Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY, USA.
Mol Cancer. 2012 Sep 11;11:65. doi: 10.1186/1476-4598-11-65.
The invasion of glioblastoma cells into regions of the normal brain is a critical factor that limits current therapies for malignant astrocytomas. Previous work has identified roles for the Rho family guanine nucleotide exchange factors Trio and Vav3 in glioblastoma invasion. Both Trio and Vav3 act on the small GTPase RhoG. We therefore examined the role of RhoG in the invasive behavior of glioblastoma cells.
We found that siRNA-mediated depletion of RhoG strongly inhibits invasion of glioblastoma cells through brain slices ex vivo. In addition, depletion of RhoG has a marginal effect on glioblastoma cell proliferation, but significantly inhibits glioblastoma cell survival in colony formation assays. We also observed that RhoG is activated by both HGF and EGF, two factors that are thought to be clinically relevant drivers of glioblastoma invasive behavior, and that RhoG is overexpressed in human glioblastoma tumors versus non-neoplastic brain. In search of a mechanism for the contribution of RhoG to the malignant behavior of glioblastoma cells, we found that depletion of RhoG strongly inhibits activation of the Rac1 GTPase by both HGF and EGF. In line with this observation, we also show that RhoG contributes to the formation of lamellipodia and invadopodia, two functions that have been shown to be Rac1-dependent.
Our functional analysis of RhoG in the context of glioblastoma revealed a critical role for RhoG in tumor cell invasion and survival. These results suggest that targeting RhoG-mediated signaling presents a novel avenue for glioblastoma therapy.
胶质母细胞瘤细胞侵入正常脑组织区域是限制恶性星形细胞瘤当前治疗方法的关键因素。先前的工作已经确定了 Rho 家族鸟嘌呤核苷酸交换因子 Trio 和 Vav3 在神经胶质瘤侵袭中的作用。Trio 和 Vav3 都作用于小分子 GTPase RhoG。因此，我们研究了 RhoG 在神经胶质瘤细胞侵袭行为中的作用。
我们发现，siRNA 介导的 RhoG 耗竭强烈抑制神经胶质瘤细胞穿过脑切片的体外侵袭。此外，RhoG 耗竭对神经胶质瘤细胞增殖的影响很小，但显著抑制集落形成实验中的神经胶质瘤细胞存活。我们还观察到 RhoG 被 HGF 和 EGF 激活，这两种因子被认为是神经胶质瘤侵袭行为的临床相关驱动因素，并且 RhoG 在人类神经胶质瘤肿瘤中过度表达，而非神经瘤性脑。为了寻找 RhoG 对神经胶质瘤细胞恶性行为的贡献机制，我们发现 RhoG 耗竭强烈抑制 HGF 和 EGF 对 Rac1 GTPase 的激活。与这一观察结果一致，我们还表明 RhoG 有助于片状伪足和侵入足的形成，这两个功能已被证明依赖于 Rac1。
我们在神经胶质瘤中对 RhoG 的功能分析表明，RhoG 在肿瘤细胞侵袭和存活中起着关键作用。这些结果表明，靶向 RhoG 介导的信号转导为神经胶质瘤治疗提供了新的途径。
