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Reproduction. 2018 Jan;155(1):61-71. doi: 10.1530/REP-17-0339. Epub 2017 Oct 24.

Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids.

Author information

1
School of Biomedical Sciences and PharmacyUniversity of Newcastle, Callaghan, New South Wales, Australia.
2
Division of Molecular MedicineNSW Health Pathology, John Hunter Hospital, Newcastle, New South Wales, Australia.
3
Stem Cell and Cancer Biology LaboratorySchool of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
4
School of Medicine and Public HealthUniversity of Newcastle, Callaghan, New South Wales, Australia.
5
Department of Maternity and GynecologyJohn Hunter Hospital, New Lambton, New South Wales, Australia.
6
School of Biomedical Sciences and PharmacyUniversity of Newcastle, Callaghan, New South Wales, Australia pradeep.tanwar@newcastle.edu.au.

Abstract

Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/β-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wild-type fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium samples. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild-type fibroids. Liquid chromatography-mass spectrometry (LC-MS), Western blotting and immunohistochemistry were used to monitor the expression of β-catenin. We showed that β-catenin expression was increased in fibroids compared to the adjacent myometrium samples. However, β-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on β-catenin expression and revealed increased levels of β-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed that β-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate β-catenin expression in fibroids, providing an attractive avenue for developing new treatments for this disease.

PMID:
29066531
DOI:
10.1530/REP-17-0339
[Indexed for MEDLINE]

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