IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression

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

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)171-184
Number of pages14
JournalMolecular Cell
Volume45
Issue number2
DOIs
Publication statusPublished - 2012 Jan 27

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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