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Background & Aims: Although there are associations among oxidative stress, NADPH oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice following administration of a liver carcinogen. Methods: Fourteen-day-old Nox1−/− mice, Nox4−/– mice, Nox1−/−; Nox4−/− (double knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1ΔHep), hepatic stellate cells (Nox1ΔHep), or macrophage (Nox1ΔMac). Some mice were also given injections of the NOX1 specific inhibitor ML171. To study the acute effects of DEN, 8–12 week old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hrs. Liver tissues were analyzed by histology, quantitative PCR, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots. Results: Nox4−/− mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1−/− mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1ΔHep and Nox1ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1ΔMac developed fewer, smaller tumors, similar to Nox1−/− mice. Following DEN injection, levels of tumor necrosis factor (TNF), interleukin 6 (IL6) and phosphorylated STAT3 were increased in livers from WT, but not Nox1−/− or Nox1ΔMac mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of TNF, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle. Conclusions: In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow HCC progression.

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Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.

ICC patients, particularly those with N1 disease, achieved significant survival improvements that were partly attributable to patient selection, adjuvant chemotherapy, and multimodal treatment after recurrence.