IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression

• DOI: 10.1016/j.molcel.2011.11.018
• Publication Date: 2011-12-22T10:59:57Z
• Authors: Mo Liu; Dung-Fang Lee; Chun-Te Chen; Chia-Jui Yen; Long-Yuan Li; Hong-Jen Lee; Chun-Ju Chang; Wei-Chao Chang; Jung-Mao Hsu; Hsu-Ping Kuo; Weiya Xia; Yongkun Wei; Pei-Chun Chiu; Chao-Kai Chou; Yi Du; Debanjan Dhar; Michael Karin; Chung-Hsuan Chen; Mien-Chie Hung
• Keywords: 0303 health sciences; Carcinoma, Hepatocellular; Tumor Necrosis Factor-alpha; Liver Neoplasms; Membrane Proteins; Nerve Tissue Proteins; Cell Biology; Models, Biological; I-kappa B Kinase; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Liver Neoplasms, Experimental; Hepatocyte Nuclear Factor 3-beta; Animals; Humans; Phosphorylation; Receptor, Notch1; Molecular Biology; Cell Proliferation; Signal Transduction

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.