c-Fos is required for TGFβ1 production and the associated paracrine migratory effects of human colon carcinoma cells
c-Fos is required for TGFβ1 production and the associated paracrine migratory effects of human colon carcinoma cells
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DOI：
10.1002/mc.20189
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发表时间：
2006-08-01
影响因子：
4.6
通讯作者：
Mulder, Kathleen M.
中科院分区：
文献类型：
--
作者：
Liu, Guangming;Ding, Wei;Mulder, Kathleen M.
在已经失去对转化生长因子P（TGF β）的生长抑制作用的响应性的肿瘤细胞中，肿瘤细胞增加的TGF β产生通常主要通过旁分泌机制促成癌症进展。在这里，我们研究了人结肠癌细胞（HCC）TGF β 1启动子中激活蛋白-1（AP-1）复合物的主要成分。与未转化的上皮细胞（UEC）相比，HCC在人TGF β 1启动子的近端AP-1位点显示AP-1的组成性激活。此外，与存在于UEC中AP-1位点的AP-1复合物中的JunD和Fra-2组分相比，c-Fos是HCC中主要可检测的AP-1组分。因此，相对于UEC，在HCC中发生了转录因子转换，关于人TGF β 1启动子的近端AP-1位点。针对cFos的小干扰RNA（siRNA）显著抑制AP-1相关位点的AP-1活性，并导致HCC分泌TGF β 1的减少。我们的研究结果首次表明，c-Fos在HCC中TGF β 1启动子近端AP-1位点的结合是肿瘤细胞产生TGF β 1所必需的。此外，我们证明了通过cFos siRNA阻断TGF β 1分泌导致以旁分泌方式抑制NIH 3 T3成纤维细胞的细胞迁移和有丝分裂。因此，c-Fos可以作为阻断肿瘤细胞分泌的TGF β 1的靶点，从而抑制与HCCCS恶性表型相关的迁移行为。(c)2006 Wiley-Liss，Inc.
In tumor cells that have lost responsiveness to the growth inhibitory effects of transforming growth factor P (TGFP), increased TGFP production by the tumor cells often contributes to cancer progression, primarily through paracrine mechanisms. Here we investigated the major components of the activator protein-1 (AP-1) complex in the TGF beta 1 promoter of human colon carcinoma cells (HCCCs). In contrast to untransformed epithelial cells (UECs), HCCCs displayed constitutive activation of AP-1 at the proximal AP-1 site in the human TGF beta 1 promoter. Further, in contrast to the JunD and Fra-2 components present in the AP-1 complex at this AP-1 site in UECs, c-Fos was the major detectable AP-1 component in HCCCs. Thus, transcriptional factor switching had occurred in HCCCs relative to the UECs, with regard to the proximal AP-1 site of the human TGF beta 1 promoter. Small interfering RNAs (siRNAs) against cFos significantly suppressed AP-1 activity at the relevant AP-1 site, and led to a decrease in TGFP1 secretion by the HCCCs. Our results indicate for the first time that c-Fos binding at the TGFP1 promoter proximal AP-1 site in HCCCs is required for TGFP1 production by the tumor cells. Further, we demonstrated that blockade of TGFP1 secretion by cFos siRNA led to a suppression of the cellular migration and mitogenesis of NIH 3T3 fibroblasts in a paracrine fashion. Thus, c-Fos may have utility as a target for blocking tumor cell-secreted TGF beta 1, thereby suppressing the migratory behavior associated with the malignant phenotype of HCCCS. (c) 2006 Wiley-Liss, Inc.