TY - JOUR
T1 - COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer
AU - Wu, Y. H.
AU - Chang, T. H.
AU - Huang, Y. F.
AU - Huang, H. D.
AU - Chou, C. Y.
N1 - Funding Information:
This study was supported by ‘To establish centers of excellence for cancer research in Taiwan’ (DOH101-TD-C-111-003), Department of Health, Executive Yuan, Taiwan. This work was supported in part by National Science Council under Grant No.: NSC 101-2911-I-009-101, NSC 101-2311-B-009-003-MY3 and NSC 100-2627-B-009-002. The research was supported in part by Taipei Medical University under grant TMU101-AE1-B44.
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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-β1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-β1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA-binding site on the COL11A1 promoter was identified as the major determinant of TGF-β1-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-β1-MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients.
AB - 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-β1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-β1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA-binding site on the COL11A1 promoter was identified as the major determinant of TGF-β1-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-β1-MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients.
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U2 - 10.1038/onc.2013.307
DO - 10.1038/onc.2013.307
M3 - Article
C2 - 23934190
AN - SCOPUS:84903633634
SN - 0950-9232
VL - 33
SP - 3432
EP - 3440
JO - Oncogene
JF - Oncogene
IS - 26
ER -