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<i>Nogo-B</i> has been reported to play a critical role in angiogenesis and the repair of damaged blood vessels; however, its role in the tumor microenvironment remains unclear. Here, we observed the differential expression of <i>Nogo-B</i> in endothelial cells from hepatocellular carcinoma (HCC) and glioma samples. Downregulation of <i>Nogo-B</i> expression correlated with the malignant phenotype of cancer and a poor prognosis for patients. In subsequent studies, endothelial <i>Nogo-B</i> inhibition robustly promoted the growth of HCC or glioma xenografts in nude mice. Intriguingly, endothelial <i>Nogo-B</i> silencing dramatically suppressed endothelial cell expansion and tumor angiogenesis, but potently enhanced the proliferation of neighboring HCC and glioma cells. Based on the results of the ELISA assay, <i>Nogo-B</i> silencing reduced TGF-β production in endothelial cells, which attenuated the phosphorylation and nuclear translocation of Smad in neighboring cancer cells. The endothelial <i>Nogo-B</i> silencing-mediated increase in cancer cell proliferation was abolished by either a TGF-β neutralizing antibody or TGF-β receptor inhibitor, indicating the essential role for TGF-β in endothelial <i>Nogo-B</i>-mediated suppression of cancer growth. These findings not only broaden our understanding of the crosstalk between cancer cells and endothelial cells but also provide a novel prognostic biomarker and a therapeutic target for cancer treatments.