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

Abstract

Purpose Surgical resection is considered as a curative treatment modality for hepatocellular carcinoma (HCC); however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to HCC 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 morphological changes, migration and invasion ability, and signal transduction in HCC cells with or without inflammatory cytokine in vitro. Finally, we analyzed the NF-κB signal pathway in tumor specimens from 232 patients with HCC by immunohistochemical staining. Results The pro-inflammatory cytokine TNF-α was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNF-α promoted HCC 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 TNF-α-mediated canonical NF-κB activation. In addition, tumor recurrence-free survival of HCC patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression. Conclusion Our results establish a signaling axis that explains how inflammatory tumor microenvironment promotes HCC 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 HCC recurrence after hepatectomy.

Mesencephalic Astrocyte‐Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin‐Related Modifier (SUMO)ylation‐Related Suppression of NF‐κB/Snail Signaling Pathway and Epithelial‐Mesenchymal Transition

“…We have verified that MANF suppresses inflammation and EMT and thereby inhibits invasion and metastases in HCC. It was reported that activation of the NF‐κB signal pathway enhances inflammation and EMT of hepatocytes . Our previous study also showed that MANF inhibits NF‐κB transcriptional activity by binding to the DNA‐binding domain of p65 in nuclei .…”

“…The results indicate that MANF can suppress hepatocyte EMT during HCC progression. Recently, it was reported that p65 overexpression in the hepatoma cell lines decreases E‐cadherin and increases vimentin level . These findings suggest that activation of the NF‐κB pathway promotes hepatocyte EMT.…”

IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion

“…Multiple cytokines, including IFN-γ, C-C motif chemokine ligand 1 (CCL1), IL-6, macrophage colony-stimulating factor (M-CSF), chemokine (C-X-C motif) ligand 9 (CXCL9), CCL3, TNF-α, TNF-β, and platelet-derived growth factor-BB (PDGF-BB), are elevated in HCC patients with severe hepatitis and correlated with poor prognosis (21). Among them, IL-6 and TNF-α/β markedly enhanced the levels of exogenous PD-L1 protein expression in FLAG-PD-L1 WT-Hep 3B and WT-SK-HEP-1 cells ( Figure 1B).…”

Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma

“…The brain was removed, and the cerebellum was isolated, fixed in 10% formalin, and embedded in paraffin. Five-micron-thick sections were cut and subjected to hematoxylin-eosin (H&E) and immunohistochemical staining as previously described (20). Immunohistochemistry was also performed using tissue arrays of clinical MBs (Alenabio; Cat.…”