Wu Ting-Jung, Chang Shih-Shin, Li Chia-Wei, Hsu Yi-Hsin, Chen Tse-Ching, Lee Wei-Chen, Yeh Chau-Ting, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University Medical School, Taoyuan, Taiwan.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
Clin Cancer Res. 2016 Apr 1;22(7):1800-12. doi: 10.1158/1078-0432.CCR-15-0780. Epub 2015 Dec 11.
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.
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.
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.
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.
手术切除被认为是肝细胞癌的一种治愈性治疗方式；然而，术后肿瘤复发率很高，导致患者生存率降低。持续性肝炎（炎症）是手术切除后肿瘤复发的危险因素之一。本研究的目的是探讨将肝脏炎症与肝细胞癌进展联系起来的潜在机制。
在本研究中，我们使用细胞因子阵列来鉴定在严重肝炎的肝脏微环境中水平升高的重要细胞因子。我们在体外评估了有或没有炎性细胞因子的肝细胞癌细胞的形态变化、迁移和侵袭能力以及信号转导。最后，我们通过免疫组织化学染色分析了232例肝细胞癌患者肿瘤标本中的NF-κB信号通路。
促炎细胞因子TNFα在肿瘤周围微环境中增加，并导致肿瘤复发和转移。具体而言，TNFα通过上调转录调节因子Snail促进肝细胞癌细胞的迁移、侵袭和上皮-间质转化（EMT）。我们确定Snail是TNFα介导的经典NF-κB激活下游的直接靶基因。此外，肝细胞癌患者的无肿瘤复发生存率与高p65和Snail表达呈负相关，与高E-钙黏蛋白表达呈正相关。
我们的结果建立了一个信号轴，解释了炎性肿瘤微环境如何促进肝细胞癌的复发和转移。这些发现表明，控制肝脏炎症和/或靶向NF-κB介导的Snail表达可能是预防肝切除术后肝细胞癌复发的潜在治疗策略。
