Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells
Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells
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DOI：
10.1038/sj.onc.1205857
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发表时间：
2002-10-10
期刊：
影响因子：
8
通讯作者：
Bos, TJ
中科院分区：
文献类型：
--
作者：
Briggs, J;Chamboredon, S;Bos, TJ
MCF 7乳腺癌细胞中c-Jun原癌基因的过表达导致与恶性进展相关的多种表型变化，包括运动性和侵袭性增加。与这些表型效应同时发生的是多个基因靶点表达的变化。我们以前证明，表达的c-Jun/骨粘连蛋白基因，而检测不到的MCF 7细胞系，是高度诱导响应稳定的c-Jun过表达（c-Jun/MCF 7）。由于c-Jun基因产物与多种不同癌症中的肿瘤细胞侵袭相关，我们研究了其在MCF 7细胞中介导c-Jun诱导的表型变化中的作用。我们发现，反义介导的抑制c-Jun/MCF 7模型中的运动性和侵袭性显著抑制。相比之下，在亲本MCF 7细胞系中稳定过表达的p53不足以刺激细胞运动或侵袭。检查的启动子区的人类p53基因揭示了三个非典型的AP-1网站。我们证明，这些网站结合c-Jun/Fra 1异源二聚体在体外，但这个和其他AP-1样网站是c-Jun刺激的c-Jun启动子激活。缺失分析鉴定了-120和-70之间的区域作为足以诱导最大启动子激活的c-Jun响应元件。该区域不含任何AP-1位点，但介导SP1“样”复合物的结合。此外，该区域是果蝇SL 2细胞中SP1/SP3反应所必需的。这些结果表明，c-Jun/MCF 7细胞中的c-Jun/MCF 7细胞在刺激运动和侵袭行为中起着重要作用，c-Jun对c-Jun启动子的激活似乎是通过间接机制发生的。
Overexpression of the c-Jun proto-oncogene in MCF7 breast cancer cells results in a variety of phenotype changes related to malignant progression including increased motility and invasion. Concurrent with these phenotypic effects are changes in the expression of multiple gene targets. We previously demonstrated that expression of the SPARC/osteonectin gene, while undetectable in the MCF7 cell line, is highly induced in response to stable c-Jun overexpression (c-Jun/MCF7). Because the SPARC gene product is associated with tumor cell invasion in a variety of different cancers, we have examined its role in mediating the phenotypic changes induced by c-Jun in MCF7 cells. We found that antisense mediated suppression of SPARC dramatically inhibits both motility and invasion in this c-Jun/MCF7 model. In contrast, stable overexpression of SPARC in the parental MCF7 cell line is not sufficient to stimulate cell motility or invasion. Examination of the promoter region of the human SPARC gene reveals three non-canonical AP-1 sites. We demonstrate that one of these sites binds c-Jun/Fra1 heterodimers in vitro, but that this and the other AP-1 like sites are dispensable with respect to c-Jun stimulated SPARC promoter activation. Deletion analysis identified a region between -120 and -70 as a c-Jun responsive element sufficient to induce maximal promoter activation. This region does not contain any AP-1 sites but does mediate binding by SP1 'like' complexes. Furthermore, this region is necessary for SP1/SP3 responsiveness in Drosophila SL2 cells. These results demonstrate that SPARC plays an important role in stimulating motility and the invasive behavior of c-Jun/MCF7 cells and that SPARC promoter activation by c-Jun appears to occur through an indirect mechanism.