Sci. STKE, 12 July 2005
CANCER BIOLOGY Compensating for Damage Leads to Tumorigenesis
Environmental pollutants, hepatic viruses, and cirrhosis, each of which can trigger chronic liver inflammation, are risk factors for hepatocellular carcinoma (HCC), liver cancer. Maeda et al. investigated HCC in mice deficient for IKKβ [a kinase that is part of the IKK (inhibitor of nuclear factor B kinase) complex that is required for activation of nuclear factor B (NF-B)] in either hepatocytes (Ikkβhep) or hepatocytes and hematopoetic-derived Kupffer cells IkkβL+H. Ikkβhep mice exhibited increased HCC tumor potential, tumor size, and tumor metastases, following exposure to the chemical carcinogen diethylnitrosamine (DEN) in young and adult mice compared with control mice, whereas IkkβL+H mice showed decreased incidence and size of HCC tumors. DEN exposure stimulated c-Jun N-terminal kinase (JNK) and IKK in control mouse livers, and JNK activation was increased in magnitude and duration in the livers from Ikkβhep mice. NF-B was activated in both hepatocytes and nonhepatocytes in the control livers, whereas it was only activated in the nonhepatocytes in the Ikkβhep livers. The tumors of the Ikkβhep mice exhibited increased abundance of proteins associated with cell proliferation, with c-Myc showing the largest increase compared with normal tissue from control or Ikkβhep mice. Prolonged JNK activation in the Ikkβhep mouse livers was prevented by feeding the mice butylated hydroxyanisole (BHA), an antioxidant--loss of NF-B leads to enhanced reactive oxygen species accumulation, which stimulates JNK. In addition, BHA reduced the level of liver injury (measured as circulating liver enzymes, which are indicative of liver damage). BHA also reduced the number and size of tumors in DEN-treated Ikkβhep mice. The IkkβL+H mouse livers showed a decrease in cytokine mRNA, whereas the livers from the Ikkβhep mice showed an increase in hepatomitogens following DEN exposure. These results suggest that loss of NF-B signaling in only hepatocytes triggers cell death and a compensatory proliferation response mediated by hepatomitogens, which are increased in response to NF-B signaling in the Kupffer cells. Thus, inflammatory cross talk between the hepatocytes and the Kupffer cells is a critical factor in HCC development.
S. Maeda, H. Kamata, J.-L. Luo, H. Leffert, M. Karin, IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990 (2005). [PubMed]
Citation: Compensating for Damage Leads to Tumorigenesis. Sci. STKE 2005, tw250 (2005).
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