Down-regulation of Notch-1 inhibits invasion by inactivation of nuclear Factor-κB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. (Retracted article. See vol. 78, pg. 5476, 2018)
Down-regulation of Notch-1 inhibits invasion by inactivation of nuclear Factor-κB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. (Retracted article. See vol. 78, pg. 5476, 2018)
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DOI：
10.1158/0008-5472.can-05-4281
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Sarkar, FH
中科院分区：
文献类型：
--
作者：
Wang, ZW;Banerjee, S;Sarkar, FH
Notch信号在人类恶性肿瘤的发生和发展中起着关键作用，但Notch-1在肿瘤侵袭中的确切作用和机制尚不清楚。在我们之前的报告中，我们发现Notch-1的下调降低了核因子-kappa B(NF-kappa B)的DNA结合活性和基质金属蛋白酶-9(MMP-9)的表达。由于核因子-kappaB、血管内皮生长因子和基质金属蛋白酶在肿瘤细胞的侵袭和转移过程中起重要作用，我们通过分子手段研究了Notch-1下调可能导致核因子-kappaB、血管内皮生长因子和基质金属蛋白酶-9的下调，从而通过Matrigel抑制胰腺癌细胞侵袭的作用和机制(S)。我们发现，小干扰RNA下调Notch-1基因的表达可降低肿瘤细胞的侵袭力，而过表达的Notch-1基因可增加肿瘤细胞的侵袭力。与这些结果一致的是，我们发现Notch-1的下调降低了NF-kappa B的DNA结合活性和VEGF的表达。Notch-1的下调不仅降低了MMP9mRNA及其蛋白的表达，而且使原MMP9蛋白失活到其活性状态。综上所述，Notch-1的下调可能是下调和失活核因子-kappaB及其靶基因如基质金属蛋白酶-9和血管内皮生长因子的表达，从而抑制肿瘤的侵袭和转移的有效途径。
Notch signaling plays a critical role in the pathogenesis and progression of human malignancies but the precise role and mechanism of Notch-1 for tumor invasion remains unclear. In our earlier report, we showed that down-regulation of Notch-1 reduced nuclear factor-kappa B (NF-kappa B) DNA-binding activity and matrix metalloproteinase-9 (MMP-9) expression. Because NF-kappa B, VEGF, and MMPs are critically involved in the processes of tumor cell invasion and metastasis, we investigated the role and mechanism(s) by which Notch-1 down-regulation (using molecular approaches) may lead to the down-regulation of NF-kappa B, vascular endothelial growth factor (VEGF), and MMP-9, thereby inhibiting invasion of pancreatic cancer cells through Matrigel. We found that the down-regulation of Notch-1 by small interfering RNA decreased cell invasion, whereas Notch-1 overexpression by cDNA transfection led to increased tumor cell invasion. Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-kappa B DNA-binding activity and VEGF expression. Down-regulation of Notch-1 also decreased not only MMP-9 mRNA and its protein expression but also inactivated the pro-MMP-9 protein to its active form. Taken together, we conclude that the down-regulation of Notch-1 could be an effective approach for the down-regulation and inactivation of NF-kappa B and its target genes, such as MMP-9 and VEGF expression, resulting in the inhibition of invasion and metastasis.