Severe Hepatitis Promotes Hepatocellular Carcinoma Recurrence via NF-kB Pathway-Mediated Epithelial–Mesenchymal Transition after Resection

[[abstract]]Purpose: Surgical resection is considered as a curative treatment modality for hepatocellular carcinoma; however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of the risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to hepatocellular carcinoma progression. Experimental Design: In this study, we used a cytokine array to identify important cytokines whose levels are increased in liver microenvironment with severe hepatitis. We evaluated the morphologic changes, migration and invasion ability, and signal transduction in hepatocellular carcinoma cells with or without inflammatory cytokine in vitro. Finally, we analyzed the NF-κB signal pathway in tumor specimens from 232 patients with hepatocellular carcinoma by immunohistochemical staining. Results: The proinflammatory cytokine TNFα was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNFα promoted hepatocellular carcinoma cancer cell migration, invasion, and epithelial–mesenchymal transition (EMT) by upregulating the transcriptional regulator, Snail. We identified Snail as a direct target gene downstream of the TNFα-mediated canonical NF-κB activation. In addition, tumor recurrence-free survival of hepatocellular carcinoma patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression. Conclusions: Our results establish a signaling axis that explains how inflammatory tumor microenvironment promotes hepatocellular carcinoma recurrence and metastasis. These findings suggest that controlling liver inflammation and/or targeting NF-κB–mediated Snail expression may be a potential therapeutic strategy to prevent hepatocellular carcinoma recurrence after hepatectomy. Clin Cancer Res; 22(7); 1800–12. ©2015 AACR