Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44
Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44
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DOI：
10.1093/carcin/bgp158
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发表时间：
2009-12-01
期刊：
影响因子：
4.7
通讯作者：
Lee, Wang Jae
中科院分区：
文献类型：
--
作者：
Kang, Jae Seung;Bae, Seyeon Y.;Lee, Wang Jae
癌细胞在逃离免疫系统后向其他部位转移，CD 70、CD 44和血管内皮生长因子（VEGF）在此过程中起重要作用。近年来研究发现，白细胞介素（IL）-18与皮肤肿瘤的发生密切相关。因此，我们研究了来自胃癌的内源性IL-18通过调节CD 70、CD 44和VEGF表达在免疫逃逸机制和转移中的作用。本研究不仅检测了10例胃癌患者的肿瘤组织和20例胃癌患者的血清中IL-18和IL-18 R的表达，而且还检测了人胃癌细胞系中IL-18和IL-18 R的表达。IL-18和IL-18 R在胃癌细胞株和肿瘤组织中均有表达。此外，与正常人血清相比，癌症患者血清中IL-18水平升高（P < 0.05）。在内源性IL-18沉默或中和后，通过流式细胞术、免疫印迹和酶联免疫吸附试验研究CD 70、CD 44和VEGF表达的变化，并通过Cr-51释放试验研究免疫易感性。CD 70表达增加，增加了癌细胞的免疫易感性。与此相反，CD 44和VEGF的表达降低，并抑制新血管形成和胃癌转移。将IL-18小干扰RNA（siRNA）转染的胃癌细胞接种到Balb/C（nu/nu）小鼠中后，通过测量肿瘤大小来确定肿瘤质量的消退。苏木精-伊红染色观察转移灶的数目和位置。在注射IL-18 siRNA转染的细胞系的小鼠中观察到肿瘤质量的消退和转移的抑制。我们的数据表明，内源性IL-18可能通过抑制CD 70促进胃癌细胞的免疫逃逸，并通过上调CD 44和VEGF增加转移能力。
Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by Cr-51-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.