The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer

上皮-间质转换 Wnt信号通路 WNT5A型 卵巢癌 癌症研究 下调和上调 癌症 医学 免疫组织化学 肿瘤科 内科学 生物 病理 转移 信号转导 细胞生物学 基因 生物化学
作者
Caroline E. Ford,G. Punnia-Moorthy,Claire Henry,E. Llamosas,Sheri Nixdorf,Jake Olivier,Rosemarie Caduff,Robyn L. Ward,Viola Heinzelmann‐Schwarz
出处
期刊:Gynecologic Oncology [Elsevier]
卷期号:134 (2): 338-345 被引量:61
标识
DOI:10.1016/j.ygyno.2014.06.004
摘要

Objective Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting β-catenin dependent and independent Wnt signalling pathways. Method Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines. Results Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of β-catenin dependent Wnt signalling were inhibited, and β-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation. Conclusion This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).
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