TY - JOUR
T1 - Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation
AU - He, Guobin
AU - Yu, Guann Yi
AU - Temkin, Vladislav
AU - Ogata, Hisanobu
AU - Kuntzen, Christian
AU - Sakurai, Toshiharu
AU - Sieghart, Wolfgang
AU - Peck-Radosavljevic, Markus
AU - Leffert, Hyam L.
AU - Karin, Michael
N1 - Funding Information:
We thank David Levy for providing Stat3 Δhep mice. G.H. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation and G.Y.Y was supported by an American Diabetes Association Postdoctoral research grant to M.K. V.T., H.O., and C.K. were supported by Arthritis Foundation Research Fellowship, Kanzawa Medical Research Foundation, and American Institute for Cancer Research Fellowship, respectively. Research was supported by grants from the National Institutes of Health (ES006376, CA113602, and CA118165) and the Superfund Basic Research Program (P42ES010337). M.K. is an American Cancer Society Research Professor.
PY - 2010/3/16
Y1 - 2010/3/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2009.12.048
DO - 10.1016/j.ccr.2009.12.048
M3 - Article
C2 - 20227042
AN - SCOPUS:74549217325
SN - 1535-6108
VL - 17
SP - 286
EP - 297
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
