title: NF-κB signaling relieves negative regulation by miR-194 in hepatocellular carcinoma by suppressing the transcription factor HNF-1α.
abstract: Constitutive activation of the proinflammatory transcription factor nuclear factor κB (NF-κB) plays an important role in progression of hepatocellular carcinoma (HCC). Emerging modulators of NF-κB signaling are noncoding RNAs, especially microRNAs (miRNAs). We previously identified miRNAs that reduced the induction of NF-κB activity upon addition of tumor necrosis factor-α (TNFα) to HCC cells. We found that among these miRNAs, the abundance of liver-enriched miR-194 was decreased in HCC tissue and that low abundance of miR-194 correlated with a high occurrence of vascular invasion. Overexpressing miR-194 suppressed HCC cell migration and invasiveness in culture and metastatic seeding in mice. Transcripts encoding tripartite motif containing 23 (TRIM23), a ubiquitin ligase involved in NF-κB activation, and chromosome 21 open reading frame 91 (C21ORF91), a protein of unknown function, were identified as direct targets of miR-194 in HCC cells; knocking down either protein decreased the activity of a luciferase NF-κB reporter. Furthermore, the NF-κB pathway activator TNFα, an inflammatory cytokine, inhibited the transcription of miR-194 by decreasing the abundance of hepatocyte nuclear factor-1α (HNF-1α). The abundance of miR-194 positively correlated with that of HNF-1α and inversely correlated with that of TNFα in human HCC tissue. Thus, we identified a pathway in which TNFα-NF-κB signaling switches off negative regulation by suppressing HNF-1α-mediated expression of miR-194, revealing insight into the mechanisms linking inflammatory pathways, miRNA, and HCC metastasis.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Huan
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Yuannv
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Linhui
authors.initials: L
authors.lastname: Liang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, China.
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. xhhe@fudan.edu.cn slhuang@fudan.edu.cn.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. xhhe@fudan.edu.cn slhuang@fudan.edu.cn.
authors.forename: Xianghuo
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm