转录因子核因子-κB 和信号转导和转录激活因子 3 的协同作用促进胃癌细胞迁移和侵袭。
A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion.
机构信息
Department of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
出版信息
BMC Gastroenterol. 2013 Feb 12;13:29. doi: 10.1186/1471-230X-13-29.
BACKGROUND
The transcription factor nuclear factor-κB (NF-κB) has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3) in controlling metastatic potential of gastric cancer cells.
METHODS
Immunohistochemistry for NF-κB p65 (RelA), phospho-Tyr705-STAT3 (pSTAT3), or matrix metalloproteinase 9 (MMP9) was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively.
RESULTS
NF-κB and STAT3 were constitutively activated and were positively correlated (P=0.038) in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P=0.001 and P=0.022, respectively), decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells.
CONCLUSION
NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
背景
转录因子核因子-κB（NF-κB）已被牵涉到胃癌转移中，但潜在的分子机制仍不清楚。我们研究了 NF-κB 与信号转导和转录激活因子 3（STAT3）之间的相互作用在控制胃癌细胞转移潜能中的作用。
方法
使用组织微阵列载玻片上的 255 例胃癌标本进行 NF-κB p65（RelA）、磷酸化 Tyr705-STAT3（pSTAT3）或基质金属蛋白酶 9（MMP9）的免疫组化染色。通过转导含有 NF-κB 抑制剂 IκBα 的突变体的逆转录病毒载体，在 SNU-638 和 MKN1 胃癌细胞系中抑制 NF-κB，通过 RNA 干扰沉默 STAT3。我们还进行了荧光素酶报告基因检测、双重免疫荧光染色和免疫印迹。通过划痕愈合试验和侵袭试验分别确定细胞迁移和侵袭。
结果
NF-κB 和 STAT3 在胃癌组织标本中持续激活并呈正相关（P=0.038）。在细胞培养实验中，NF-κB 抑制降低了 STAT3 的表达和激活，而 STAT3 沉默并不影响 NF-κB 的激活。此外，NF-κB 抑制和 STAT3 沉默以协同方式降低了胃癌细胞的迁移和侵袭。此外，NF-κB 激活和 STAT3 激活均与胃癌组织中的 MMP9 呈正相关（P=0.001 和 P=0.022），降低了 E-钙粘蛋白的表达，增加了培养细胞中的 Snail 和 MMP9 的表达。
结论
NF-κB 和 STAT3 呈正相关，并协同促进胃癌细胞的转移潜能。因此，NF-κB 和 STAT3 双重抑制剂的使用可能会增强胃癌抗转移治疗的疗效。
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