A novel anticancer effect of thalidomide:: Inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-κB
A novel anticancer effect of thalidomide:: Inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-κB
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DOI：
10.1158/1078-0432.ccr-06-1393
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发表时间：
2006-12-01
影响因子：
11.5
通讯作者：
Chen, Ching-Chow
中科院分区：
文献类型：
--
作者：
Lin, Yi-Chu;Shun, Chia-Tung;Chen, Ching-Chow
目的：沙利度胺具有抗血管生成和抗转移作用。细胞间粘附分子-1（ICAM-1）参与单核细胞与上皮细胞的粘附和癌细胞的侵袭。在这项研究中，我们进一步研究了ICAM-1在肿瘤发生中的作用，包括肿瘤的形成和转移。实验设计：采用免疫组化方法检测人肺癌组织中ICAM-1蛋白的表达。建立ICAM-1过表达的A549细胞株（A549/ICAM-1），研究ICAM-1对A549细胞体外侵袭和体内肿瘤转移的直接影响。瞬时转染和荧光素酶测定，电泳迁移率变动分析，染色质免疫沉淀进行评估的活性和结合的核因子-κ B的ICAM-1启动子。裸鼠移植瘤模型进行了评价沙利度胺的抗癌作用。结果：ICAM-1在人肺癌标本中的高表达与晚期癌症（III期和IV期）的更大风险相关。A549/ICAM-1细胞在体外可诱导细胞侵袭和体内肿瘤转移。抗ICAM-1抗体和沙利度胺对这些事件有抑制作用。沙利度胺还通过抑制核因子-κ B与ICAM-1启动子的结合来抑制肿瘤坏死因子-α诱导的ICAM-1表达。结论：本研究为ICAM-1作为肿瘤生物学治疗的靶点提供了一个框架，沙利度胺可能对人肺癌有效。
Purpose: Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated.Experimental Design: Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-kappa B to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide.Results: High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappa B binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation.Conclusion: These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.