WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway.
Abnormal activation the WNT/β-catenin signaling pathway has been associated with ovarian carcinomas, but a specific WNT ligand and pertinent downstream mechanisms are not fully understood. In this study, we found abundant WNT7A in the epithelium of serous ovarian carcinomas, but not detected in borderline and benign tumors, normal ovary, or endometrioid carcinomas. To characterize the role of WNT7A in ovarian tumor growth and progression, nude mice were injected either intraperitoneally or subcutaneously with WNT7A knocked down SKOV3.ip1 and overexpressed SKOV3 cells. In the intraperitoneal group, mice receiving SKOV3.ip1 cells with reduced WNT7A expression developed significantly fewer tumor lesions. Gross and histologic examination revealed greatly reduced invasion of WNT7A knockdown cells into intestinal mesentery and serosa compared with the control cells. Tumor growth was regulated by loss or overexpression of WNT7A in mice receiving subcutaneous injection as well. In vitro analysis of cell function revealed that cell proliferation, adhesion, and invasion were regulated by WNT7A. The activity of the T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter was stimulated by overexpression of WNT7A in ovarian cancer cells. Cotransfection with WNT7A and FZD5 receptor further increased activity, and this effect was inhibited by cotransfection with SFRP2 or dominant negative TCF4. Overexpression of WNT7A stimulated matrix metalloproteinase 7 (MMP7) promoter, and mutation of TCF-binding sites in MMP7 promoter confirmed that activation of MMP7 promoter by WNT7A was mediated by β-catenin/TCF signaling. Collectively, these results suggest that reexpression of WNT7A during malignant transformation of ovarian epithelial cells plays a critical role in ovarian cancer progression mediated by WNT/β-catenin signaling pathway.
Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
Shin
S
Yoshioka
Mandy L
ML
King
Sophia
S
Ran
Hiroshi
H
Okuda
James A
JA
MacLean
Mary E
ME
McAsey
Norihiro
N
Sugino
Laurent
L
Brard
Kounosuke
K
Watabe
Kanako
K
Hayashi
D000818:Animals; D001483:Base Sequence; D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
C498589:FZD5 protein, human; D051157:Frizzled Receptors; D051820:TCF Transcription Factors; C092778:WNT7A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7