NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.
NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.
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DOI：
10.1158/0008-5472.can-15-2511
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Bar-Eli M
中科院分区：
文献类型：
--
作者：
Shoshan E;Braeuer RR;Kamiya T;Mobley AK;Huang L;Vasquez ME;Velazquez-Torres G;Chakravarti N;Ivan C;Prieto V;Villares GJ;Bar-Eli M
活化T细胞核因子（Nuclear Factor of Activated T Cell，NFAT 1，NFATC 2）是T细胞活化过程中与白细胞介素-2（interleukin-2，IL-2）结合并调控IL-2表达的转录因子。NFAT 1在先天性和适应性免疫应答中具有重要作用，但其在癌症中的作用尚不完全清楚。我们以前证明，NFAT 1有助于黑色素瘤的生长和转移，通过调节autotaxin基因（Enpp 2）。在这里，我们报告了黑色素瘤细胞系和肿瘤标本中NFAT 1表达与转移潜力之间的强相关性。为了阐明黑色素瘤进展过程中NFAT 1过表达的机制，我们对NFAT 1表达稳定沉默的高转移性黑色素瘤细胞系进行了微阵列研究。我们鉴定并验证了NFAT 1的两个下游靶点，IL-8和MMP-3。因此，转移性黑色素瘤细胞系中的NFAT 1消耗与IL-8和MMP-3表达减少相关，而弱转移性细胞系中的NFAT 1过表达诱导这些靶点的表达。NFAT 1表达的恢复使IL-8和MMP-3表达水平恢复到基线，表明两者都是NFAT 1的直接靶点。此外，体内研究表明，NFAT 1和MMP-3促进黑色素瘤肿瘤生长和肺转移。总的来说，我们的研究结果为NFAT 1在黑色素瘤进展中赋予了新的作用，强调了免疫调节因子在不可预测的肿瘤微环境中可能获得的多方面功能。
Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates interleukin-2 expression during T cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL-8 and MMP-3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL-8 and MMP-3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL-8 and MMP-3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP-3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment.