Abstract
BackgroundInhibition of angiogenesis in prostatic cancer could be a brand-new method to suppress tumour progression. Nodal/ALK4 has been associated with vascularization in many cancers. However, the relationship between and role of Nodal/ALK4 and miR-185 in human prostatic cancer is still unknown.MethodsProstatic cancer DU145 cells and LNCaP cells were used to investigate the angiogenic effect induced by Nodal and the anti-angiogenic roles of miR-185. Colony formation assay, MTT assay, transwell assay and tube formation assay were used to explore cell proliferation, migration and tube-forming ability, respectively. A luciferase reporter assay confirmed the binding relationship between miR-185 and ALK4. The expression levels of miR-185, ALK4 and VEGF were detected by qRT-PCR and Western blotting. The effects of miR-185 and Nodal in prostate cancer were also investigated in animal experiments.ResultsVEGF expression was increased in DU145 cells and LNCaP cells after Nodal incubation, and Nodal activated the proliferation ability of prostatic cancer cells and the migration and tube-forming ability of human umbilical vein endothelial cells (HUVECs), which were all inhibited by treatment with the Nodal inhibitor SB431524. Bioinformatics analysis and luciferase assay were used to verify miR-185 as a target of ALK4. Prostatic cancer cell proliferation was inhibited by overexpression of miR-185, which was shown to regulate the migration and angiogenesis of HUVECs by targeting ALK4 for suppression. miR-185 also showed a significant inverse correlation with Nodal treatment and reversed the angiogenic effects induced by Nodal. More importantly, for the first time, xenograft experiments indicated that overexpression of miR-185 suppressed tumour development.ConclusionThe Nodal/ALK4 pathway is important in the angiogenesis of prostate cancer and can be inhibited by targeting miR-185 to downregulate ALK4. These findings provide a new perspective on the mechanism of prostate cancer formation.
Highlights
Inhibition of angiogenesis in prostatic cancer could be a brand-new method to suppress tumour progression
Nodal promoted prostate cancer cell-induced angiogenesis To determine whether Nodal treatment affected prostate cancer cell angiogenesis, DU145 cells and LNCaP cells were divided into three groups: control, Nodal, and Nodal+SB431524, where SB431524 is an inhibitor of Nodal
Compared to DU145 cells or LNCaP cells treated with Nodal alone, Human umbilical vein endothelial cells (HUVEC) co-cultured with DU145 cells or LNCaP cells decreased the number of migrated HUVECs after treatment with Nodal+SB431524 (Fig. 1d)
Summary
Inhibition of angiogenesis in prostatic cancer could be a brand-new method to suppress tumour progression. Nodal/ALK4 has been associated with vascularization in many cancers. The relationship between and role of Nodal/ALK4 and miR-185 in human prostatic cancer is still unknown. It was reported in the literature that Nodal was highly expressed in prostate cancer cells such as WPE, DU145, and LNCaP and could regulate prostate cancer proliferation by activating smad 2/3 phosphorylation by activin receptor-like kinase 4 (ALK4) [6]. Another report indicated that Nodal could promote the formation of tumour angiogenesis mimicry in malignant tumours such as breast cancer [7]. Whether the Nodal/ ALK4 pathway is related to the regulation of prostate cancer angiogenesis has not been reported in the literature
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