Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1, a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expression in glioblastoma is associated with increased aggressiveness of the tumor. Here, we show that NF1-loss in patient-derived glioma cells using shRNA increases self-renewal, heightens cell invasion, and promotes mesenchymal subtype and epithelial mesenchymal transition-specific gene expression that enhances tumorigenesis. The neurofibromin protein contains at least four major domains, with the GAP-related domain being the most well-studied. In this study, we report that the leucine-rich domain (LRD) of neurofibromin inhibits invasion of human glioblastoma cells without affecting their proliferation. Moreover, under conditions tested, the NF1-LRD fails to hydrolyze Ras-GTP to Ras-GDP, suggesting that its suppressive function is independent of Ras signaling. We further demonstrate that rare variants within the NF1-LRD domain found in a subset of the patients are pathogenic and reduce NF1-LRD’s invasion suppressive function. Taken together, our results show, for the first time, that NF1-LRD inhibits glioma invasion, and provides evidence of a previously unrecognized function of NF1-LRD in glioma biology.
IntroductionNeurofibromin (NF1), a tumour suppressor and RAS-GTPase activating protein, is one of the highly mutated genes in cancer. Dysregulated NF1 expression promotes tumorigenesis, impairs learning and memory and affects neural development. Loss of NF1 expression is observed in approximately 13% of all glioma and is associated with increased malignancy. Additionally, NF1-loss increases glioma stem cells self-renewal, heightens cell invasion, and promotes mesenchymal transition resulting in enhanced tumour aggressiveness. However, aside from its RAS-GAP function, it is not clear how NF1 mitigate cell invasion and mesenchymal transition. Herein, we show that the leucine-rich domain (LRD) of NF1 plays a role in cell invasion.Material and methodsPatient-derived glioma cells was used in this study. Immunohistochemistry staining was use for assessing proneural and mesenchymal markers expression.Results and discussionsExogenous expression of LRD in NF1-knockdown glioma cells inhibited cell invasion in vitro and in vivo. Using immunohistochemistry staining for cancer stem cell markers associated with proneural (Sox2) and mesenchymal (CD44 and vimentin) subtype of glioblastoma, we found high Sox2 but low vimentin expression in LRD-expressing tumour when compared with the NF1-knockdown tumour.ConclusionOur data suggests that LRD may play a role in reverting mesenchymal GBM to a less invasive and therapy-sensitive subtype.
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