WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer.

Abstract

We previously characterized the link between WNT7A and the progression of ovarian cancer. Other groups have identified FGF1 as a relevant risk factor in ovarian cancer. Here, we show a linkage between these two signaling pathways that may be exploited to improve treatment and prognosis of patients with ovarian cancer. High expression of WNT7A and FGF1 are correlated in ovarian carcinomas and poor overall patient survival. A chromatin immunoprecipitation assay demonstrated that WNT7A/β-catenin signaling directly regulates FGF1 expression via TCF binding elements in the FGF1-1C promoter locus. In vitro gene manipulation studies revealed that FGF1 is sufficient to drive the tumor-promoting effects of WNT7A. In vivo xenograft studies confirmed that the stable overexpression of WNT7A or FGF1 induced a significant increase in tumor incidence, whereas FGF1 knockdown in WNT7A overexpressing cells caused a significant reduction in tumor size. Niclosamide most efficiently abrogated WNT7A/β-catenin signaling in our model, inhibited β-catenin transcriptional activity and cell viability, and increased cell death. Furthermore, niclosamide decreased cell migration following an increase in E-cadherin subsequent to decreased levels of SLUG. The effects of niclosamide on cell functions were more potent in WNT7A-overexpressing cells. Oral niclosamide inhibited tumor growth and progression in an intraperitoneal xenograft mouse model representative of human ovarian cancer. Collectively, these results indicate that FGF1 is a direct downstream target of WNT7A/β-catenin signaling and this pathway has potential as a therapeutic target in ovarian cancer. Moreover, niclosamide is a promising inhibitor of this pathway and may have clinical relevance.

• Authors: M L King, M E Lindberg, G R Stodden, H Okuda, S D Ebers, A Johnson, A Montag, E Lengyel, J A MacLean Ii, K Hayashi
• Journal: Oncogene (Oncogene) Vol. 34 Issue 26 Pg. 3452-62 (Jun 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25174399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• WNT7A protein, human
• Wnt Proteins
• beta Catenin
• Fibroblast Growth Factor 1
• Niclosamide

Topics

• Animals
• Cell Proliferation (drug effects, genetics)
• Cells, Cultured
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Female
• Fibroblast Growth Factor 1 (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Niclosamide (pharmacology)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Wnt Proteins (physiology)
• Wnt Signaling Pathway (physiology)
• beta Catenin (physiology)