Background No in-depth systematic evidence is available for assessing retinoblastoma malignancy and eligibility for subsequent treatment. Methods The Cochrane Library, EMBASE, PubMed, Web of Science, and China Biology Medicine databases were searched, and 16 studies comprising 718 retinoblastoma patients were included. Pooled odds ratios (ORs) and summary correlation coefficients (r) with 95% confidence intervals (CIs) in random-effects, fixed-effects or quality-effects models were calculated using Review Manager 5.3 and MetaXL. GO functional annotation and KEGG pathway analysis were performed using the GO and STRING databases. Results We observed significant associations between high levels of MMP-1 (OR, 4.21; 95% CI 1.86–9.54), MMP-2 (OR, 11.18; 95% CI 4.26–29.30), MMP-9 (OR, 10.41, 95% CI 4.26–25.47), and VEGF (OR, 8.09; 95% CI 4.03–16.20) with tumor invasion; high levels of MMP-1 (OR, 3.58; 95% CI 1.48–8.71), MMP-2 (OR, 2.96; 95% CI 1.32–6.64), MMP-9 (OR, 5.49; 95% CI 3.55–8.48) and VEGF (OR, 5.30; 95% CI 2.93–9.60) with poor differentiation; and overexpression of MMP-9 (OR, 5.17; 95% CI 2.85–9.38) with advanced clinical stages. Moreover, MMP-9 and VEGF expression were positively correlated (r, 0.61; 95% CI 0.38–0.77). Multiple GO terms were enriched associated with MMP-1, MMP-2, MMP-9 and VEGF, and they are closely associated with pathways, proteoglycans and microRNAs related to cancer. Conclusions MMP-1, MMP-2, MMP-9 and VEGF play important roles in the development and progression of retinoblastoma. High levels of MMP-1, MMP-2, MMP-9 and VEGF are credible implications for increased malignancy, thus the need for more aggressive treatments. Electronic supplementary material The online version of this article (10.1186/s12967-019-1975-3) contains supplementary material, which is available to authorized users.

No abstract

Objective To investigate the regulation of special protein 1 (SP1) and hypoxia‐inducible factor‐1α (HIF1α) on human microvascular endothelial cells (HMEC‐1) under hypoxic conditions. Methods The expression of SP1 and HIF1α under normoxia and hypoxic conditions were assessed by Western blot. SP1 and HIF1α were knocked down by small interfering RNA (siRNA) under hypoxic conditions. The proliferation, migration, and invasion of HMEC‐1 were measured by cell counting kit 8, 5‐ethynyl‐2′‐deoxyuridine and Transwell coculture system. Western blot analysis and Immunofluorescence were carried out to study the mechanisms of simultaneously inhibiting the adenosine triphosphatase (CD39), 5′‐nucleotidase (CD73), adenosine, and vascular endothelial growth factor (VEGF). We compared the inhibitory effects between groups concurrently interfering SP1, HIF‐1α, and ranibizumab under hypoxic conditions. Results Under hypoxic conditions, the protein expression of SP1 and HIF1α was increased in HMEC‐1, contrarily, SP1 siRNA and HIF1α siRNA downregulated the expression. Simultaneous inhibition of SP1 and HIF1α demonstrated a much greater restraint of proliferation, migration, and invasion characteristics on HMEC‐1 than respectively knocking down SP1 or HIF1α and anti‐VEGF drugs (0.5 mg/mL ranibizumab) (siRNA and the VEGF inhibitor were applied separately in different groups). Meanwhile, simultaneous inhibition of SP1 and HIF1α effectively reduced the expression of CD39, CD73, adenosine, and VEGF on HMEC‐1 under hypoxic conditions. Conclusions Our study demonstrated that both SP1 and HIF1α played important roles in HMEC‐1 under hypoxia condition. Simultaneous inhibition of SP1 and HIF1α effectively decreased the activity of HMEC‐1 under hypoxic conditions through the CD39‐CD73‐adenosine and VEGF angiogenesis pathways. Our study may provide a new approach to the treatment of retinal neovascular diseases.