Upregulated IL-19 in Breast Cancer Promotes Tumor Progression and Affects Clinical Outcome
Upregulated IL-19 in Breast Cancer Promotes Tumor Progression and Affects Clinical Outcome
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DOI：
10.1158/1078-0432.ccr-11-1532
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发表时间：
2012-02-01
影响因子：
11.5
通讯作者：
Chang, Ming-Shi
中科院分区：
文献类型：
--
作者：
Hsing, Chung-Hsi;Cheng, Hung-Chi;Chang, Ming-Shi
目的：白细胞介素19(IL-19)在乳腺浸润性导管癌(IDC)组织中表达，而在正常乳腺组织中不表达。本研究旨在探讨IL-19在乳腺癌发病机制及临床转归中的作用。实验设计：采用免疫组织化学和/或实时定量聚合酶链式反应技术检测60例和143例乳腺IDC患者肿瘤组织中IL-19的表达。我们研究了IL-19对乳腺癌细胞的细胞因子和趋化因子的产生以及增殖和迁移的影响。结果：在IDC标本中，IL-19高表达与肿瘤分期、高转移率、低生存期相关。在体外，IL-19诱导4T1乳腺癌细胞IL-1β、IL-6、转化生长因子-β、基质金属蛋白酶2、MMP9和CXCR4的转录，诱导纤维连接蛋白的表达和组装，并促进癌细胞的增殖和迁移，这一作用可被抗IL-19单抗抑制。IL-19基因敲除的4T1细胞内源性纤维连接蛋白表达较低，癌细胞迁移能力较弱。在4T1细胞中，低氧诱导IL-19和CXCR4的表达，并被抗IL-19单抗抑制。IL-19在非侵袭性67NR癌细胞中的过表达促进了细胞的增殖和迁移。在体内，注射IL-19高表达的67NR细胞克隆的小鼠肺内出现较大的肿瘤和更多的转移微结节。结论：乳腺癌组织中IL-19的高表达与临床预后不良有关。IL-19在乳腺癌的发病机制中起关键作用。临床癌症资源；18(3)；713-25。(C)2011年AACR。
Purpose: Interleukin (IL)-19 was expressed in invasive ductal carcinoma (IDC) of the breast tissue but not in healthy breast tissue. We explored the effects of IL-19 on the pathogenesis of breast cancer and its clinical outcome.Experimental Design: Tumor expression of IL-19 was assessed by immunohistochemistry and/or real-time quantitative PCR between two groups of patients with breast IDC (n = 60 and 143, respectively) with available clinical and survival data. We examined the effects of IL-19 on cytokine and chemokine production as well as proliferation and migration in breast cancer cells. Mice were injected with IL-19-overexpressing or vector control 67NR cells and the tumor growth and lung metastatic micronodules were measured.Results: Of the IDC specimens, high IL-19 expression was associated with advanced tumor stage, high tumor metastasis, and worse survival. In vitro, IL-19 induced transcripts of IL-1 beta, IL-6, TGF-beta, matrix metalloproteinase (MMP)2, MMP9, and CXCR4 in 4T1 breast cancer cells; induced fibronectin expression and assembly; and promoted cancer cell proliferation and migration, which were inhibited by anti-IL-19 monoclonal antibody (mAb). Endogenous fibronectin expression and cancer cell migration were lower in IL-19 knockdown 4T1 cells. In 4T1 cells, hypoxia induced IL-19 and CXCR4 expression, which was inhibited by anti-IL-19 mAb. IL-19 overexpression in noninvasive 67NR cancer cells increased cell proliferation and migration. In vivo, mice injected with IL-19-overexpressing 67NR cell clones showed larger tumors and more metastatic micronodules in the lung.Conclusions: High IL-19 expression in breast cancer tissue is associated with a poor clinical outcome. IL-19 is pivotal in the pathogenesis of breast cancer. Clin Cancer Res; 18(3); 713-25. (C)2011 AACR.