1. Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation
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Michael Karin, Wolfgang Sieghart, Vladislav Temkin, Toshiharu Sakurai, Hyam L. Leffert, Christian Kuntzen, Guobin He, Markus Peck-Radosavljevic, Hisanobu Ogata, and Guann-Yi Yu
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Male ,STAT3 Transcription Factor ,Transcriptional Activation ,medicine.medical_specialty ,Cancer Research ,medicine.disease_cause ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,STAT3 ,030304 developmental biology ,0303 health sciences ,biology ,Kinase ,Liver Neoplasms ,NF-kappa B ,NF-κB ,Cell Biology ,medicine.disease ,NFKB1 ,digestive system diseases ,3. Good health ,I-kappa B Kinase ,Mice, Inbred C57BL ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Oncology ,030220 oncology & carcinogenesis ,Hepatocyte ,Cancer research ,biology.protein ,Hepatocytes ,Tumor promotion ,Liver cancer ,Oxidative stress ,Gene Deletion - Abstract
The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta'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 IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB 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-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.
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