Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation

Guobin He, Guann Yi Yu, Vladislav Temkin, Hisanobu Ogata, Christian Kuntzen, Toshiharu Sakurai, Wolfgang Sieghart, Markus Peck-Radosavljevic, Hyam L. Leffert, Michael Karin

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294 Citations (Scopus)

Abstract

The NF-κB activating kinase IKKβ suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKβ's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKβ long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKβ/NF-κB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-κB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.

Original languageEnglish
Pages (from-to)286-297
Number of pages12
JournalCancer Cell
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 16 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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    He, G., Yu, G. Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavljevic, M., Leffert, H. L., & Karin, M. (2010). Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation. Cancer Cell, 17(3), 286-297. https://doi.org/10.1016/j.ccr.2009.12.048