title: IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression.
abstract: Proinflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/S111, thereby suppressing FOXA2 transactivation activity and leading to decreased NUMB expression, and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report a TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Liu
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Hong-Jen
authors.initials: HJ
authors.lastname: Lee
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Wei
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chiu
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Yi
authors.initials: Y
authors.lastname: Du
authors.forename: Debanjan
authors.initials: D
authors.lastname: Dhar
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C496502:FOXA2 protein, human; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D051550:I-kappa B Kinase