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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
来源:
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.
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页数:20
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