核因子-κB 激活通路的抗血管生成干预延缓大鼠肝癌发生。

Delayed hepatocarcinogenesis through antiangiogenic intervention in the nuclear factor-kappa B activation pathway in rats.

机构信息

Department of Diagnostics, Medical College, Affiliated Hospital of Nantong University, Nantong 226001, China.

出版信息

Hepatobiliary Pancreat Dis Int. 2010 Apr;9(2):169-74.

PMID:20382589

Abstract

BACKGROUND

The active form of nuclear factor-kappa B (NF-kappaB) is involved in the initiation, generation, and development of hepatocellular carcinoma (HCC), and is up-regulated in inflammation-associated malignancies. We investigated the dynamic expression of NF-kappaB and its influences on the occurrence of HCC through antiangiogenic (thalidomide) intervention in NF-kappaB activation.

METHODS

Hepatoma models were induced with 2-fluorenylacetamide (2-FAA, 0.05%) in male Sprague-Dawley rats, and thalidomide (100 mg/kg body weight) was administered intragastrically to intervene in NF-kappaB activation. The pathological changes in the liver of sacrificed rats were assessed after hematoxylin and eosin staining. NF-kappaB mRNA was amplified by RT-nested PCR. The alterations of NF-kappaB and vascular endothelial growth factor (VEGF) expression were analyzed by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting.

RESULTS

Rat hepatocytes showed denatured, precancerous, and cancerous stages in hepatocarcinogenesis, with an increasing tendency of hepatic NF-kappaB, NF-kappaB mRNA, and VEGF expression, and their values in the HCC group were higher than those in controls (P<0.001). In the thalidomide-treated group, the morphologic changes generated only punctiform denaturation and necrosis at the early or middle stages, and nodular hyperplasia or a little atypical hyperplasia at the final stages, with the expression of NF-kappaB (X2=9.93, P<0.001) and VEGF (X2=8.024, P<0.001) lower than that in the 2-FAA group.

CONCLUSION

NF-kappaB is overexpressed in hepatocarcinogenesis and antiangiogenic treatment down-regulates the expression of NF-kappaB and VEGF, and delays the occurrence of HCC.

摘要

背景

核因子-κB（NF-κB）的活性形式参与了肝细胞癌（HCC）的发生、发展，并且在炎症相关恶性肿瘤中上调。我们通过抗血管生成（沙利度胺）干预 NF-κB 激活来研究 NF-κB 的动态表达及其对 HCC 发生的影响。

方法

雄性 Sprague-Dawley 大鼠用 2-氟乙酰氨（2-FAA，0.05%）诱导肝癌模型，沙利度胺（100mg/kg 体重）灌胃干预 NF-κB 激活。苏木精-伊红染色后评估处死大鼠肝脏的病理变化。通过 RT-nestedPCR 扩增 NF-κBmRNA。通过酶联免疫吸附试验、免疫组织化学和 Western blot 分析 NF-κB 和血管内皮生长因子（VEGF）表达的变化。

结果

在肝癌发生过程中，大鼠肝细胞表现出变性、癌前和癌性阶段，肝 NF-κB、NF-κBmRNA 和 VEGF 表达呈增加趋势，HCC 组的这些值高于对照组（P<0.001）。在沙利度胺治疗组中，早期或中期仅产生点状变性和坏死，晚期仅产生结节性增生或少量非典型增生，NF-κB（X2=9.93，P<0.001）和 VEGF（X2=8.024，P<0.001）的表达低于 2-FAA 组。