c-Fos is required for TGFβ1 production and the associated paracrine migratory effects of human colon carcinoma cells

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Abstract

In tumor cells that have lost responsiveness to the growth inhibitory effects of transforming growth factor β (TGFβ), increased TGFβ 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 TGFβ1 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 TGFβ1 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 TGFβ1 promoter. Small interfering RNAs (siRNAs) against c-Fos significantly suppressed AP-1 activity at the relevant AP-1 site, and led to a decrease in TGFβ1 secretion by the HCCCs. Our results indicate for the first time that c-Fos binding at the TGFβ1 promoter proximal AP-1 site in HCCCs is required for TGFβ1 production by the tumor cells. Further, we demonstrated that blockade of TGFβ1 secretion by c-Fos 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 TGFβ1, thereby suppressing the migratory behavior associated with the malignant phenotype of HCCCs. © 2006 Wiley-Liss, Inc.

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