MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade

Mechtler, Peter; Singhal, Ruchi; Kichina, Julia V.; Bard, Jonathan; Buck, Michael; Kandel, Eugene

doi:10.18632/oncotarget.4005

Cited by 20 publications

(20 citation statements)

References 57 publications

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“…For instance, NF-κB inhibition by oxytocin could induce the up-regulation of miR-195 which promotes apoptosis and inhibits proliferation of breast cancer cells [ 36 ]. In addition, miR-497 has been identified as a regulatory miR by NF-κB in a previous study [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

Wang

Guo²,

Zhou

et al. 2020

J Exp Clin Cancer Res

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Background Colon cancer represents one of the leading causes of gastrointestinal tumors in industrialized countries, and its incidence appears to be increasing at an alarming rate. Accumulating evidence has unveiled the contributory roles of cancer stem cells (CSCs) in tumorigenicity, recurrence, and metastases. The functions of NF-kappa B (NF-κB) activation on cancer cell survival, including colon cancer cells have encouraged us to study the role of NF-κB in the maintenance of CSCs in colon cancer. Methods Tumor samples and matched normal samples were obtained from 35 colon cancer cases. CSCs were isolated from human colon cancer cell lines, where the stemness of the cells was evaluated by cell viability, colony-forming, spheroid-forming, invasion, migration, and apoptosis assays. NF-κB activation was then performed in subcutaneous tumor models of CSCs by injecting lipopolysaccharides (LPS) i.p. Results We found that NF-κB activation could reduce the expression of miR-195-5p and miR-497-5p, where these two miRNAs were determined to be downregulated in colon cancer tissues, cultured colon CSCs, and LPS-injected subcutaneous tumor models. Elevation of miR-195-5p and miR-497-5p levels by their specific mimic could ablate the effects of NF-κB on the stemness of colon cancer cells in vivo and in vitro, suggesting that NF-κB could maintain the stemness of colon cancer cells by downregulating miR-195-5p/497–5p. MCM2 was validated as the target gene of miR-195-5p and miR-497-5p in cultured colon CSCs. Overexpression of MCM2 was shown to restore the stemness of colon cancer cells in the presence of miR-195-5p and miR-497-5p, suggesting that miR-195-5p and miR-497-5p could impair the stemness of colon cancer cells by targeting MCM2 in vivo and in vitro. Conclusions Our work demonstrates that the restoration of miR-195-5p and miR-497-5p may be a therapeutic strategy for colon cancer treatment in relation to NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

Wang

Guo²,

Zhou

et al. 2020

J Exp Clin Cancer Res

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“…In the course of several studies 18,19 that relied on high-throughput sequencing of short RNAs, we consistently saw the presence of molecules that correspond to the sequence of the human DROSHA gene. The molecules that attracted our attention uniquely map to 2 closely-situated areas at the predicted boundary of intron 7 and exon 6 in DROSHA transcript variant 1 (GeneBank accession number NM_013235.4) ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Indeed, many transcription factors are subjects to inhibitory control by the miRNA, which are transcriptional targets of the very same proteins. 18,21,22 However, the discovered miRNA may be a clue about a more global mechanism of RNAi regulation in human cells. To the best of our knowledge, this report presents the first evidence pointing to the existence of a miRNA, which is encoded within the DROSHA gene and can potentially target expression of at least one of the isoforms of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Next-generation sequencing of pools of short RNAs was described earlier. 18,19 Predictions of new miRNAs were made using miRDeep2 software. 25 Folding of the predicted hairpin was analyzed using Vienna RNA Package 38 (accessed at http:// rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi) with "minimum free energy (MFE) and partition function" and "avoid isolated base pairs" options selected.…”

Section: Methodsmentioning

confidence: 99%

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The evidence for a microRNA product of human DROSHA gene

et al. 2017

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MicroRNAs are short RNA molecules that regulate function and stability of a large subset of eukaryotic mRNAs. In the main pathway of microRNA biogenesis, a short "hairpin" is excised from a primary transcript by ribonuclease DROSHA, followed by additional nucleolytic processing by DICER and inclusion of the mature microRNA into the RNA-induced silencing complex. We report that a microRNA-like molecule is encoded by human DROSHA gene within a predicted stem-loop element of the respective transcript. This putative mature microRNA is complementary to DROSHA transcript variant 1 and can attenuate expression of the corresponding protein. The findings suggest a possibility for a negative feedback loop, wherein DROSHA processes its own transcript and produces an inhibitor of its own biosynthesis.

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“…The TNF-α signaling network, which governs cell fate, has been extensively studied over the past decades [34, 81, 82]. The balance between cell survival and apoptosis is mainly attributed to two modules, the survival module and the apoptosis module.…”

Section: Methodsmentioning

confidence: 99%

Synonymous mutations in oncogenesis and apoptosis versus survival unveiled by network modeling

Chen

et al. 2016

Oncotarget

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Synonymous mutations, which do not alter the encoded amino acid, have been routinely assumed to be ‘neutral’ and would have no effect on phenotype or fitness. Yet increasing observations have emerged to overturn this conventional concept. However, convicted elucidation of how synonymous mutations exert biological consequences in oncogenesis is still lacking. By performing systematic analysis of the TNF-α signaling network model, we identify the critical dose which separates the cell survival and apoptosis regions and define the sensitive parameters with single-parameter sensitivity analysis. Combining with the cancer-related mutation spectra obtained from 9 cancers, our results hint that, similar as missense and nonsense mutations, synonymous mutations are also strongly correlated with the parameter sensitivity of the critical dose, providing possible causal mechanism of the mutations in cancer development. Based on such a correlation, we furthermore dissect that members of caspases family proteases (caspase3, 6, 8) could jointly inhibit NFκB activation, providing efficient pro-apoptotic behavior. Thus, we argue that apoptosis module could suppress survival module through negative feedback of caspases family on NFκB.

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MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade

Cited by 20 publications

References 57 publications

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

The evidence for a microRNA product of human DROSHA gene

Synonymous mutations in oncogenesis and apoptosis versus survival unveiled by network modeling

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