miR-29 b Mediates NFk B Signaling in KRAS-Induced Non – Small Cell Lung Cancers

A global understanding of miRNA function in EGFR signaling pathwaysmay provide insights into improving themanagement 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 and monitored miRNA expression patterns bymicroarray 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-transduced BEAS-2B cells, introduction of anti-miR29b constructs increased the sensitivity to apoptosis, arguing that miR-29bmediated apoptotic resistance conferredbymutant KRAS. Mechanistic investigations traced this effect to the ability of miR29b to targetTNFAIP3/A20, a negative regulatorofNF-kB signaling. Accordingly, overexpression of an miR-29b–refractory isoform of TNFAIP3 restored NF-kB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target ofmiR-29b.Wealsonoted 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.