標題: | COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer |
作者: | Wu, Y-H Chang, T-H Huang, Y-F Huang, H-D Chou, C-Y 生物科技學系 生物資訊及系統生物研究所 Department of Biological Science and Technology Institude of Bioinformatics and Systems Biology |
關鍵字: | COL11A1;tumor progression;ovarian carcinoma |
公開日期: | 26-六月-2014 |
摘要: | Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type XI alpha 1 (COL11A1) in cell invasiveness and tumor formation and the prognostic impact of COL11A1 expression in ovarian cancer. Microarray analysis suggested that COL11A1 is a disease progression-associated gene that is linked to ovarian cancer recurrence and poor survival. Small interference RNA-mediated specific reduction in COL11A1 protein levels suppressed the invasive ability and oncogenic potential of ovarian cancer cells and decreased tumor formation and lung colonization in mouse xenografts. A combination of experimental approaches, including real-time RT-PCR, casein zymography and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated MMP3 expression and suppressed binding of Ets-1 to its putative MMP3 promoter-binding site, suggesting that the Ets-1-MMP3 axis is upregulated by COL11A1. Transforming growth factor (TGF)-beta (TGF-beta 1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-beta 1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA-binding site on the COL11A1 promoter was identified as the major determinant of TGF-beta 1-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are associated with advanced disease stage. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.006 and P=0.018, respectively) among patients with high expression levels of tissue COL11A1 mRNA compared with those with low expression. We conclude that COL11A1 may promote tumor aggressiveness via the TGF-beta 1-MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients. |
URI: | http://dx.doi.org/10.1038/onc.2013.307 http://hdl.handle.net/11536/24925 |
ISSN: | 0950-9232 |
DOI: | 10.1038/onc.2013.307 |
期刊: | ONCOGENE |
Volume: | 33 |
Issue: | 26 |
起始頁: | 3432 |
結束頁: | 3440 |
顯示於類別: | 期刊論文 |