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

doi:10.1016/j.molcel.2011.11.018

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

Molecular & Cellular Oncology

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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 language	English (US)
Pages (from-to)	171-184
Number of pages	14
Journal	Molecular cell
Volume	45
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2011.11.018
State	Published - Jan 27 2012

ASJC Scopus subject areas

Molecular Biology
Cell Biology

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility

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10.1016/j.molcel.2011.11.018

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Liu, M., Lee, D. F., Chen, C. T., Yen, C. J., Li, L. Y., Lee, H. J., Chang, C. J., Chang, W. C., Hsu, J. M., Kuo, H. P., Xia, W., Wei, Y., Chiu, P. C., Chou, C. K., Du, Y., Dhar, D., Karin, M., Chen, C. H., & Hung, M. C. (2012). IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression. Molecular cell, 45(2), 171-184. https://doi.org/10.1016/j.molcel.2011.11.018

@article{626cc8d12ba24c5dac4c58a0192c62a8,

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.",

author = "Mo Liu and Lee, {Dung Fang} and Chen, {Chun Te} and Yen, {Chia Jui} and Li, {Long Yuan} and Lee, {Hong Jen} and Chang, {Chun Ju} and Chang, {Wei Chao} and Hsu, {Jung Mao} and Kuo, {Hsu Ping} and Weiya Xia and Yongkun Wei and Chiu, {Pei Chun} and Chou, {Chao Kai} and Yi Du and Debanjan Dhar and Michael Karin and Chen, {Chung Hsuan} and Hung, {Mien Chie}",

note = "Funding Information: We thank S. Zhang, J. Shi, B. Spohn, J.-F. Lee, and Z. Han for their technical support. This work was partially supported by the National Institutes of Health (NIH) (R01 CA109311, P01 CA099031, and MD Anderson's Cancer Center Support Grant, CA016672); NHRI-EX100-9603BC, NSC100-2325-B-039-003, and DOH99-TD-I-111-TM026 (to L.-Y.L.); The University of Texas MD Anderson Cancer Center–China Medical University and Hospital Sister Institution Fund; The Kadoorie Charitable Foundation; NSC99-2632-001-MY3; DOH100-TD-C-111-005; and a research assistant scholarship from the University of Texas Graduate School of Biomedical Sciences at Houston to M.L. We thank Dr. Karen Muller for scientific editing of our manuscript. ",

year = "2012",

month = jan,

day = "27",

doi = "10.1016/j.molcel.2011.11.018",

language = "English (US)",

volume = "45",

pages = "171--184",

journal = "Molecular cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression

AU - Liu, Mo

AU - Lee, Dung Fang

AU - Chen, Chun Te

AU - Yen, Chia Jui

AU - Li, Long Yuan

AU - Lee, Hong Jen

AU - Chang, Chun Ju

AU - Chang, Wei Chao

AU - Hsu, Jung Mao

AU - Kuo, Hsu Ping

AU - Xia, Weiya

AU - Wei, Yongkun

AU - Chiu, Pei Chun

AU - Chou, Chao Kai

AU - Du, Yi

AU - Dhar, Debanjan

AU - Karin, Michael

AU - Chen, Chung Hsuan

AU - Hung, Mien Chie

N1 - Funding Information: We thank S. Zhang, J. Shi, B. Spohn, J.-F. Lee, and Z. Han for their technical support. This work was partially supported by the National Institutes of Health (NIH) (R01 CA109311, P01 CA099031, and MD Anderson's Cancer Center Support Grant, CA016672); NHRI-EX100-9603BC, NSC100-2325-B-039-003, and DOH99-TD-I-111-TM026 (to L.-Y.L.); The University of Texas MD Anderson Cancer Center–China Medical University and Hospital Sister Institution Fund; The Kadoorie Charitable Foundation; NSC99-2632-001-MY3; DOH100-TD-C-111-005; and a research assistant scholarship from the University of Texas Graduate School of Biomedical Sciences at Houston to M.L. We thank Dr. Karen Muller for scientific editing of our manuscript.

PY - 2012/1/27

Y1 - 2012/1/27

N2 - 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.

AB - 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.

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U2 - 10.1016/j.molcel.2011.11.018

DO - 10.1016/j.molcel.2011.11.018

M3 - Article

C2 - 22196886

AN - SCOPUS:84856264859

SN - 1097-2765

VL - 45

SP - 171

EP - 184

JO - Molecular cell

JF - Molecular cell

IS - 2

ER -

IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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