A functional genomics screen for microRNA regulators of NF-kappaB signaling

Olarerin-George, Anthony O.; Anton, Lauren; Hwang, Yi‐Ting; Elovitz, Michal A.; Hogenesch, John B.

doi:10.1186/1741-7007-11-19

Cited by 48 publications

(37 citation statements)

References 57 publications

(66 reference statements)

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“…We show that miR-124 reconstitution promotes NFKB1 /p65 suppression, leading to reduced NF-κB transcriptional activity and altered expression of key cytokines. This is consistent with a previous study identifying miR-124 as the top negative regulator of NF-κB in a miRNA mimic functional screen (43). Whether this is a direct suppression of the p65 3′ UTR by miR-124 remains unclear.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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“…Another epigenetic member involved in the NF-jB expression is the microRNA-181b-1 (Ma et al 2011). A similar study performed by Olarein-George et al, in which he studied the role of microRNA-517a and microRNA-517c in NFjB activity, reports of which stated that there exists a significant correlation from the modelling point of view (Olarerin-George et al 2013). Another study performed by Wu et al, proved that increase in microRNA-23b expression alters the functioning of NF-jB and thus augments the sepsis (Wu et al 2015).…”

Section: The Micrornas Expression In Sepsis and Its Implications In Nmentioning

confidence: 76%

The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs

Păpurică¹,

Rogobete²,

Săndesc³

et al. 2016

Biochem Genet

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Critical polytrauma patients present a series of pathophysiological disturbances, biochemical and molecular dysfunction, which comprise to be the major cause of intensive care unit admission. In regard to molecular damage, there exists a series of factors, which all together contribute to the aggravation of the clinical status leading to increased mortality rate in these patients. One of the most important biochemical factors involved is the nuclear transcription factor B (NF-κB). Impaired NF-κB functioning is reflected on the clinical status of the patient through increased production of pro-inflammatory molecule, leading to multiple organ dysfunction syndrome. In addition to this, through microRNAs interactions, various pathophysiological as well as biochemical disturbances are produced, which altogether further reduce the patient's survival rate. In this paper, we would like to present the modifications seen in the expression of NF-κB in critically polytraumatized patients with sepsis. In additions to this, we would like to discuss the correlation between the microRNAs and its further implications in clinical status of these patients.

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“…C19MC miRNAs are processed from the cluster (812), are primate-specific, conserved in humans, and comprise 46 miRNA genes, including the miR-517 family (813). miR-517 is known to be antiviral (814, 815), while miR-517a overexpression is apoptotic (816) and can inhibit trophoblast invasion (817). Importantly for our argument, miR-517 molecules are overexpressed following infection (818, 819).…”

Section: Proteomic and Similar Biomarkers – Circulating And Placentalmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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A functional genomics screen for microRNA regulators of NF-kappaB signaling

Cited by 48 publications

References 57 publications

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

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

The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs

A Dormant Microbial Component in the Development of Preeclampsia

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