A critical ETV4/Twist1/Vimentin axis in Ha-RAS-induced aggressive breast cancer.

Autor: Liu W; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Gajendran B; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China.; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou, China., Sample KM; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Wang C; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Hu A; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Chen B; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Li Y; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China., Zacksenhaus E; Department of Medicine, University of Toronto, Toronto, ON, Canada.; Division of Advanced Diagnostics, Toronto General Research Institute-University Health Network, Toronto, ON, Canada., Ben-David Y; State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China. yaacovbendavid@gzcnp.cn.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, China. yaacovbendavid@gzcnp.cn.
Jazyk: angličtina
Zdroj: Cancer gene therapy [Cancer Gene Ther] 2022 Nov; Vol. 29 (11), pp. 1590-1599. Date of Electronic Publication: 2022 Apr 27.
DOI: 10.1038/s41417-022-00471-4
Abstrakt: RAS oncogenes are major drivers of diverse types of cancer. However, they are largely not druggable, and therefore targeting critical downstream pathways and dependencies is an attractive approach. We have isolated a tumorigenic cell line (FE1.2), which exhibits mesenchymal characteristics, after inoculating Ha-Ras-expressing retrovirus into mammary glands of rats, and subsequently isolated a non-aggressive revertant cell line (FC5). This revertant has lost the rat Ha-Ras driver and showed a more epithelial morphology, slower proliferation in culture, and reduced tumorigenicity in vivo. Re-expression of human Ha-RAS in these cells (FC5-RAS) reinduced mesenchymal morphology, higher proliferation rate, and tumorigenicity that was still significantly milder than parental FE1.2 cells. RNA-seq analysis of FC5-RAS vs FC5-Vector cells identified multiple genes whose expressions were regulated by Ha-RAS. This analysis also identified many genes including those controlling cell growth whose expression was altered by loss of HA-Ras in FC5 cells but remained unchanged upon reintroduction of Ha-RAS. These results suggest that targeting the Ha-Ras driver oncogene induces partial tumor regression, but it still denotes strong efficacy for cancer therapy. Among the RAS-responsive genes, we identified Twist1 as a critical mediator of epithelial-to-mesenchymal transition through the direct transcriptional regulation of vimentin. Mechanistically, we show that Twist1 is induced by the ETS gene, ETV4, downstream of Ha-RAS, and that inhibition of ETV4 suppressed the growth of breast cancer cells driven by the Ha-RAS pathway. Targeting the ETV4/Twist1/Vimentin axis may therefore offer a therapeutic modality for breast tumors driven by the Ha-RAS pathway.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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