Research ArticleCancer

Regulation of autophagy, NF-κB signaling, and cell viability by miR-124 in KRAS mutant mesenchymal-like NSCLC cells

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Science Signaling  12 Sep 2017:
Vol. 10, Issue 496, eaam6291
DOI: 10.1126/scisignal.aam6291

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Subtype selectivity in cancer

Activating mutations in the protein KRAS are common in non–small cell lung cancers (NSCLCs). However, tumors of the mesenchymal subtype of KRAS mutant NSCLC are not responsive to RAS pathway inhibitors. By comparing tumor samples and cell lines of epithelial and mesenchymal NSCLCs, Mehta et al. found that loss of the microRNA miR-124 in mesenchymal tumor cells enables increased abundance of autophagy and related proteins, which promoted cell survival. Introducing miR-124 or inhibiting autophagy in the mesenchymal tumor cells triggered their apoptosis. These findings identify alternative molecular targets for potentially treating this subtype of NSCLC.


KRAS mutant non–small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Despite having the same “driver” mutation, mesenchymal NSCLCs are less responsive than are epithelial NSCLCs to inhibition of the RAS pathway. Identifying alternative networks that promote survival specifically in mesenchymal NSCLC may lead to more effective treatments for this subtype. Through their numerous targets in cellular signaling pathways, noncoding microRNAs (miRNAs) often function as tumor suppressors or oncogenes. In particular, some miRNAs regulate the epithelial-mesenchymal transition (EMT). We derived an EMT-related miRNA signature by profiling the abundance of miRNAs in a panel of epithelial (KE) or mesenchymal (KM) KRAS mutant NSCLC cell lines. This signature revealed a number of suppressed miRNAs in KM cell lines, including members of the miR-200 family, which can suppress tumor progression by inhibiting EMT. Reconstituting KM cells with one of these miRNAs, miR-124, disrupted autophagy and decreased cell survival by reducing the abundance of p62, which is both an adaptor for selective autophagy and a regulator of the transcription factor nuclear factor κB (NF-κB). Suppression of p62 by miR-124 correlated with reduced abundance of the autophagy activator beclin 1 (BECN1), the ubiquitin ligase TRAF6, and the NF-κB subunit RELA/p65. The abundance of miR-124 inversely correlated with the expression of BECN1 and TRAF6 in patient NSCLC samples. These findings reveal how the loss of miR-124 promotes cell survival networks in the aggressive mesenchymal subtype of KRAS mutant NSCLC, which might lead to improved subtype-selective therapeutic strategies for patients.

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