β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis
β2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis
复制标题
DOI：
10.1158/1078-0432.ccr-06-2060
复制
发表时间：
2006-12-15
影响因子：
11.5
通讯作者：
Chung, Leland W. K.
中科院分区：
文献类型：
--
作者：
Nomura, Takeo;Huang, Wen-Chin;Chung, Leland W. K.
目的：β 2-微球蛋白（β 2 M）是一种由癌症和宿主炎症细胞分泌的可溶性蛋白质，具有多种生物学功能，包括抗原呈递。由于β 2 M在人肾细胞癌中的异常表达已有报道，我们研究了β 2 M过表达对癌细胞生长的影响，并分析了其分子信号通路。我们建立了在人肾细胞癌（SN 12 C）细胞中过表达β 2 M的克隆细胞系，然后在体外和体内检查细胞生长，并研究β 2 M-β 2 M-β 2 M的表达。结果：我们的研究结果显示β 2 M表达与（a）在塑料培养皿上和作为Matrigel集落的体外生长、（B）在Boyden小室中的细胞侵袭和迁移以及（c）细胞的血管内皮生长因子（VEGF）表达和分泌正相关。此外，我们发现β 2 M通过蛋白激酶A-CREB轴增加环AMP反应元件结合蛋白（CREB）的磷酸化介导其作用，导致VEGF表达和分泌增加。在收敛与此信号轴，2 M过表达也激活磷脂酰肌醇3-激酶/Akt和丝裂原活化蛋白激酶途径。β 2 M过表达诱导小鼠皮下组织和骨中SN 12 C的加速生长。使用小干扰RNA阻断β 2 M信号通路导致凋亡，增加caspase-3和caspase-9的活化和裂解的聚（ADP-核糖）polymerase.Conclusions：我们的研究结果首次表明，β 2 M-蛋白激酶A-CREB-VEGF信号轴在支持肾细胞癌的生长和进展中起着至关重要的作用，并揭示了一个新的治疗靶点。
Purpose: beta(2)-Microglobulin (beta 2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of beta 2M has been reported in human renal cell carcinoma, we investigated the effects of beta 2M overexpression on cancer cell growth and analyzed its molecular signaling pathway.Experimental Design: We established clonal cell lines that overexpressed beta 2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the beta 2M-mediated downstream cell signaling pathway.Results: Our results showed that beta 2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that beta 2M mediates its action through increased phosphorylation of cyclic AMP responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, 2 M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. beta 2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the beta 2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly (ADP-ribose) polymerase.Conclusions: Our results showed for the first time that the beta 2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.