Inhibiting GIT1 reduces the growth, invasion, and angiogenesis of osteosarcoma

Abstract

BackgroundGIT1, a scaffold protein with ubiquitous multi-domain, is involved in many cellular processes. In recent years, it was proved that GIT1 participated in various tumors’ growth or metastasis. However, the biological function of GIT1 in osteosarcoma is still unclear. In this study, we aimed to investigate the role and mechanism of GIT1 in osteosarcoma.Materials and methodsHuman osteosarcoma tissues were obtained to investigate the distribution of GIT1. Adequate osteosarcoma cells were stably infected with lentivirus to knockdown GIT1 level and then was used to carry out cell invasion and vascular endothelial growth factor (VEGF) assay in vitro. Orthotopic femoral osteosarcoma model was constructed to investigate the growth, invasion, and angiogenesis in vivo. Western blot was used to detect extracellular signal-regulated kinase (ERK1/2) activation and hypoxia-inducible factor-1 (HIF-1α) expression.ResultsIn this study, we found that GIT1 was distributed in human osteosarcoma tissues and highly expressed in osteosarcoma (OS) cells. Knockdown of GIT1 inhibited cell invasion and VEGF release in vitro and suppressed tumor growth, invasion, and angiogenesis in vivo. Furthermore, knockdown of GIT1 substantially downregulated the protein levels of p-ERK and HIF-1α in OST cells and inhibition of p-ERK by PD98059 could significantly decrease the expression of HIF-1α and concentration of VEGF in GIT1-shRNA-treated cells.ConclusionGIT1 knockdown can effectively inhibit the growth, invasion, and angiogenesis of osteosarcoma. Thus, GIT1 might act as an oncogenic factor in osteosarcoma and could be a potential molecular target for osteosarcoma gene therapy.

YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA

“…HCC is the most common primary malignant liver tumor with abundant tumor vascular network, which provides the evidence for the clinical therapies targeted vascular endothelial growth factor (VEGF) for the treatment of unresectable HCC (2). Angiogenesis is critical to multiple tumor invasion and metastasis (3, 4). Targeted angiogenesis therapy is an important anti-tumor strategy at present and it is particularly important to understand the transcriptional regulation of tumor angiogenesis (5, 6).…”

G-Protein-Coupled Receptor Kinase-Interacting Protein 1 (GIT1) Promotes Head and Neck Squamous Cell Carcinoma Metastases via Activating the PI3K/AKT/mTOR Signal Pathway

“…Zhao et al discovered that MeCP2 facilitated cell growth by upregulating GIT1 expression in gastric cancer [ 20 ]. In osteosarcoma, GIT1 was discovered to be highly expressed, and GIT1 knockout repressed cell invasion, cell growth, and angiogenesis [ 21 ]. Consistent with our findings, GIT1 knockout was confirmed to inhibit tumor growth in breast cancer [ 11 , 22 ].…”

Integrated Role of Nanotechnology and Pharmacogenetics in Diagnosis and Treatment of Diseases

“…OS cell-specific aptamer (LC09) -functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9 in both orthotopic OS and lung metastasis, showed effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis [98]. Zhang et al evaluated G-protein-coupled Receptor Kinase Interactor-1(GIT1), as a target for the treatment of osteosarcoma and suggested that knowdown of GIT1 inhibited cell invasion and VEGF release in vitro and suppressed tumor growth, invasion, and angiogenesis in vivo, and also resulted in downregulation of hypoxia-inducible factor1α (HIF1α) and extracellular signal-regulated kinase (ERK1/2) pathways [99]. Moreover studies have shown that ALDH1B1, a subfamily of Aldehyde dehydrogenases (ALDHs), is upregulated in OS.…”