Roles of NF-κB Signaling in the Regulation of miRNAs Impacting on Inflammation in Cancer

Biomedicines - Tập 6 Số 2 - Trang 40
Γεώργιος Μαρκόπουλος1,2, Eugenia Roupakia1,2, Maria Tokamani3, Georgia Alabasi1,2, Raphael Sandaltzopoulos3, Kenneth B. Marcu1,4,5,6, Evangelos Kolettas1,2
1Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 45110 Ioannina, Greece
2Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
3Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
4Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 115-27 Athens, Greece
5Department of Biology, San Diego State University, San Diego, CA 92182-4614, USA
6Departments of Biochemistry and Cell Biology, Microbiology and Pathology, Stony Brook University, Stony Brook, NY 11794-5215, USA

Tóm tắt

The NF-κB family of transcription factors regulate the expression of genes encoding proteins and microRNAs (miRNA, miR) precursors that may either positively or negatively regulate a variety of biological processes such as cell cycle progression, cell survival, and cell differentiation. The NF-κB-miRNA transcriptional regulatory network has been implicated in the regulation of proinflammatory, immune, and stress-like responses. Gene regulation by miRNAs has emerged as an additional epigenetic mechanism at the post-transcriptional level. The expression of miRNAs can be regulated by specific transcription factors (TFs), including the NF-κB TF family, and vice versa. The interplay between TFs and miRNAs creates positive or negative feedback loops and also regulatory networks, which can control cell fate. In the current review, we discuss the impact of NF-κB-miRNA interplay and feedback loops and networks impacting on inflammation in cancer. We provide several paradigms of specific NF-κB-miRNA networks that can regulate inflammation linked to cancer. For example, the NF-κB-miR-146 and NF-κB-miR-155 networks fine-tune the activity, intensity, and duration of inflammation, while the NF-κB-miR-21 and NF-κB-miR-181b-1 amplifying loops link inflammation to cancer; and p53- or NF-κB-regulated miRNAs interconnect these pathways and may shift the balance to cancer development or tumor suppression. The availability of genomic data may be useful to verify and find novel interactions, and provide a catalogue of 162 miRNAs targeting and 40 miRNAs possibly regulated by NF-κB. We propose that studying active TF-miRNA transcriptional regulatory networks such as NF-κB-miRNA networks in specific cancer types can contribute to our further understanding of the regulatory interplay between inflammation and cancer, and also perhaps lead to the development of pharmacologically novel therapeutic approaches to combat cancer.

Từ khóa


Tài liệu tham khảo

Hanahan, 2011, Hallmarks of cancer: The next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013

Dawson, 2012, Cancer epigenetics: From mechanism to therapy, Cell, 150, 12, 10.1016/j.cell.2012.06.013

Esteller, 2011, Cancer epigenetics reaches mainstream oncology, Nat. Med., 17, 330, 10.1038/nm.2305

Perkins, 2007, Integrating cell-signalling pathways with NF-κB and IKK function, Nat. Rev. Mol. Cell Biol., 8, 49, 10.1038/nrm2083

Penzo, 2009, Sustained NF-κB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1, J. Cell. Physiol., 218, 215, 10.1002/jcp.21596

Perkins, 2012, The diverse and complex roles of NF-κB subunits in cancer, Nat. Rev. Cancer, 12, 121, 10.1038/nrc3204

Hayden, 2012, NF-κB, the first quarter-century: Remarkable progress and outstanding questions, Genes Dev., 26, 203, 10.1101/gad.183434.111

Chen, 2011, NF-κB in lung cancer, a carcinogenesis mediator and a prevention and therapy target, Front. Biosci. (Landmark Ed.), 16, 1172, 10.2741/3782

Taniguchi, K., and Karin, M. (2018). Nf-κB, inflammation, immunity and cancer: Coming of age. Nat. Rev. Immunol.

Perkins, 2004, Nf-κB: Tumor promoter or suppressor?, Trends Cell Biol., 14, 64, 10.1016/j.tcb.2003.12.004

Markopoulos, 2017, A step-by-step microRNA guide to cancer development and metastasis, Cell. Oncol., 40, 303, 10.1007/s13402-017-0341-9

Markopoulos, 2017, Senescence-associated microRNAs target cell cycle regulatory genes in normal human lung fibroblasts, Exp. Gerontol., 96, 110, 10.1016/j.exger.2017.06.017

Bartel, 2018, Metazoan microRNAs, Cell, 173, 20, 10.1016/j.cell.2018.03.006

Bartel, 2004, MicroRNAs: Genomics, biogenesis, mechanism, and function, Cell, 116, 281, 10.1016/S0092-8674(04)00045-5

Taganov, 2007, MicroRNAs and immunity: Tiny players in a big field, Immunity, 26, 133, 10.1016/j.immuni.2007.02.005

Boldin, 2012, MicroRNAs, new effectors and regulators of NF-κB, Immunol. Rev., 246, 205, 10.1111/j.1600-065X.2011.01089.x

Mehta, 2016, MicroRNAs as regulatory elements in immune system logic, Nat. Rev. Immunol., 16, 279, 10.1038/nri.2016.40

Mann, 2017, An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses, Nat. Commun., 8, 851, 10.1038/s41467-017-00972-z

Hobert, 2008, Gene regulation by transcription factors and microRNAs, Science, 319, 1785, 10.1126/science.1151651

Martinez, 2009, The interplay between transcription factors and microRNAs in genome-scale regulatory networks, Bioessays, 31, 435, 10.1002/bies.200800212

Chariot, 2009, The NF-κB-independent functions of IKK subunits in immunity and cancer, Trends Cell Biol., 19, 404, 10.1016/j.tcb.2009.05.006

Karin, 2005, NF-κB: Linking inflammation and immunity to cancer development and progression, Nat. Rev. Immunol., 5, 749, 10.1038/nri1703

Tew, 2014, Chapter three-IKK/nuclear factor-κB and oncogenesis: Roles in tumor-initiating cells and in the tumor microenvironment, Advances in Cancer Research, Volume 121, 125

Grivennikov, 2010, Immunity, inflammation, and cancer, Cell, 140, 883, 10.1016/j.cell.2010.01.025

Takahashi, 2010, Tobacco smoke promotes lung tumorigenesis by triggering IKKβ-and JNK1-dependent inflammation, Cancer Cell, 17, 89, 10.1016/j.ccr.2009.12.008

Zaynagetdinov, 2012, Epithelial nuclear factor-κB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes, Oncogene, 31, 3164, 10.1038/onc.2011.480

Greten, 2004, IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer, Cell, 118, 285, 10.1016/j.cell.2004.07.013

Karin, 2009, NF-κB as a critical link between inflammation and cancer, Cold Spring Harb. Perspect. Biol., 1, a000141, 10.1101/cshperspect.a000141

Xia, 2014, Nf-κB, an active player in human cancers, Cancer Immunol. Res., 2, 823, 10.1158/2326-6066.CIR-14-0112

Stathopoulos, 2007, Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis, Proc. Natl. Acad. Sci. USA, 104, 18514, 10.1073/pnas.0705316104

Basseres, 2010, Requirement of the NF-κB subunit p65/RelA for K-Ras-induced lung tumorigenesis, Cancer Res., 70, 3537, 10.1158/0008-5472.CAN-09-4290

Karin, 2011, Inflammation meets cancer, with NF-κB as the matchmaker, Nat. Immunol., 12, 715, 10.1038/ni.2060

Vlantis, 2011, Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice, J. Clin. Investig., 121, 2781, 10.1172/JCI45349

Xia, 2012, Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model, Nat. Cell Biol., 14, 257, 10.1038/ncb2428

Basseres, 2014, IKK is a therapeutic target in Kras-induced lung cancer with disrupted p53 activity, Genes Cancer, 5, 41, 10.18632/genesandcancer.5

Kim, 2014, Epidermal p65/NF-κB signalling is essential for skin carcinogenesis, EMBO Mol. Med., 6, 970, 10.15252/emmm.201303541

Koliaraki, 2015, IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer, J. Exp. Med., 212, 2235, 10.1084/jem.20150542

Kawauchi, 2008, P53 reulates glucose metabolism through an IKK-Nf-κB pathway and inhibits cell transformation, Nat. Cell Biol., 10, 611, 10.1038/ncb1724

Johnson, 2011, P53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-κB, Cancer Res., 71, 5588, 10.1158/0008-5472.CAN-10-4252

Mauro, 2011, NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration, Nat. Cell Biol., 13, 1272, 10.1038/ncb2324

Tornatore, 2012, The nuclear factor κB signaling pathway: Integrating metabolism with inflammation, Trends Cell Biol., 22, 557, 10.1016/j.tcb.2012.08.001

Oeckinghaus, 2011, Crosstalk in NF-κB signaling pathways, Nat. Immunol., 12, 695, 10.1038/ni.2065

Lin, 2007, A cytokine-mediated link between innate immunity, inflammation, and cancer, J. Clin. Investig., 117, 1175, 10.1172/JCI31537

Mantovani, 2008, Cancer-related inflammation, Nature, 454, 436, 10.1038/nature07205

Colotta, 2009, Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability, Carcinogenesis, 30, 1073, 10.1093/carcin/bgp127

Balkwill, 2012, Cancer-Related Inflammation: Common Themes and Therapeutic Opportunities, Semin. Cancer Biol., 22, 33, 10.1016/j.semcancer.2011.12.005

Aggarwal, 2011, Nf-κB in cancer: A matter of life and death, Cancer Discov., 1, 469, 10.1158/2159-8290.CD-11-0260

Allavena, 2008, Pathways connecting inflammation and cancer, Curr. Opin. Genet. Dev., 18, 3, 10.1016/j.gde.2008.01.003

DiDonato, 2012, Nf-κB and the link between inflammation and cancer, Immunol. Rev., 246, 379, 10.1111/j.1600-065X.2012.01099.x

Liang, 2004, NF-κB and its regulation on the immune system, Cell Mol. Immunol., 1, 343

Disis, 2010, Immune regulation of cancer, J. Clin. Oncol., 28, 4531, 10.1200/JCO.2009.27.2146

Hoesel, 2013, The complexity of Nf-κB signaling in inflammation and cancer, Mol. Cancer, 12, 86, 10.1186/1476-4598-12-86

Baud, 2009, Is Nf-κB a good target for cancer therapy? Hopes and pitfalls, Nat. Rev. Drug Discov., 8, 33, 10.1038/nrd2781

Baldwin, 2012, Regulation of cell death and autophagy by IKK and Nf-κB: Critical mechanisms in immune function and cancer, Immunol. Rev., 246, 327, 10.1111/j.1600-065X.2012.01095.x

Cartwright, 2016, NFKB1: A suppressor of inflammation, ageing and cancer, FEBS J., 283, 1812, 10.1111/febs.13627

Moghaddam, 2009, Promotion of lung carcinogenesis by chronic obstructive pulmonary disease—Like airway inflammation in a k-ras–induced mouse model, Am. J. Respir. Cell Mol. Biol., 40, 443, 10.1165/rcmb.2008-0198OC

Meira, 2008, DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice, J. Clin. Investig., 118, 2516

Caetano, 2016, Il6 blockade reprograms the lung tumor microenvironment to limit the development and progression of k-ras-mutant lung cancer, Cancer Res., 76, 3189, 10.1158/0008-5472.CAN-15-2840

Sansone, 2007, Il-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland, J. Clin. Investig., 117, 3988, 10.1172/JCI32533

Wang, 2014, Nf-κB functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells, Cell Rep., 9, 90, 10.1016/j.celrep.2014.08.049

Wang, 2002, Nf-κB2 p100 is a pro-apoptotic protein with anti-oncogenic function, Nat. Cell Biol., 4, 888, 10.1038/ncb872

Jacque, 2013, Relb inhibits cell proliferation and tumor growth through p53 transcriptional activation, Oncogene, 32, 2661, 10.1038/onc.2012.282

Pierron, 2016, Nf-κB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2, Oncogene, 35, 2813, 10.1038/onc.2015.468

Wang, 2016, Tumor-suppressor NfκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of mir-494, Oncogene, 35, 4080, 10.1038/onc.2015.470

Xiao, 2013, The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas, Cancer Cell, 23, 527, 10.1016/j.ccr.2013.03.009

Xie, 2015, IκB kinase α functions as a tumor suppressor in epithelial-derived tumors through an NF-κB-independent pathway (review), Oncol. Rep., 34, 2225, 10.3892/or.2015.4229

Song, 2018, IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways, Proc. Natl. Acad. Sci. USA, 115, E812, 10.1073/pnas.1717520115

Lawrence, 2005, IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation, Nature, 434, 1138, 10.1038/nature03491

Liu, 2011, IKKα represses a network of inflammation and proliferation pathways and elevates c-myc antagonists and differentiation in a dose-dependent manner in the skin, Cell Death Differ., 18, 1854, 10.1038/cdd.2011.56

Li, 2013, Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice, J. Clin. Investig., 123, 2231, 10.1172/JCI64498

Liu, 2007, Proinflammatory stimuli induce IKKα-mediated phosphorylation of pias1 to restrict inflammation and immunity, Cell, 129, 903, 10.1016/j.cell.2007.03.056

Yang, 2010, Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation, Am. J. Pathol., 176, 2646, 10.2353/ajpath.2010.090751

Natoli, 2006, Shaping alternative NF-κB-dependent gene expression programs: New clues to specificity, Cell Death Differ., 13, 693, 10.1038/sj.cdd.4401880

Wang, 2012, The transcriptional specificity of NF-κB dimers is coded within the κB DNA response elements, Cell Rep., 2, 824, 10.1016/j.celrep.2012.08.042

Kolovos, 2016, Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response, Genome Res., 26, 1478, 10.1101/gr.210005.116

Dejardin, 2002, The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways, Immunity, 17, 525, 10.1016/S1074-7613(02)00423-5

Jin, 2012, The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling, Nat. Immunol., 13, 1101, 10.1038/ni.2423

Bren, 2001, Transcription of the relb gene is regulated by NF-κB, Oncogene, 20, 7722, 10.1038/sj.onc.1204868

Jacque, 2005, Rela repression of relb activity induces selective gene activation downstream of tnf receptors, Proc. Natl. Acad. Sci. USA, 102, 14635, 10.1073/pnas.0507342102

Madge, 2010, Classical NF-κB activation negatively regulates noncanonical NF-κB-dependent cxcl12 expression, J. Biol. Chem., 285, 38069, 10.1074/jbc.M110.147207

Ramakrishnan, 2004, Receptor-specific signaling for both the alternative and the canonical NF-κB activation pathways by NF-κB-inducing kinase, Immunity, 21, 477, 10.1016/j.immuni.2004.08.009

Lam, 2008, Compensatory IKKα activation of classical NF-κB signaling during IKKβ inhibition identified by an RNA interference sensitization screen, Proc. Natl. Acad. Sci. USA, 105, 20798, 10.1073/pnas.0806491106

Shembade, 2011, The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule tax1bp1, Nat. Immunol., 12, 834, 10.1038/ni.2066

Pelzer, 2011, IKKα takes control of canonical NF-κB activation, Nat. Immunol., 12, 815, 10.1038/ni.2082

Gloire, 2007, Promoter-dependent effect of IKKα on NF-κB/p65 DNA binding, J. Biol. Chem., 282, 21308, 10.1074/jbc.M610728200

Araki, 2008, IKK/Nf-κB signaling pathway inhibits cell-cycle progression by a novel rb-independent suppression system for E2F transcription factors, Oncogene, 27, 5696, 10.1038/onc.2008.184

Sfikas, 2012, The canonical NF-κB pathway differentially protects normal and human tumor cells from ros-induced DNA damage, Cell. Signal., 24, 2007, 10.1016/j.cellsig.2012.06.010

Batsi, 2009, Chronic NF-κB activation delays rasv12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response, Mech. Ageing Dev., 130, 409, 10.1016/j.mad.2009.04.002

Guttridge, 1999, NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin d1, Mol. Cell Biol., 19, 5785, 10.1128/MCB.19.8.5785

Park, 2005, Formation of an IKKα-dependent transcription complex is required for estrogen receptor-mediated gene activation, Mol. Cell, 18, 71, 10.1016/j.molcel.2005.03.006

Hu, 2004, IκB kinase promotes tumorigenesis through inhibition of forkhead foxo3a, Cell, 117, 225, 10.1016/S0092-8674(04)00302-2

Chiu, 2016, NF-κB-driven suppression of foxo3a contributes to egfr mutation-independent gefitinib resistance, Proc. Natl. Acad. Sci. USA, 113, E2526, 10.1073/pnas.1522612113

Zazzeroni, 2001, Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling, Nature, 414, 308, 10.1038/35104560

Papa, 2004, Gadd45β mediates the Nf-κB suppression of JNK signalling by targeting MKK7/JNKK2, Nat. Cell Biol., 6, 146, 10.1038/ncb1093

Chang, 2005, Enhanced G2-M arrest by nuclear factor- κB-dependent p21waf1/cip1 induction, Mol. Cancer Res., 3, 345, 10.1158/1541-7786.MCR-05-0028

Chang, 2006, Nuclear factor-κB dimer exchange promotes a p21waf1/cip1 superinduction response in human T leukemic cells, Mol. Cancer Res., 4, 101, 10.1158/1541-7786.MCR-05-0259

Batsi, 2009, Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(kip1)-dependent g1/s cell cycle arrest in conjunction with NF-κB activation, Biochem. Pharmacol., 78, 33, 10.1016/j.bcp.2009.03.017

Julien, 2007, Activation of NF-κB by akt upregulates snail expression and induces epithelium mesenchyme transition, Oncogene, 26, 7445, 10.1038/sj.onc.1210546

Schmidt, 2007, Critical role for nf-κB-induced junb in vegf regulation and tumor angiogenesis, EMBO J., 26, 710, 10.1038/sj.emboj.7601539

Min, 2008, NF-κB and epithelial to mesenchymal transition of cancer, J. Cell Biochem., 104, 733, 10.1002/jcb.21695

Yan, 2007, Regulation of matrix metalloproteinase gene expression, J. Cell Physiol., 211, 19, 10.1002/jcp.20948

Clark, 2008, The regulation of matrix metalloproteinases and their inhibitors, Int. J. Biochem. Cell Biol., 40, 1362, 10.1016/j.biocel.2007.12.006

Folgueras, 2010, Matrix metalloproteinases: Evolution, gene regulation and functional analysis in mouse models, Biochim. Biophys. Acta, 1803, 3, 10.1016/j.bbamcr.2009.07.004

Parks, 2004, Matrix metalloproteinases as modulators of inflammation and innate immunity, Nat. Rev. Immunol., 4, 617, 10.1038/nri1418

Fingleton, 2017, Matrix metalloproteinases as regulators of inflammatory processes, Biochim. Biophys. Acta, 1864, 2036, 10.1016/j.bbamcr.2017.05.010

Fong, 1996, Timp1 and adverse prognosis in non-small cell lung cancer, Clin. Cancer Res., 2, 1369

Aljada, 2004, Upregulation of the tissue inhibitor of metalloproteinase-1 protein is associated with progression of human non-small-cell lung cancer, J. Clin. Oncol., 22, 3218, 10.1200/JCO.2004.02.110

Rius, 2008, NF-κB links innate immunity to the hypoxic response through transcriptional regulation of hif-1α, Nature, 453, 807, 10.1038/nature06905

D’Ignazio, L., Batie, M., and Rocha, S. (2017). Hypoxia and inflammation in cancer, focus on hif and NF-κB. Biomedicines, 5.

Bandarra, 2015, Hif-1α restricts NF-κB-dependent gene expression to control innate immunity signals, Dis. Models Mech., 8, 169

Triner, 2016, Hypoxia-inducible factors: A central link between inflammation and cancer, J. Clin. Investig., 126, 3689, 10.1172/JCI84430

Bandarra, 2016, NF-κB and hif crosstalk in immune responses, FEBS J., 283, 413, 10.1111/febs.13578

Triner, D., Xue, X., Schwartz, A.J., Jung, I., Colacino, J.A., and Shah, Y.M. (2017). Epithelial hypoxia-inducible factor 2α facilitates the progression of colon tumors through recruiting neutrophils. Mol. Cell Biol., 37.

Hunter, 2015, The Nf-κB subunit c-rel regulates bach2 tumour suppressor expression in b-cell lymphoma, Oncogene, 35, 3476, 10.1038/onc.2015.399

Hunter, 2016, C-rel and its many roles in cancer: An old story with new twists, Br. J. Cancer, 114, 1, 10.1038/bjc.2015.410

Rocha, 2003, P53-and mdm2-independent repression of Nf-κB transactivation by the arf tumor suppressor, Mol. Cell, 12, 15, 10.1016/S1097-2765(03)00223-5

Campbell, 2004, Active repression of antiapoptotic gene expression by RelA (p65) Nf-κB, Mol. Cell, 13, 853, 10.1016/S1097-2765(04)00131-5

Campbell, 2006, Cisplatin mimics arf tumor suppressor regulation of RelA (p65) nuclear factor-κB transactivation, Cancer Res., 66, 929, 10.1158/0008-5472.CAN-05-2234

Msaki, 2011, The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration, Mol. Biol. Cell, 22, 3032, 10.1091/mbc.e11-04-0280

Perkins, 2015, The importance of the p50 Nf-κB subunit, Cell Cycle, 14, 2877, 10.1080/15384101.2015.1010952

Moles, 2016, A RelA(p65) thr505 phospho-site mutation reveals an important mechanism regulating Nf-κB-dependent liver regeneration and cancer, Oncogene, 35, 4623, 10.1038/onc.2015.526

Klapproth, 2009, The IKK2/Nf-κB pathway suppresses myc-induced lymphomagenesis, Blood, 114, 2448, 10.1182/blood-2008-09-181008

Cao, 2006, Nf-κB1 (p50) homodimers differentially regulate pro-and anti-inflammatory cytokines in macrophages, J. Biol. Chem., 281, 26041, 10.1074/jbc.M602222200

Wang, 2009, Nf-κB p50 regulates c/ebpα expression and inflammatory cytokine-induced neutrophil production, J. Immunol., 182, 5757, 10.4049/jimmunol.0803861

Elsharkawy, 2010, The Nf-κB p50: P50: Hdac-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes, J. Hepatol., 53, 519, 10.1016/j.jhep.2010.03.025

Voce, 2015, NFKB1 is a haploinsufficient DNA damage-specific tumor suppressor, Oncogene, 34, 2807, 10.1038/onc.2014.211

Wilson, 2015, NfκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma, Nat. Commun., 6, 6818, 10.1038/ncomms7818

Shomer, 2015, Kpc1-mediated ubiquitination and proteasomal processing of Nf-κB1 p105 to p50 restricts tumor growth, Cell, 161, 333, 10.1016/j.cell.2015.03.001

Martin, 2014, IKKα negatively regulates asc-dependent inflammasome activation, Nat. Commun., 5, 4977, 10.1038/ncomms5977

Xiao, 2015, Opposed expression of IKKα: Loss in keratinizing carcinomas and gain in non-keratinizing carcinomas, Oncotarget, 6, 25499, 10.18632/oncotarget.4548

Esteller, 2011, Non-coding RNAs in human disease, Nat. Rev. Genet., 12, 861, 10.1038/nrg3074

Georgakilas, 2015, Diana-mirgen v3. 0: Accurate characterization of microRNA promoters and their regulators, Nucleic Acids Res., 44, D190, 10.1093/nar/gkv1254

Niu, 2012, DNA damage induces Nf-κB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion, J. Biol. Chem., 287, 21783, 10.1074/jbc.M112.355495

Ma, 2014, NF-κB-dependent microRNA-425 upregulation promotes gastric cancer cell growth by targeting PTEN upon il-1β induction, Mol. Cancer, 13, 40, 10.1186/1476-4598-13-40

Takata, 2013, MicroRNA-140 acts as a liver tumor suppressor by controlling Nf-κB activity by directly targeting DNA methyltransferase 1 (dnmt1) expression, Hepatology, 57, 162, 10.1002/hep.26011

Takata, 2011, MicroRNA-22 and microRNA-140 suppress Nf-κB activity by regulating the expression of Nf-κB coactivators, Biochem. Biophys. Res. Commun., 411, 826, 10.1016/j.bbrc.2011.07.048

Huan, 2016, Role of microRNAs in inflammation-associated liver cancer, Cancer Biol Med., 13, 407, 10.20892/j.issn.2095-3941.2016.0071

Nagel, 2007, Regulation of the p27(kip1) tumor suppressor by mir-221 and mir-222 promotes cancer cell proliferation, EMBO J., 26, 3699, 10.1038/sj.emboj.7601790

Voorhoeve, 2007, Classifying microRNAs in cancer: The good, the bad and the ugly, Biochim. Biophys. Acta, 1775, 274

Kedde, 2010, A pumilio-induced RNA structure switch in p27-3′ utr controls mir-221 and mir-222 accessibility, Nat. Cell Biol., 12, 1014, 10.1038/ncb2105

Karagkouni, 2017, DIANA-TarBase v8: A decade-long collection of experimentally supported miRNA–gene interactions, Nucleic Acids Res., 46, D239, 10.1093/nar/gkx1141

Yin, 2015, Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting Nf-κB p65 to evoke reactive oxygen species generation and p53 activation, Oncogene, 34, 691, 10.1038/onc.2013.597

Kong, 2015, Tumor-suppressive microRNA-497 targets IKKβ to regulate Nf-κB signaling pathway in human prostate cancer cells, Am. J. Cancer Res., 5, 1795

Keklikoglou, 2012, MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting Nf-κB and TGF-β signaling pathways, Oncogene, 31, 4150, 10.1038/onc.2011.571

Iliopoulos, 2009, An epigenetic switch involving Nf-κB, lin28, let-7 microRNA, and il6 links inflammation to cell transformation, Cell, 139, 693, 10.1016/j.cell.2009.10.014

Iliopoulos, 2010, Stat3 activation of mir-21 and mir-181b-1 via PTEN and cyld are part of the epigenetic switch linking inflammation to cancer, Mol. Cell, 39, 493, 10.1016/j.molcel.2010.07.023

Olarerin-George, A.O., Anton, L., Hwang, Y.-C., Elovitz, M.A., and Hogenesch, J.B. (2013). A functional genomics screen for microRNA regulators of NF-κB signaling. BMC Biol., 11.

Feng, X., Wang, H., Ye, S., Guan, J., Tan, W., Cheng, S., Wei, G., Wu, W., Wu, F., and Zhou, Y. (2012). Up-regulation of microRNA-126 may contribute to pathogenesis of ulcerative colitis via regulating NF-κB inhibitor iκBα. PLoS ONE, 7.

Huang, 2016, Mir-126: A novel regulator in colon cancer, Biomed. Rep., 4, 131, 10.3892/br.2015.549

Zhou, 2018, MicroRNA-223 suppresses the canonical NF-κB pathway in basal keratinocytes to dampen neutrophilic inflammation, Cell Rep., 22, 1810, 10.1016/j.celrep.2018.01.058

Haneklaus, 2013, Mir-223: Infection, inflammation and cancer, J. Intern. Med., 274, 215, 10.1111/joim.12099

Chen, Q., Wang, H., Liu, Y., Song, Y., Lai, L., Han, Q., Cao, X., and Wang, Q. (2012). Inducible microRNA-223 down-regulation promotes tlr-triggered il-6 and il-1β production in macrophages by targeting stat3. PLoS ONE, 7.

Li, 2010, MicroRNAs modulate the noncanonical transcription factor NF-κB pathway by regulating expression of the kinase IKKα during macrophage differentiation, Nat. Immunol., 11, 799, 10.1038/ni.1918

Li, 2011, Mir-223 regulates migration and invasion by targeting artemin in human esophageal carcinoma, J. Biomed. Sci., 18, 24, 10.1186/1423-0127-18-24

Li, 2011, MiRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor epb41l3, Mol. Cancer Res., 9, 824, 10.1158/1541-7786.MCR-10-0529

Tang, 2015, Mir-223 inhibited cell metastasis of human cervical cancer by modulating epithelial-mesenchymal transition, Int. J. Clin. Exp. Pathol., 8, 11224

Aqeilan, 2009, Mir-15a and mir-16-1 in cancer: Discovery, function and future perspectives, Cell Death Differ., 17, 215, 10.1038/cdd.2009.69

Chen, 2008, Regulation of IKKβ by mir-199a affects Nf-κB activity in ovarian cancer cells, Oncogene, 27, 4712, 10.1038/onc.2008.112

Zhao, 2011, Nf-κB dysregulation in microRNA-146a—Deficient mice drives the development of myeloid malignancies, Proc. Natl. Acad. Sci. USA, 108, 9184, 10.1073/pnas.1105398108

Bazzoni, 2009, Induction and regulatory function of mir-9 in human monocytes and neutrophils exposed to proinflammatory signals, Proc. Natl. Acad. Sci. USA, 106, 5282, 10.1073/pnas.0810909106

Guo, 2009, MicroRNA-9 inhibits ovarian cancer cell growth through regulation of Nf-κB1, FEBS J., 276, 5537, 10.1111/j.1742-4658.2009.07237.x

Liu, 2010, Sp1/NFκB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia, Cancer Cell, 17, 333, 10.1016/j.ccr.2010.03.008

Li, 2010, Involvement of Nf-κB/mir-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells, Cell Death Differ., 18, 16, 10.1038/cdd.2010.103

Kumar, 2008, Suppression of non-small cell lung tumor development by the let-7 microRNA family, Proc. Natl. Acad. Sci. USA, 105, 3903, 10.1073/pnas.0712321105

Iliopoulos, 2014, MicroRNA circuits regulate the cancer-inflammation link, Sci. Signal., 7, pe8, 10.1126/scisignal.2005053

Xiang, 2014, Stat3 induction of mir-146b forms a feedback loop to inhibit the Nf-κB to il-6 signaling axis and stat3-driven cancer phenotypes, Sci. Signal., 7, ra11, 10.1126/scisignal.2004497

Jeong, 2017, A constitutive intrinsic inflammatory signaling circuit composed of mir-196b, Meis2, PPP3CC, and p65 drives prostate cancer castration resistance, Mol. Cell, 65, 154, 10.1016/j.molcel.2016.11.034

Papadopoulos, 2009, Diana-mirpath: Integrating human and mouse microRNAs in pathways, Bioinformatics, 25, 1991, 10.1093/bioinformatics/btp299