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

Abstract

KRAS mutant non-small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Mesenchymal NSCLCs and associated “KM” cell lines are generally less responsive than their epithelial counterparts to inhibition of the RAS pathway; identifying alternative networks that promote mesenchymal NSCLC survival may lead to more effective treatments for this subtype. Non-coding microRNA (miRNA) signatures can stratify tumors into diverse molecular subtypes. By regulating numerous targets in cancer-associated signaling pathways, miRNAs can function as tumor suppressors or oncogenes. In particular, some miRNAs regulate the epithelial-mesenchymal transition (EMT). Here, 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 silenced or suppressed miRNAs in KM cell lines, including members of the miR-200 family, which can promote tumor suppression by inhibiting EMT. Reconstituting KM cells with one of these miRNAs, miR-124, disrupted autophagy and decreased cell survival by suppressing the abundance of p62, an adaptor for selective autophagy and regulator of the transcription factor NF-κB. Suppression of p62 by miR-124 correlated with reduced abundance of the autophagy activator Beclin 1, the ubiquitin ligase TRAF6 and the NF-κB subunit RELA/p65. Abundance of miR-124 inversely correlated with expression of BECN1 and TRAF6 in patient NSCLC samples. These findings identify a role for miR-124 in regulating cell survival networks in a specific subtype of KRAS mutant NSCLC cell lines, which might lead to improved subtype-selective therapeutic strategies for patients.

Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer

“…Recent research indicates that circHIPK3 functions as a ceRNA to sequester multiple miRNAs [16,19,28], among which MIR124-3p is a well-known tumor suppressor and its regulation role in autophagy was recently being emphasized [29]. It has been reported that IL6R is regulated by circHIPK3-MIR124-3p axis [16].…”

From Oxidative Stress Damage to Pathways, Networks, and Autophagy via MicroRNAs

“…For example, miR-9 affects autophagy by targeting the products of the essential autophagy-related (ATG) genes ATG5 [ 68 ] and Beclin1 [ 75 ], whereas miR-17 targets ATG7 [ 66 ], Beclin1 [ 64 ], and p62/SQSTM1 [ 70 ]. miR-124 targets Beclin1 [ 74 ] and p62/SQSTM1 [ 71 ]. Modulation of this set of miRNAs that we identified by in silico analysis (miR-9, miR-16, miR-17, miR-93, miR-101, miR-124, miR-128, miR-200, miR-429, and miR-497) thus appears to have a strong potential to concertedly mediate the effects of oxidative stress on both protein ubiquitination and autophagy.…”

MiR-124-3p helps to protect against acute respiratory distress syndrome by targeting p65

“…Furthermore, it has been shown that miR-124-3p can suppress inflammatory responses in traumatic acute lung injuries and thereby ameliorate those injuries [11]. A previous study of non-small cell lung cancers indicated that miR-124 helped to regulate autophagy, NF-kappa signaling, and cell viability, and that suppression of p62 expression by miR-124 was correlated with the NF-kappa subunit, RELA/p65 [14]. In a study of retinal microglia cells, it was shown that miR-124 directly controls Rac1 expression; furthermore, that study also revealed a miR-124-dependent mechanism in which Rac1 activation-mediated reactive oxygen species production stimulated p65 NF-kappa phosphorylation and induced the release of TNF-alpha from retinal microglial cells [15].…”