Abstract B46: Activation of TWIST1 by COL11A1 decreases cell sensitivity to paclitaxel by modulating NFκB -mediated Iκκβ expression

Abstract

Abstract Background: We have shown that collagen type XI alpha 1 (COL11A1) promotes ovarian tumorigenesis via upregulating the Transforming growth factor beta 1 (TGF-β)/ Matrix metalloproteinases 3 (MMP3) axis and upregulated COL11A1 expression enhanced metastatic potential to the lungs. COL11A1 expression is also associated with chemoresistance to cisplatin and paclitaxel in ovarian cancer cells. In this study, we verified how COL11A1 to regulate twist-related protein 1 (TWIST1) in ovarian cancer cells. Methods: ES2 and TOV-21G cells transfected with a small interference RNA of COL11A1 (shCOL11A1) and OVCAR3 and OVCAR4 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis assay, luciferase assay, chromatin immunoprecipitation assay, immunofluorescence assay, anchorage-independent soft-agar assay, invasion assay and xenograft animal study were performed in this study. COL11A1 and TWIST1 mRNA expression levels of 104 ovarian tumors were determined by real-time RT-PCR. Results: We found that the level of COL11A1 expression in a panel of ovarian cancer cells was positively correlated with the expressions of TWIST1 and Iκκβ. Mechanistic studies indicated that a decrease in TWIST1 caused by COL11A1-suppressed Iκκβ transcription was achieved by derepression of binding of Sp1 to the Iκκβ promoter. COL11A1-mediated nuclear factor-kappaB (NF-κB) activation, via the activation of Iκκβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, which was associated with epithelial-to-mesenchymal transition. In addition, TWIST1 messenger RNA level was positively associated with COL11A1 messenger RNA expression level in ovarian tumors. Conclusions: COL11A1 activates NF-κB signaling by increasing Iκκβ transcription, which results in progression of ovarian cancer and poorer patient outcomes. We suggest that Iκκβ may potentially be targeted in patients with COL11A1-positive tumors. Citation Format: Yi-Hui Wu, Cheng-Yang Chou. Activation of TWIST1 by COL11A1 decreases cell sensitivity to paclitaxel by modulating NFκB -mediated Iκκβ expression. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B46.