Zhu Zhichuan, Liu Yongjie, Li Kui, Liu Jiwei, Wang Hongtao, Sun Bing, Xiong Zhiqi, Jiang Hualiang, Zheng Jing, Hu Zelan
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China, Department of Neurosurgery, Shanghai Neurosurgical Center, Huashan Hospital, Fudan University, Shanghai 200030, China and Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Neurosurgery, Shanghai Neurosurgical Center, Huashan Hospital, Fudan University, Shanghai 200030, China and.
Carcinogenesis. 2014 Aug;35(8):1901-10. doi: 10.1093/carcin/bgu123. Epub 2014 May 29.
The membrane protein tyrosine phosphatase receptor U (PTPRU) has been shown to function as a negative regulator of adhesion and proliferation in certain cancer cell types, primarily through its dephosphorylation of β-catenin and inhibition of subsequent downstream signaling. In the present study, we set out to characterize the role of PTPRU in glioma and found that, while the expression of full-length PTPRU protein is low in these tumors, a number of non-full-length PTPRU isoforms are highly expressed. Among these isoforms, one in particular is localized to the nucleus, and its expression is increased in glioma tissues in a manner that positively correlates with malignancy grade. Short hairpin RNA knockdown of endogenous PTPRU in human and rat glioma cell lines suppressed proliferation, survival, invasion, migration, adhesion and vasculogenic tube formation in vitro, as well as intracranial tumor progression in vivo. In addition, knocking down PTPRU reduced tyrosine phosphorylation (pY) and transcriptional activity of β-catenin, and we were able to specifically rescue the cell migration defect by expressing a LEF1-β-catenin fusion protein in PTPRU-depleted cells. PTPRU knockdown also led to increased tyrosine pY of the E3 ubiquitin ligase c-Cbl and to the destabilization of several focal adhesion proteins. Taken together, our findings demonstrate that endogenous PTPRU promote glioma progression through their effect on β-catenin and focal adhesion signaling.
膜蛋白酪氨酸磷酸酶受体U（PTPRU）已被证明在某些癌细胞类型中作为粘附和增殖的负调节因子发挥作用，主要是通过其对β-连环蛋白的去磷酸化作用以及对随后下游信号传导的抑制。在本研究中，我们着手研究PTPRU在胶质瘤中的作用，发现虽然这些肿瘤中全长PTPRU蛋白的表达较低，但许多非全长PTPRU异构体高度表达。在这些异构体中，有一种特别定位于细胞核，并且其在胶质瘤组织中的表达以与恶性程度呈正相关的方式增加。在人和大鼠胶质瘤细胞系中，通过短发夹RNA敲低内源性PTPRU可抑制体外增殖、存活、侵袭、迁移、粘附和血管生成管形成，以及体内颅内肿瘤进展。此外，敲低PTPRU可降低β-连环蛋白的酪氨酸磷酸化（pY）和转录活性，并且我们能够通过在PTPRU缺失的细胞中表达LEF1-β-连环蛋白融合蛋白来特异性挽救细胞迁移缺陷。PTPRU敲低还导致E3泛素连接酶c-Cbl的酪氨酸pY增加以及几种粘着斑蛋白不稳定。综上所述，我们的研究结果表明，内源性PTPRU通过其对β-连环蛋白和粘着斑信号传导的影响促进胶质瘤进展。
