Hanselmann Steffen, Wolter Patrick, Malkmus Jonas, Gaubatz Stefan
Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
Oncotarget. 2017 Dec 22;9(4):4985-4997. doi: 10.18632/oncotarget.23577. eCollection 2018 Jan 12.
In this study, we investigated whether proteins that are involved in cytokinesis are potential targets for therapy of lung cancer. We find that the microtubule-associated protein PRC1 (protein required for cytokinesis 1), which plays a key role in organizing anti-parallel microtubule in the central spindle in cytokinesis, is overexpressed in lung cancer cell lines compared to normal cells. Increased expression of PRC1 is correlated with a poor prognosis of human lung adenocarcinoma patients. Lentiviral delivered, inducible RNAi of PRC1 demonstrated that proliferation of lung cancer cell lines strongly depends on PRC1. Significantly, we also show that PRC1 is required for tumorigenesis using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. When PRC1 is depleted by RNA interference, lung tumor formation is significantly reduced. Although PRC1 has been suggested to regulate Wnt/ß-catenin signaling in cancer cells, we find no evidence for a role of PRC1 in this pathway in lung cancer. Instead, we show that the depletion of PRC1 results in a strong increase in bi- and multinuclear cells due to defects in cytokinesis. This ultimately leads to apoptosis and senescence. Together these data establish PRC1 as a potential target for therapy of lung cancer.
在本研究中，我们调查了参与胞质分裂的蛋白质是否为肺癌治疗的潜在靶点。我们发现，微管相关蛋白PRC1（胞质分裂1所需蛋白）在肺癌细胞系中相较于正常细胞呈过表达，该蛋白在胞质分裂过程中对中央纺锤体中反平行微管的组织起关键作用。PRC1表达增加与人类肺腺癌患者的不良预后相关。慢病毒介导的PRC1诱导型RNA干扰表明，肺癌细胞系的增殖强烈依赖于PRC1。重要的是，我们还利用由致癌性K-RAS和p53缺失驱动的非小细胞肺癌小鼠模型表明，肿瘤发生需要PRC1。当通过RNA干扰使PRC1缺失时，肺肿瘤形成显著减少。尽管有人提出PRC1在癌细胞中调节Wnt/β-连环蛋白信号通路，但我们未发现PRC1在肺癌该信号通路中发挥作用的证据。相反，我们表明，由于胞质分裂缺陷，PRC1的缺失导致双核和多核细胞大量增加。这最终导致细胞凋亡和衰老。这些数据共同证明PRC1是肺癌治疗的一个潜在靶点。
