Wnt5A and TGFβ1 Converges through YAP1 Activity and Integrin Alpha v Up-Regulation Promoting Epithelial to Mesenchymal Transition in Ovarian Cancer Cells and Mesothelial Cell Activation

被引:21
作者
Dehghani-Ghobadi, Zeinab [1 ]
Sheikh Hasani, Shahrzad [2 ]
Arefian, Ehsan [3 ]
Hossein, Ghamartaj [1 ]
机构
[1] Univ Tehran, Coll Sci, Sch Biol, Dev Biol Lab,Dept Anim Biol, Tehran 1417614411, Iran
[2] Univ Tehran Med Sci, Imam Khomeini Hosp, Dept Gynecol Oncol Valiasr, Tehran 1419733141, Iran
[3] Univ Tehran, Coll Sci, Sch Biol, Mol Virol Lab,Dept Microbiol, Tehran 1417614411, Iran
关键词
epithelial to mesenchymal transition; ovarian cancer; Wnt5A; TGF131/Smad signaling; hippo-YAP1/TAZ signaling; integrin alpha v; mesothelial cell activation; TGF-BETA; ALPHA-V-BETA-6; MECHANISMS; EXPRESSION; CARCINOMA; MIGRATION; FIBROSIS; BIOLOGY; LIGAND;
D O I
10.3390/cells11020237
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
In this paper, we investigate whether Wnt5A is associated with the TGF-beta 1/Smad2/3 and Hippo-YAP1/TAZ-TEAD pathways, implicated in epithelial to mesenchymal transition (EMT) in epithelial ovarian cancer. We used 3D and 2D cultures of human epithelial ovarian cancer cell lines SKOV-3, OVCAR-3, CAOV-4, and different subtypes of human serous ovarian cancer compared to normal ovary specimens. Wnt5A showed a positive correlation with TAZ and TGF beta 1 in high- and low-grade serous ovarian cancer specimens compared to borderline serous and normal ovaries. Silencing Wnt5A by siRNAs significantly decreased Smad2/3 activation and YAP1 expression and nuclear shuttling in ovarian cancer (OvCa) cells. Furthermore, Wnt5A was required for TGF beta 1-induced cell migration and invasion. In addition, inhibition of YAP1 transcriptional activity by Verteporfin (VP) altered OvCa cell migration and invasion through decreased Wnt5A expression and inhibition of Smad2/3 activation, which was reverted in the presence of exogenous Wnt5A. We found that the activation of TGF beta 1 and YAP1 nuclear shuttling was promoted by Wnt5A-induced integrin alpha v. Lastly, Wnt5A was implicated in activating human primary omental mesothelial cells and subsequent invasion of ovarian cancer cells. Together, we propose that Wnt5A could be a critical mediator of EMT-associated pathways.
引用
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页数:20
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