MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells
MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells
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DOI：
10.1093/carcin/bgq241
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发表时间：
2011-02-01
期刊：
影响因子：
4.7
通讯作者：
Jung, Young Do
中科院分区：
文献类型：
--
作者：
Park, Jung Sun;Park, Ji Hye;Jung, Young Do
在人胃癌中观察到nantai受体（RON）和尿激酶纤溶酶原激活物受体（uPAR）的过表达。然而，RON和uPAR在胃癌中的相互作用尚不清楚。本研究探讨巨噬细胞刺激蛋白（MSP， RON配体）对人胃癌AGS细胞中uPAR表达及其信号通路的影响。MSP诱导的uPAR信使RNA表达呈时间和浓度依赖性。MSP还能诱导uPAR启动子活性。RNA特异性小干扰RNA （siRNA）的引入显著影响了msp诱导的uPAR转录。缺失和定点突变研究表明，转录因子核因子- κ B （nf - κ B）和激活蛋白(AP)-1的结合位点参与了msp诱导的uPAR表达。利用编码突变型NF-kappa B信号分子和AP-1诱饵的表达载体进行的研究证实，NF-kappa B和AP-1对于msp诱导的uPAR表达至关重要。此外，MSP诱导细胞外信号调节激酶1/2 （Erk-1/2）、c-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）的激活。显性阴性突变体（K97M和TAM67）和Erk-1/2和JNK的特异性抑制剂能够抑制msp诱导的uPAR表达。MSP预处理的AGS细胞显示出显著增强的侵袭性，sirna靶向的RON和upar中和抗体部分消除了这种侵袭性。上述结果表明，MSP通过MAPK、AP-1和NF-kappa B信号通路诱导uPAR表达，进而刺激人胃癌AGS细胞的细胞侵袭性。
Overexpression of recepteur d'Origine nantais (RON) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between RON and uPAR in gastric cancer is unclear. The present study investigated the effect of macrophage-stimulating protein (MSP, the RON ligand) on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. uPAR messenger RNA expression was induced by MSP in a time- and concentration-dependent manner. MSP also induced uPAR promoter activity. The introduction of RON-specific small interfering RNA (siRNA) significantly affected the MSP-induced uPAR transcription. Deleted and site-directed mutagenesis studies demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-kappa B) and activator protein (AP)-1 in the MSP-induced uPAR expression. Studies with expression vectors encoding mutated-type NF-kappa B signaling molecules and AP-1 decoy confirmed that NF-kappa B and AP-1 were essential for the MSP-induced uPAR expression. In addition, MSP induced the activation of extracellular signal-regulated kinase-1/2 (Erk-1/2), c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Dominant-negative mutants (K97M and TAM67) and specific inhibitors of Erk-1/2 and JNK were able to suppress the MSP-induced uPAR expression. AGS cells pretreated with MSP showed a remarkably enhanced invasiveness, which was partially abrogated by siRNA-targeted RON and uPAR-neutralizing antibodies. The above results suggest that MSP induces uPAR expression via MAPK, AP-1 and NF-kappa B signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.