Of all pathological types of renal cell cancer (RCC), clear cell renal cell carcinoma (ccRCC) has the highest incidence. Cyclovirobuxine (CVB), a triterpenoid alkaloid isolated from Buxus microphylla, exhibits antitumour activity against gastric cancer and breast cancer; however, the mechanism by which CVB inhibits ccRCC remains unclear. The aim of our study was to explore the antitumour effects of CVB on ccRCC and to elucidate its exact mechanism. Cell viability, proliferation, cell cycle distribution, apoptosis, wound healing and invasion were evaluated. Furthermore, Western blotting, immunofluorescence staining, immunohistochemical staining, and bioinformatics analyses were utilized to comprehensively probe the molecular mechanisms. The in vivo curative effect of CVB was explored using a 786-O xenograft model established in nude mice. CVB reduced cell viability, proliferation, angiogenesis, the epithelial-mesenchymal transition (EMT), migration and invasion. In addition, CVB induced cell cycle arrest in S phase and promoted apoptosis. The expression of the EMT-related transcription factor Snail was significantly downregulated by CVB via the inhibition of the AKT, STAT3 and MAPK pathways. We revealed that insulin-like growth factor binding protein 3 (IGFBP3) was the true therapeutic target of CVB. CVB exerted anti-ccRCC effects by blocking the IGFBP3-AKT/STAT3/MAPK-Snail pathway. Targeted inhibition of IGFBP3 with CVB treatment may become a promising therapeutic regimen for ccRCC.

中文翻译：

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环罗布星通过抑制IGFBP3-AKT/STAT3/MAPK-Snail信号通路抑制透明细胞肾细胞癌的进展

在所有病理类型的肾细胞癌（RCC）中，透明细胞肾细胞癌（ccRCC）的发病率最高。Cyclovirobuxine (CVB) 是一种从小叶黄杨中分离出来的三萜类生物碱，对胃癌和乳腺癌具有抗肿瘤活性；然而，CVB 抑制 ccRCC 的机制仍不清楚。我们研究的目的是探索 CVB 对 ccRCC 的抗肿瘤作用并阐明其确切机制。评估细胞活力、增殖、细胞周期分布、细胞凋亡、伤口愈合和侵袭。此外，还利用蛋白质印迹、免疫荧光染色、免疫组织化学染色和生物信息学分析来全面探讨分子机制。体内_采用裸鼠786-O异种移植模型探讨CVB的疗效。CVB 降低了细胞活力、增殖、血管生成、上皮-间质转化 (EMT)、迁移和侵袭。此外，CVB诱导细胞周期停滞在S期并促进细胞凋亡。CVB 通过抑制 AKT、STAT3 和 MAPK 通路显着下调 EMT 相关转录因子 Snail 的表达。我们发现胰岛素样生长因子结合蛋白 3 (IGFBP3) 是 CVB 的真正治疗靶点。CVB 通过阻断 IGFBP3-AKT/STAT3/MAPK-Snail 通路发挥抗 ccRCC 作用。用 CVB 治疗靶向抑制 IGFBP3 可能成为 ccRCC 的有希望的治疗方案。