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IKK? activation of NOTCH links tumorigenesis via FOXA2 suppression.

ABSTRACT: Proinflammatory cytokine TNF? plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNF?-mediated tumor development remains unclear. Here, we show that IKK?, an important downstream kinase of TNF?, 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 IKK?, 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 IKK? and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNF?/IKK?-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report a TNF?/IKK?/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.

SUBMITTER: Liu M

PROVIDER: S-EPMC3268914 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression.

Liu Mo M Lee Dung-Fang DF Chen Chun-Te CT Yen Chia-Jui CJ Li Long-Yuan LY Lee Hong-Jen HJ Chang Chun-Ju CJ Chang Wei-Chao WC Hsu Jung-Mao JM Kuo Hsu-Ping HP Xia Weiya W Wei Yongkun Y Chiu Pei-Chun PC Chou Chao-Kai CK Du Yi Y Dhar Debanjan D Karin Michael M Chen Chung-Hsuan CH Hung Mien-Chie MC

Molecular cell 20111222 2

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 cel ...[more]

PMID: 22196886

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IKK? activation of NOTCH links tumorigenesis via FOXA2 suppression.

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IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression.

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