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Retinoblastoma binding protein 2 (RBP2) promotes HIF-1alpha-VEGF-induced angiogenesis of non-small cell lung cancer via the Akt pathway.

Authors: Qi, L  Zhu, F  Li, SH  Si, LB  Hu, LK  Tian, H 
Citation: Qi L, etal., PLoS One. 2014 Aug 27;9(8):e106032. doi: 10.1371/journal.pone.0106032. eCollection 2014.
Pubmed: (View Article at PubMed) PMID:25162518
DOI: Full-text: DOI:10.1371/journal.pone.0106032

BACKGROUND: 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). METHODS: Immunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1alpha (HIF-1alpha), 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. RESULTS: Of the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1alpha 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-1alpha 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-1alpha, and activated the HIF-1alpha via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2. CONCLUSIONS: The RBP2 protein may stimulate HIF-1alpha 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.


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CRRD Object Information
CRRD ID: 9588530
Created: 2014-10-30
Species: All species
Last Modified: 2014-10-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.