Hepatocyte Necrosis Induced by Oxidative Stress and IL-1α Release Mediate Carcinogen-Induced Compensatory Proliferation and Liver Tumorigenesis

Abstract

SUMMARY Hepatocyte IκB kinase β (IKKβ) inhibits hepatocarcinogenesis by suppressing accumulation of reactive oxygen species (ROS) and liver damage, whereas JNK1 activation promotes ROS accumulation, liver damage and carcinogenesis. We examined whether hepatocyte p38α, found to inhibit liver carcinogenesis, acts similarly to IKKβ in control of ROS metabolism and cell death. Hepatocyte-specific p38α ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant. In addition to elevated ROS accumulation, hepatocyte death, augmented by loss of either IKKβ or p38α, was associated with release of IL-1α. Inhibition of IL-1α action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1α release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

“…37 Oxidative stress exerts many pro-tumorigenic effects, such as altered gene expression, enhanced proliferation, high DNA mutation rates, as well as genomic instability. 38 Importantly, administration of antioxidants and selenium compounds to Mdr2 Ϫ/Ϫ mice reduced tumor incidence and growth by inhibition of mediators that control inflammation and response to oxidative stress. 39 In addition to induced ROS production in cells with ectopic S100A8 and S100A9 expression, we found reduced phosphorylation of the p38 MAPK in comparison with mock controls.…”

“…and S100A9 interfere with p38 MAPK activity and thereby cause ROS production, as has been demonstrated in liver-specific p38␣ knockout mice. 38 Detailed analysis will be required to unravel the exact molecular mechanism; however, p38␣ has already been shown to suppress normal and cancer cell proliferation by antagonizing the c-Jun N-terminal kinase/cJun pathway. 41 In addition, we demonstrated that HCC cell lines with ectopic expression of S100A8 and S100A9 were almost resistant against TNF-␣-induced apoptosis.…”

MAPK signaling in inflammation-associated cancer development

“…Two recent reports using conditional p38α mice indicate that p38α suppresses inflammation-associated liver cancer development (Hui et al, 2007a;Sakurai et al, 2008). In the HCC model used in these studies, carcinogen treatment initiates a wide-range of cell death and tissue repair, similar to the acute phase of hepatitis.…”

“…p38α was found to suppress proliferation of tumor cells via antagonizing of the JNK-c-Jun pathway (Hui et al, 2007a). Alternatively, it has been proposed that p38α can alleviate ROS accumulation and liver damage, thus attenuate proliferation of initial tumor cells in this inflammatory scenario (Sakurai et al, 2008). The tumor suppressive role of p38 has been demonstrated in lung cancer development.…”

The enigmatic processing and secretion of interleukin-33

“…11,[53][54][55] As with an alarmin such as high mobility group protein-1, release of IL-1a by necrotic cells is supposed to be the major route of its production. 33,[42][43][44]56,57 Therefore, IL-33 release might resemble that of pro-IL-1a and high mobility group protein-1. Lüthi et al have confirmed that IL-33 is not a substrate of inflammatory caspase-1, -4 and -5 and can be released by necrotic cells without being inactivated.…”