School of Medicine, Medical College of Georgia, Augusta, GA, USA.
Int J Cancer. 2011 Dec 15;129(12):2825-35. doi: 10.1002/ijc.25964. Epub 2011 May 5.
Loss of WASF3 function in breast cancer cells results in loss of invasion phenotypes and reduced metastatic potential. By using oligonucleotide arrays, we now demonstrate that knockdown of WASF3 leads to the upregulation of the KISS1 metastasis suppressor gene with concomitant reduced invasion and loss of matrix metalloproteinases (MMP)-9 activity. Using a luciferase reporter, KISS1 transcription is significantly increased in the absence of WASF3. Knockdown of KISS1 in WASF3-silenced cells resulted in the recovery of the invasion phenotype. WASF3 knockdown also resulted in elevated IκBα levels in the cytoplasm and reduced levels of nuclear factor-kappa-B (NF-κB) p65/50 subunits in the nucleus. Tumor necrosis factor-alpha (TNF-α) has been associated with cell invasion through induction of MMP-9 production via KISS1 regulation of the NF-κB pathway. When WASF3 knockdown cells are treated with TNF-α, no effect is seen on invasion or nuclear translocation of NF-κB. Thus, coordinated expression patterns of the WASF3 metastasis promoter gene and the KISS1 metastasis suppressor gene appear to exert their influence through inhibition of NF-κB signaling, which in turn regulates MMP-9 production facilitating invasion.
乳腺癌细胞中 WASF3 功能的丧失导致侵袭表型的丧失和转移潜能的降低。通过使用寡核苷酸阵列，我们现在证明，WASF3 的敲低导致 KISS1 转移抑制基因的上调，同时伴随侵袭减少和基质金属蛋白酶（MMP）-9 活性降低。使用荧光素酶报告基因，在没有 WASF3 的情况下，KISS1 转录显著增加。在 WASF3 沉默细胞中敲低 KISS1 导致侵袭表型的恢复。WASF3 敲低还导致细胞质中 IκBα 水平升高，核中核因子-κB（NF-κB）p65/50 亚基水平降低。肿瘤坏死因子-α（TNF-α）通过调节 NF-κB 途径诱导 MMP-9 产生与细胞侵袭有关。当用 TNF-α 处理 WASF3 敲低细胞时，不会对侵袭或 NF-κB 的核易位产生影响。因此，WASF3 转移促进基因和 KISS1 转移抑制基因的协调表达模式似乎通过抑制 NF-κB 信号传导发挥作用，NF-κB 信号传导反过来又调节 MMP-9 的产生，促进侵袭。
