Department of Neurosurgery, University of Pennsylvania School of Medicine, 502 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA.
Department of Biomedicine, Cancer Metastasis, University of Basel, 4058, Basel, Switzerland.
J Neurooncol. 2017 Dec;135(3):487-496. doi: 10.1007/s11060-017-2610-x. Epub 2017 Aug 29.
SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs. Using paired differentiated and stem cell primary cultures, we investigated the association of SHP2 expression with the tumor stem cell compartment. Proliferation and soft agar assays were used to demonstrate the functional contribution of SHP2 to cell growth and transformation. SHP2 expression correlated with SOX2 expression in GSC lines and was decreased in differentiated cells. Forced differentiation of GSCs by removal of growth factors, as confirmed by loss of SOX2 expression, also resulted in decreased SHP2 expression. Lentiviral-mediated knockdown of SHP2 inhibited proliferation. Finally, growth in soft-agar was similarly inhibited by loss of SHP2 expression. Our results show that SHP2 function is required for cell growth and transformation of the GSC compartment in GBM.
SHP2 是一种细胞质蛋白酪氨酸磷酸酶（PTPase），参与多种信号通路，是第一个被鉴定的原癌基因 PTPase。先前在胶质母细胞瘤（GBM）中的研究表明，SHP2 PTPase 活性在调节贴壁 GBM 细胞系的致癌表型方面发挥作用。编码 SHP2 的基因 PTPN11 的突变在 GBM 中的发生率越来越高。鉴于 SHP2 在神经干细胞发育中的重要性，以及神经胶质瘤干细胞（GSCs）在 GBM 发生中的重要性，我们探讨了 SHP2 在 GSCs 中的功能作用。我们使用配对的分化和干细胞原代培养物，研究了 SHP2 表达与肿瘤干细胞区室的关联。增殖和软琼脂测定用于证明 SHP2 对细胞生长和转化的功能贡献。SHP2 的表达与 GSC 系中的 SOX2 表达相关，在分化细胞中减少。通过去除生长因子证实的 GSCs 的强制分化，也导致 SHP2 表达减少。通过慢病毒介导的 SHP2 敲低抑制增殖。最后，通过 SHP2 表达的缺失，软琼脂中的生长也受到类似的抑制。我们的结果表明，SHP2 功能对于 GBM 中 GSC 区室的细胞生长和转化是必需的。
