Radiation Enhances the Invasiveness of Irradiated and Nonirradiated Bystander Hepatoma Cells Through a VEGF-MMP2 Pathway Initiated by p53
Radiation Enhances the Invasiveness of Irradiated and Nonirradiated Bystander Hepatoma Cells Through a VEGF-MMP2 Pathway Initiated by p53
复制标题
辐射通过 p53 启动的 VEGF-MMP2 途径增强受辐射和未受辐射旁观者肝癌细胞的侵袭性。
DOI：
10.1667/rr3355.1
复制
发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
Shao, Chunlin
中科院分区：
文献类型：
--
作者：
He, Mingyuan;Dong, Chen;Shao, Chunlin
最近的证据表明，照射可以促进肝细胞癌细胞的侵袭性，并对周围未照射的癌细胞的侵袭行为产生影响，这可能会增强肿瘤的整体侵袭性。然而，TP 53肿瘤抑制基因在照射的肝癌细胞和它们的非照射旁观者的侵袭中的作用在很大程度上仍然未知。在本研究中，我们发现，辐射增加了人肝癌HepG 2细胞的侵袭力，并与SU 1498（血管内皮生长因子受体2，VEGFR 2的抑制剂）和GM 6001（基质金属蛋白酶2，MMP 2的抑制剂）的细胞预处理表明，辐射增强的侵袭力与MMP 2和VEGF信号之间的相互作用。此外，虽然辐射诱导p53的表达和磷酸化，但用pifithrin-alpha抑制p53功能或用p53 siRNA转染细胞显著降低了MMP 2和VEGF的活化，并导致辐射诱导的侵袭性降低。有趣的是，我们还发现，非辐照的旁观者细胞的侵袭性也升高后，与辐照的细胞和旁观者的侵袭潜力调节旁分泌的方式由MMP 2和VEGF从辐照的细胞通过p53依赖性机制。总之，我们的数据表明，辐射诱导的p53上调是负责促进VEGF-MMP 2途径参与增强辐射和旁观者肝癌细胞的侵袭力。(C)2013年，辐射研究学会
Recent evidence has shown that irradiation can promote the invasiveness of hepatocellular carcinoma cells and have an impact on the invasive behavior of nonirradiated surrounding cancer cells, which may enhance overall tumor aggressiveness. However, the role of the TP53 tumor suppressor gene in the invasion of irradiated hepatoma cells and their nonirradiated bystanders remain largely unknown. In the present study, we found that irradiation increased the invasiveness of human hepatoma HepG2 cells, and pretreatment of the cells with SU1498 (an inhibitor of vascular endothelial growth factor receptor 2, VEGFR2) and GM6001 (an inhibitor of matrix metalloproteinases 2, MMP2) demonstrated that radiation-enhanced invasiveness is associated with the interplay between MMP2 and VEGF signaling. In addition, while radiation-induced expression and phosphorylation of p53, inhibition of p53 function with pifithrin-alpha or transfection of cells with p53 siRNA significantly reduced the activation of both MMP2 and VEGF and resulted in a reduction of radiation-induced invasiveness. Interestingly, we also found that the invasiveness of the nonirradiated bystander cells was also elevated after co-culturing with irradiated cells and that bystander invasive potential was regulated paracrine in a manner by MMP2 and VEGF from the irradiated cells through a p53-dependent mechanism. Taken together, our data demonstrate that radiation-induced up-regulation of p53 is responsible for the promotion of VEGF-MMP2 pathway involved in the enhancement of invasiveness of both irradiated and bystander hepatoma cells. (C) 2013 by Radiation Research Society