COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer.
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.
Cancer Research Center, National Cheng Kung University Hospital, Tainan, Taiwan, ROC.
Y-H
YH
Wu
Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan, ROC.
T-H
TH
Chang
Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan, ROC.
Y-F
YF
Huang
1] Department of Biological Science and Technology, National Chiao Tung University, Hsin Chu, Taiwan, ROC [2] Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin Chu, Taiwan, ROC.
H-D
HD
Huang
Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan, ROC.
C-Y
CY
Chou
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality*; D011401:Promoter Regions, Genetic / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000096:biosynthesis / Q000378:metabolism; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; C574182:COL11A1 protein, human; D024161:Collagen Type XI; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3