Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29717114.
- Also identified by DOI 10.1038/s41467-018-04042-w and PMC identifier 5931552.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD<sub>8</sub> is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD<sub>8</sub> in cancer, correlating with Wnt-11. FZD<sub>8</sub> co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD<sub>8</sub> forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD<sub>8</sub> and TGFBR1. Targeting FZD<sub>8</sub> may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.
Medical subject headings
- Prostatic Neoplasms
- Receptors, Cell Surface
- Signal Transduction
- Transforming Growth Factor beta
- Wnt Proteins