Department of Physiology, Yong Loo Lin School of Medicine, Neurobiology/Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore.
Oncogene. 2012 Feb 2;31(5):595-610. doi: 10.1038/onc.2011.256. Epub 2011 Jun 27.
Semaphorins are implicated in glioma progression, although little is known about the underlying mechanisms. We have reported plexin-B3 expression in human gliomas, which upon stimulation by Sema5A causes significant inhibition of cell migration and invasion. The concomitant inactivation of Rac1 is of mechanistic importance because forced expression of constitutively active Rac1 abolishes these inhibitory effects. Furthermore, Sema5A induces prominent cell collapse and ramification of processes reminiscent of astrocytic morphology, which temporally associate with extensive disassembly of actin stress fibers and disruption of focal adhesions, followed by accumulation of actin patches in protrusions. Mechanistically, Sema5A induces transient protein kinase C (PKC) phosphorylation of fascin-1, which can reduce its actin-binding/bundling activities and temporally parallels its translocation from cell body to extending processes. PKC inhibition or fascin-1 knockdown is sufficient to abrogate Sema5A-induced morphological differentiation, whereas the process is hastened by forced expression of fascin-1. Intriguingly, Sema5A induces re-expression of glial fibrillary acidic protein (GFAP), which when silenced restricts differentiation of glioma cells to bipolar instead of multipolar morphology. Therefore, we hypothesize complementary functions of fascin-1 and GFAP in the early and late phases of Sema5A-induced astrocytic differentiation of gliomas, respectively. In summary, Sema5A and plexin-B3 impede motility but promote differentiation of human gliomas. These effects are plausibly compromised in high-grade human astrocytomas in which Sema5A expression is markedly reduced, hence leading to infiltrative and anaplastic characteristics. This is evident by increased invasiveness of glioma cells when endogenous Sema5A is silenced. Therefore, Sema5A and plexin-B3 represent potential novel targets in counteracting glioma progression.
信号蛋白在神经胶质瘤的进展中起作用，尽管其潜在机制仍知之甚少。我们曾报道过在人类神经胶质瘤中存在神经纤毛蛋白-B3 的表达，其在 Sema5A 的刺激下可显著抑制细胞迁移和侵袭。Rac1 的同时失活具有重要的机制意义，因为强制表达组成型激活的 Rac1 会消除这些抑制作用。此外，Sema5A 诱导细胞明显崩溃和突起的分支，这让人联想到星形胶质细胞的形态，这与肌动蛋白应力纤维的广泛解体和焦点黏附的破坏以及随后在突起中积累肌动蛋白斑同时发生。从机制上讲，Sema5A 诱导 fascin-1 的短暂蛋白激酶 C（PKC）磷酸化，这可以降低其肌动蛋白结合/成束活性，并与它从细胞体向延伸过程中的易位同时发生。PKC 抑制或 fascin-1 敲低足以消除 Sema5A 诱导的形态分化，而 fasin-1 的强制表达则加速了这一过程。有趣的是，Sema5A 诱导神经胶质纤维酸性蛋白（GFAP）的重新表达，而沉默 GFAP 会限制神经胶质瘤细胞向双极而不是多极形态的分化。因此，我们假设 fascin-1 和 GFAP 在 Sema5A 诱导的神经胶质瘤星形细胞分化的早期和晚期阶段分别具有互补功能。总之，Sema5A 和神经纤毛蛋白-B3 抑制运动但促进人类神经胶质瘤的分化。这些作用在 Sema5A 表达明显降低的高级别人类星形细胞瘤中可能受到损害，从而导致浸润性和间变性特征。当内源性 Sema5A 被沉默时，神经胶质瘤细胞的侵袭性增加证明了这一点。因此，Sema5A 和神经纤毛蛋白-B3 代表了对抗神经胶质瘤进展的潜在新靶点。
