Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1
Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1
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DOI：
10.1038/onc.2010.194
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发表时间：
2010-08-05
期刊：
影响因子：
8
通讯作者：
Fisher, P. B.
中科院分区：
文献类型：
--
作者：
Dash, R.;Su, Z-Z;Fisher, P. B.
CCN家族分泌型整合素结合蛋白的高表达与肿瘤细胞的黏附、增殖、侵袭和迁移等肿瘤状态的许多基本成分有关。因此，CCN1在包括乳腺癌在内的多种癌症中表达升高，其表达与患者预后不良直接相关。利用消减杂交法，结合诱导癌细胞终末分化，我们克隆了干扰素(干扰素)调节的激活蛋白抑制因子(AP)-1抑制基因(SARI)，它是一种干扰素-β诱导的、具有肿瘤选择性生长抑制作用的基因。用腺病毒(Ad.SARI)抑制AP-1功能，下调CCN1在多个肿瘤细胞系中的表达，导致对锚定非依赖性细胞生长和肿瘤细胞侵袭的严重抑制。SARI的过表达通过抑制AP-1结合降低了CCN1启动子的活性。因此，SARI选择性地阻断了稳定过表达c-jun的大鼠胚胎成纤维细胞中转化状态的表达。这些结果表明，SARI抑制AP-1反式激活因子与CCN1启动子顺式元件的结合，可能是通过与c-Jun1相互作用来实现的。总体而言，SARI可以通过抑制CCN1的转录直接抑制CCN1诱导的转化，也可以通过抑制c-jun的表达间接地抑制AP-1的活性。在这些情况下，对AP-1活性“上瘾”的转化细胞对SARI介导的对转化表型表达的抑制变得敏感。Oncogene(2010)29,4412-4423；doi：10.1038/onc.2010.194；2010年6月7日在线发布
Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction-hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-beta-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad. SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the cis-element of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells 'addicted' to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype. Oncogene (2010) 29, 4412-4423; doi: 10.1038/onc.2010.194; published online 7 June 2010