title: MiR-26 down-regulates TNF-α/NF-κB signalling and IL-6 expression by silencing HMGA1 and MALT1.
abstract: MiR-26 has emerged as a key tumour suppressor in various cancers. Accumulating evidence supports that miR-26 regulates inflammation and tumourigenicity largely through down-regulating IL-6 production, but the underlying mechanism remains obscure. Here, combining a transcriptome-wide approach with manipulation of cellular miR-26 levels, we showed that instead of directly targeting IL-6 mRNA for gene silencing, miR-26 diminishes IL-6 transcription activated by TNF-α through silencing NF-κB signalling related factors HMGA1 and MALT1. We demonstrated that miR-26 extensively dampens the induction of many inflammation-related cytokine, chemokine and tissue-remodelling genes that are activated via NF-κB signalling pathway. Knocking down both HMGA1 and MALT1 by RNAi had a silencing effect on NF-κB-responsive genes similar to that caused by miR-26. Moreover, we discovered that poor patient prognosis in human lung adenocarcinoma is associated with low miR-26 and high HMGA1 or MALT1 levels and not with levels of any of them individually. These new findings not only unravel a novel mechanism by which miR-26 dampens IL-6 production transcriptionally but also demonstrate a direct role of miR-26 in down-regulating NF-κB signalling pathway, thereby revealing a more critical and broader role of miR-26 in inflammation and cancer than previously realized.
authors.affiliation: Department of Biochemistry and Molecular Biology, McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Chyi-Ying A
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, Houston, TX 77030, USA School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Ho
authors.affiliation: Department of Biochemistry and Molecular Biology, McGovern Medical School, Houston, TX 77030, USA Ann-Bin.Shyu@uth.tmc.edu.
authors.forename: Ann-Bin
authors.initials: AB
authors.lastname: Shyu
mesh_terms: D020413:3' Untranslated Regions; D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation; D020868:Gene Silencing; D025741:HMGA1a Protein / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D020169:Caspases; D025741:HMGA1a Protein; D015850:Interleukin-6; D035683:MicroRNAs; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; C508600:IL6 protein, human; C528163:MIRN26 microRNA, human; C400109:MALT1 protein, human