Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
The Second Hospital of Shi JiaZhuang, Shi Jiazhuang, 050000, China.
Exp Cell Res. 2021 Aug 1;405(1):112666. doi: 10.1016/j.yexcr.2021.112666. Epub 2021 May 27.
Vimentin protein is one of the main cytoskeleton and plays an important role in cell motility and metastasis. Nowadays, vimentin is widely studied as an epithelial-mesenchymal transition (EMT) marker of cancer cells while its involvement in cancer proliferation is poorly understood. In this study, we investigated the participation of vimentin in regulating cancer proliferation by silencing VIM gene in four cancer cell lines. Our results demonstrated that vimentin loss significantly induced cancer cell proliferation both in vitro and in vivo, which has not been reported so far. Mechanistically, knockdown of vimentin expression activated AKT phosphorylation and its downstream β-catenin signaling. Nuclear translocation and transcriptional activity of β-catenin was enhanced after silencing vimentin expression. Furthermore, vimentin loss could prevent Rictor from autophagy-dependent degradation via reducing AMPK-mediated autophagy signaling. AICAR, an AMPK activator, down-regulated Rictor and p-AKT levels while vimentin knockdown could rescue the effects. In vivo, it was also found that Ki67 expression and p-AKT/β-catenin signaling pathway were obviously up-regulated in the tumor tissues in which vimentin was silenced compared to control groups. Taken together, these data showed the novel function of vimentin in regulating cancer proliferation via Rictor/AKT/β-catenin signaling pathway, which suggested that it need more careful consideration before inhibiting metastatic cancers through targeting vimentin.
波形蛋白是细胞骨架的主要成分之一，在细胞运动和转移中发挥重要作用。目前，波形蛋白被广泛研究为癌细胞上皮-间充质转化（EMT）的标志物，而其在癌症增殖中的作用尚未被充分了解。在这项研究中，我们通过在四种癌细胞系中沉默 VIM 基因来研究波形蛋白在调节癌症增殖中的作用。我们的结果表明，波形蛋白缺失显著诱导了体外和体内的癌细胞增殖，这迄今为止尚未有报道。从机制上讲，波形蛋白表达的敲低激活了 AKT 的磷酸化及其下游β-连环蛋白信号通路。沉默波形蛋白表达后，β-连环蛋白的核易位和转录活性增强。此外，波形蛋白缺失可以通过减少 AMPK 介导的自噬信号来防止 Rictor 发生自噬依赖性降解。AMPK 激活剂 AICAR 下调了 Rictor 和 p-AKT 水平，而波形蛋白的敲低可以挽救这些作用。在体内，与对照组相比，在沉默波形蛋白的肿瘤组织中，Ki67 表达和 p-AKT/β-连环蛋白信号通路明显上调。总之，这些数据表明，波形蛋白通过 Rictor/AKT/β-连环蛋白信号通路调节癌症增殖的新功能，这表明在通过靶向波形蛋白抑制转移性癌症之前，需要更加谨慎地考虑。
