期刊
ONCOGENE
卷 33, 期 26, 页码 3432-3440出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.307
关键词
COL11A1; tumor progression; ovarian carcinoma
资金
- 'To establish centers of excellence for cancer research in Taiwan', Department of Health, Executive Yuan, Taiwan [DOH101-TD-C-111-003]
- Taipei Medical University [TMU101-AE1-B44]
- [NSC 101-2911-I-009-101]
- [NSC 101-2311-B-009-003-MY3]
- [NSC 100-2627-B-009-002]
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.
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