RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

Abstract

Glioblastoma (GBM) is a highly vascularized malignant tumor that depends on new blood vessel formation. Small molecules targeting the angiogenic process may be an effective anti-GBM therapeutic strategy. We previously demonstrated that RhoJ promoted the progression and invasion of GBM. RhoJ has also been shown to be expressed in endothelial cells and plays an important role in regulating endothelial cell migration and tumor angiogenesis. Therefore, we aimed to evaluate the role and mechanism of actions of RhoJ in GBM angiogenesis. We analyzed the expression of RhoJ in different grade gliomas and investigated its role in GBM angiogenesis in vivo and in vitro. Furtherly, RNA sequencing (RNA-seq), Western blotting and immunofluorescence were performed to identify the molecular mechanism of RhoJ in regulating endothelial cell behavior and GBM angiogenesis. Here, we found that silencing RhoJ resulted in inhibition of HUVEC cell migration and blood vessel formation. Overexpression of RhoJ promoted the expression of CD31, EpCAM and moesin, suggesting RhoJ facilitated angiogenesis and the malignant progression of GBM. RNA-seq data showed that VEGF/TNF signaling pathway positively regulated RhoJ. The expression levels of RhoJ was upregulated with the stimulation of VEGF, and reduced by the treatment of JNK inhibitor SP600125. It was also found that the activity of PAK-BRAF-ERK was down-regulated upon RhoJ and JNK knockdown. In conclusion, these results suggested that RhoJ plays an essential role in regulating GBM angiogenesis through the JNK/VEGFR2-PAK-ERK signaling pathway and there might exist a VEGF-JNK/ERK-VEGF circuitry. Thus, RhoJ may be a candidate therapeutic target for anti-angiogenesis treatment in GBM.

Elucidating the Associated Biological Function and Clinical Significance of RHOJ Expression in Urothelial Carcinoma

“…We discovered an association between elevated RHOJ expression in bladder cancer patients and inferior prognosis with decreased survival rates, indicating its potential value as a prognostic indicator. These results are consistent with previous investigations where amplified RHOJ expression was connected to detrimental clinical consequences in distinct cancer forms [ 36 , 37 , 38 , 39 , 40 ]. Moreover, the high expression of RHOJ demonstrated a significant correlation with diverse clinical features linked to cancer metastasis and disease advancement, highlighting its worth as a crucial biomarker for disease severity and tumor aggression.…”

“…The alignment of RHOJ expression with metastasis corresponds to its established function in cell migration and angiogenesis in endothelial cells. RHOJ has been reported to regulate cytoskeletal dynamics, which is a crucial process in cell migration and invasion, thereby contributing to the metastatic potential of cancer cells [ 36 , 37 , 39 , 41 , 42 ]. The proteins encoded by the Rho family of genes, which includes RHOJ , are involved in the regulation of the actin cytoskeleton in cells, influencing cell structure, division, and migration.…”

“…Notably, we also discovered a depletion in gene sets linked to cell division, such as E2F targets and MYC targets, hinting at a potential inhibitory influence of RHOJ on cell proliferation. This paradoxical observation requires further investigation, given that RHOJ has previously been linked to promoting cell proliferation and survival in other forms of cancer [ 36 , 37 , 38 , 39 ]. The variation in RHOJ expression across different immune cell populations indicates its potential impact on the tumor immune microenvironment, highlighting its significance in cancer immunotherapy.…”

SENP1-Mediated deSUMOylation Regulates the Tumor Remodeling of Glioma Stem Cells Under Hypoxic Stress

“…It has been found that in the malignant evolution of GBM, tumor microenvironment can induce the expression of abnormal cellular proteins, which in turn affects the changes of downstream signaling pathways, accelerating or delaying the progression of GBM. 22 , 23 SUMOylation can promote cells sensing extracellular stimuli, mobilize specific signal transduction pathways in cells, change the biological behaviors of cells, and adapt to changes in the extracellular environment. 24 , 25 Among them, SENP1 is one of the hot spots in the progression of tumor.…”

Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer

“…Although the role of PAK1 in tumor angiogenesis has not been studied in detail, one study does suggest a role for PAK1 in the regulation of tumor angiogenesis in ovarian cancer [ 136 ]. A recent study in glioblastoma reports augmented angiogenesis involving VEGF-mediated activation of PAKs and ERK signaling pathways [ 137 ]. Our study in a PCa tumor xenograft model demonstrated impaired tumor angiogenesis with PAK1 or PAK6 gene knockdown, with PAK1 suppression exhibiting a superior anti-angiogenic effect than PAK6 suppression [ 55 ].…”