<p>Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway</p>

Abstract

Background: Rho-GTPases and their activators, guanine nucleotide exchange factors (GEFs), are increasingly being recognized as essential mediators of oncogenic signaling. Although it is known that P-Rex1, a member of the Dbl family of GEFs for the Rac small GTPase, contributes to the migration of cancer cells, its exact role in liver cancer and the underlying mechanisms remain unclear. Materials and Methods: Public datasets from the Gene Expression Omnibus database (GEO) and clinical liver cancer samples were analyzed to explore the expression of P-Rex1. P-Rex1 knockdown and overexpression cell lines were established using a recombinant lentiviral transfection system. BrdU and colony formation assays were performed to determine cell viability. Migratory capacity was analyzed using a transwell migration assay and an in vitro wound-healing assay. Nude mice bearing subcutaneous xenograft tumors were established to determine the effects of P-Rex1 on tumorigenesis in vivo. The role of P-Rex1 in hepatocarcinogenesis was determined through Western blot and coimmunoprecipitation. Results: Induced expression of endogenous P-Rex1 was identified in liver cancer tumors when compared with adjacent nonmalignant tissues from clinical data. In response to HGF treatment, P-Rex1-knockdown cells displayed reduced proliferation and migration in vitro as well as reduced xenograft tumor growth in vivo. Overexpression of P-Rex1 promoted liver cancer cell proliferation and migration. P-Rex1 primarily acts as a downstream effector of GPCR signaling. This study demonstrated that downregulation of P-Rex1 led to a significant decrease in the phosphorylation of Akt and Erk1/2 by reducing the phosphorylation of the tyrosine kinase receptor c-Met. Furthermore, a physical association between P-Rex1 and c-Met was observed after HGF treatment, suggesting that P-Rex1 may be involved in the HGF/c-Met signaling pathway. Conclusion: These results support the role of P-Rex1 as a novel player in liver cancer, which suggest that targeting P-Rex1 may provide a potential strategy for liver cancer treatment.

P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells

“…The P-Rex1-dependent regulation of cell-cycle progression and/or cell proliferation has previously been reported, mostly in cancer cells but also in melanoblasts and endothelial cells, and it is often found associated with altered Erk activity and expression levels of cell-cycle regulators [ 16 , 60 , 61 , 62 ]. However, P-Rex1 does not seem to affect these processes universally, as others have reported a lack of effect of P-Rex1 on the proliferation of breast cancer cells [ 63 ].…”

CXCR4 promotes gefitinib resistance of Huh7 cells by activating the c‐Met signaling pathway

“…Many studies have confirmed the role of c‐Met in the procession of HCC. P‐Rex1 promotes proliferation and migration of HCC cells and enhances xenograft tumor growth in vivo by activating the HGF/c‐Met signaling pathway [ 23 ]. The HGF/c‐Met signaling pathway participates in the liver metastasis of colorectal cancer in mice [ 24 ].…”

Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma

“…Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) is a Rac guanine nucleotide exchange factor (RacGEF) that is upregulated in numerous adult cancers, including breast cancer, prostate cancer, melanoma, and liver cancer (11)(12)(13)(14)(15). It is activated downstream of phosphoinositide 3-kinase (PI3K) and G-protein coupled receptors (GPCRs) to promote activation of Rac (12), which has been implicated in cell migration, a process that is critical for tumor metastasis (13).…”

“…It is activated downstream of phosphoinositide 3-kinase (PI3K) and G-protein coupled receptors (GPCRs) to promote activation of Rac (12), which has been implicated in cell migration, a process that is critical for tumor metastasis (13). Although P-Rex1 demonstrates negligible protein expression in most benign tissues (13)(14)(15), it is thought to stimulate numerous aspects of oncogenesis, including migration, invasion, and metastasis in various malignancies (13,(15)(16)(17)(18).…”