Int J Biol Sci 2021; 17(13):3522-3537. doi:10.7150/ijbs.62114 This issue

Research Paper

Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway

Yadong Liu1,2,5*, Huiyan Lv3*, Xingyi Li4*, Jiannan Liu5, Song Chen5, Yaodong Chen6, Yinshan Jin5, Ruihua An5, Shiliang Yu5✉, Zhigang Wang1,2✉

1. Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
2. State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing 400016, China.
3. Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, No.23 You Zheng Street, Harbin 150001, Heilongjiang, China.
4. Department of Ultrasonic Imaging, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, China.
5. Department of Urology, The First Affiliated Hospital of Harbin Medical University, No.23 You Zheng Street, Harbin 150001, Heilongjiang, China.
6. Department of Ultrasonic Imaging, First Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China.
*These authors contributed equally to this work.

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Citation:
Liu Y, Lv H, Li X, Liu J, Chen S, Chen Y, Jin Y, An R, Yu S, Wang Z. Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway. Int J Biol Sci 2021; 17(13):3522-3537. doi:10.7150/ijbs.62114. Available from https://www.ijbs.com/v17p3522.htm

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Abstract

Graphic abstract

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.

Keywords: Cyclovirobuxine, clear cell renal cell carcinoma (ccRCC), IGFBP3, AKT/STAT3/MAPK, Snail, EMT