p16INK4A Represses the paracrine tumor-promoting effects of breast stromal fibroblasts

被引:66
作者
Al-Ansari, M. M. [1 ]
Hendrayani, S. F. [1 ]
Shehata, A. I. [2 ]
Aboussekhra, A. [1 ]
机构
[1] Dept Mol Oncol, Riyadh, Saudi Arabia
[2] King Saud Univ, Dept Microbiol, Riyadh, Saudi Arabia
关键词
AUF1; breast cancer; cell nonautonomous tumor suppression; p16(INK4A); stromal fibroblasts; GENE-EXPRESSION; MOLECULAR CHARACTERIZATION; CANCER; SUPPRESSOR; MICROENVIRONMENT; CARCINOMAS; P21(WAF1/CIP1); INHIBITION; INDUCTION; INVASION;
D O I
10.1038/onc.2012.270
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16(INK4A) expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16(INK4A) downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial-mesenchymal transition state. By contrast, increase in p16(INK4A) level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16(INK4A)-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16(INK4A)-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16(INK4A)-proficient fibroblasts. These results provide the first indication that p16(INK4A) downregulation in breast stromal fibroblasts is an important step toward their activation.
引用
收藏
页码:2356 / 2364
页数:9
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