关键词:

芦荟大黄素, RRS1, 血管生成, 三阴性乳腺癌, HIF-1α

Abstract:

This study aims to investigate the effect of aloe-emodin (AE) on inhibiting angiogenesis in triple-negative breast cancer (TNBC),its direct target,and the underlying molecular mechanism. In vitro,TNBC cells were treated with AE at 0, 10,20 and 40 μmol/ L,and cell proliferation,migration/ invasion,and angiogenic capacity were assessed by CCK-8,wound healing / Transwell,and tube formation assays,respectively. In vivo,a xenograft tumor model was established,and immunohistochemistry was used to detect tumor cell density and microvessel density based on CD31 (cluster of differentiation 31) staining. Molecular docking,pull-down assays,and cellular thermal shift assay (CETSA) were employed to identify the target, and knockdown/ overexpression combined with Western blot were used to verify the signaling pathway. The results showed that AE suppressed TNBC cell proliferation,migration,invasion,and angiogenesis in a concentration-dependent manner,and reduced tumor cell density and microvessel density in vivo (P < 0. 05,P < 0. 01 or P < 0. 001). Molecular docking,pull-down, and CETSA revealed that AE could directly bind to ribosome biogenesis regulator 1 homolog (RRS1) and downregulate its expression (P < 0. 05,P < 0. 01 or P < 0. 001). Knockdown of RRS1 inhibited angiogenesis,while overexpression had the opposite effect (P < 0. 05,P < 0. 01 or P < 0. 001). Transcriptomic analysis combined with Western blot suggested that RRS1 regulated the hypoxia-inducible factor 1α (HIF-1α) pathway,and AE modulated the expression of RRS1 and downstream HIF-1α-related proteins (P < 0. 05,P < 0. 01 or P < 0. 001). In conclusion,AE may inhibit TNBC angiogenesis through downregulating RRS1,with the HIF-1α pathway serving as a potential downstream mechanism.

Key words:

aloe-emodin, RRS1, angiogenesis, triPle-negative breast cancer, HIF-1α