, Stefan, Schlup, Cornelia, Schäfer, Stephan C, Berezowska, Sabina, Rieger, Gregor, Dorn, Patrick, Tschan, Mario P, Vassella, Erik
• Format: Journal Article
• Language: English
• Published: United States 15.07.2016
• Subjects: Apoptosis; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Humans; Lung Neoplasms - pathology; MAP Kinase Signaling System; MicroRNAs - physiology; Mutation; NF-kappa B - physiology; Proto-Oncogene Proteins p21(ras) - genetics; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - physiology; Signal Transduction - physiology; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2580

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.