Shu Jing, Huang Mengge, Tian Qiang, Shui Qinglin, Zhou Yujian, Chen Junxia
Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
J Mol Histol. 2015 Apr;46(2):157-71. doi: 10.1007/s10735-014-9608-x. Epub 2015 Jan 7.
Angiogenin (ANG) is a multifunctional secreted protein that belongs to the pancreatic ribonuclease A super family, which has been conceived to play a more important role in cell survival, growth and proliferation than the mediation of angiogenesis. Accumulating evidences suggest that the expression and activity of ANG increased significantly in a variety of human cancers. Recent studies showed that ANG activates cell signaling pathway through the putative receptor on endothelial cells. However, the underlying mechanisms remain largely unknown. AKT/mTOR signaling pathway participates in cell growth, cell-cycle progression and cell apoptosis. The purpose of our study was to determine whether ANG implicated in growth and metastasis of bladder cancer cells through regulating AKT/mTOR signaling pathway. In this study, we constructed ANG siRNA plasmids that transfected into human bladder cancer T24 cells. We demonstrated that knockdown of ANG could inhibit cell proliferation, regulate cell cycle and induce apoptosis. We also found that down-regulation of ANG remarkably reduced the phosphorylation of signaling targets AKT, GSK-3β and mTOR. Furthermore, down-regulation of ANG increased expression of ribonuclease inhibitor, which is a cytoplasmic acidic protein with many functions. Finally, ANG siRNA led to the suppression for tumorigenesis and metastasis in vivo. Taken together, these findings highlight for the first time that ANG could play a pivotal role in the development of bladder cancer through regulating AKT/mTOR signaling pathway. The targeting of ANG and associated factors could provide a novel strategy to inhibit human bladder cancer.
血管生成素（ANG）是一种多功能分泌蛋白，属于胰腺核糖核酸酶A超家族，人们认为它在细胞存活、生长和增殖中所起的作用比介导血管生成更为重要。越来越多的证据表明，ANG在多种人类癌症中的表达和活性显著增加。最近的研究表明，ANG通过内皮细胞上的假定受体激活细胞信号通路。然而，其潜在机制在很大程度上仍然未知。AKT/mTOR信号通路参与细胞生长、细胞周期进程和细胞凋亡。我们研究的目的是确定ANG是否通过调节AKT/mTOR信号通路参与膀胱癌细胞的生长和转移。在本研究中，我们构建了ANG siRNA质粒并将其转染到人膀胱癌细胞T24中。我们证明，敲低ANG可抑制细胞增殖、调节细胞周期并诱导细胞凋亡。我们还发现，ANG的下调显著降低了信号靶点AKT、GSK - 3β和mTOR的磷酸化水平。此外，ANG的下调增加了核糖核酸酶抑制剂的表达，核糖核酸酶抑制剂是一种具有多种功能的细胞质酸性蛋白。最后，ANG siRNA导致体内肿瘤发生和转移受到抑制。综上所述，这些发现首次突出表明，ANG可能通过调节AKT/mTOR信号通路在膀胱癌的发展中起关键作用。靶向ANG及相关因子可能为抑制人类膀胱癌提供一种新策略。
