Abstract
BackgroundPathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC).MethodsImmunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD34. Two pairs of siRNA sequences and pcDNA3-HA-RBP2 were used to down-regulate and up-regulate RBP2 expression in H1975 and SK-MES-1 cells. An endothelial cell tube formation assay, VEGF enzyme-linked immunosorbent assay, real-time PCR and western blotting were performed to detect the potential mechanisms mediated by RBP2 in tumor angiogenesis.ResultsOf the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1α expression (P = 0.028), high VEGF expression (P = 0.048), increased tumor angiogenesis (P = 0.033) and poor prognosis (P = 0.037); high MVD was associated with high HIF-1α expression (P = 0.034), high VEGF expression (P = 0.001) and poor prognosis (P = 0.040). Multivariate analysis indicated that RBP2 had an independent influence on the survival of patients with stage I NSCLC (P = 0.044). By modulating the expression of RBP2, our findings suggested that RBP2 protein depletion decreased HUVECs tube formation by down-regulating VEGF in a conditioned medium. RBP2 stimulated the up-regulation of VEGF, which was dependent on HIF-1α, and activated the HIF-1α via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2.ConclusionsThe RBP2 protein may stimulate HIF-1α expression via the activation of the PI3K/Akt signaling pathway under normoxia and then stimulate VEGF expression. These findings indicate that RBP2 may play a critical role in tumor angiogenesis and serve as an attractive therapeutic target against tumor aggressiveness for early-stage NSCLC patients.
Highlights
Non-small cell lung cancer (NSCLC) is among the most common malignancies leading to cancer-related death worldwide [1]
To further investigate the potential roles of Retinoblastoma binding protein 2 (RBP2) in tumor angiogenesis, we provide evidence showing that high RBP2 expression in non-small cell lung cancer (NSCLC) cell lines significantly promotes tumor angiogenesis and elucidate the mechanism involved in the activation of Akt signaling, induction of hypoxia-inducible factor-1a (HIF-1a) protein accumulation and vascular endothelial growth factor (VEGF) expression under normoxia
Relationships between RBP2 protein expression and clinicopathologic factors were examined by the chi-square test and our data showed that RBP2 overexpression was associated with tumor size (P = 0.030), high HIF-1a expression (P = 0.028) and high VEGF expression (P = 0.048)
Summary
Non-small cell lung cancer (NSCLC) is among the most common malignancies leading to cancer-related death worldwide [1]. It has been proposed that vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a (HIF-1a) play critical roles in tumor angiogenesis. VEGF, which is the most extensively characterized endothelial cell-specific angiogenic factor, leads to increased vascular permeability and plays a significant role in physiological and pathological angiogenesis [5,6]. Many studies have suggested that HIF-1a could lead to the elevated expression of various genes involved in diverse biological functions under normoxia, including cell proliferation, apoptosis, migration, invasion and angiogenesis [10,11]. Pathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
