Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer

Murillo-Garzón, Virginia; Gorroño-Etxebarria, Irantzu; Åkerfelt, Malin; Puustinen, Mikael C.; Sistonen, Lea; Nees, Matthias; Carton, James; Waxman, Jonathan; Kypta, Robert M.

doi:10.1038/s41467-018-04042-w

Cited by 81 publications

(85 citation statements)

References 68 publications

(91 reference statements)

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“…A recent study, showed that in PCa, wild type p53 transcriptionally repressed FZD8 by directly interacting with the FZD8 promoter . This study and another study, showed the critical role of FZD8 in PCa bone metastasis. Other Frizzled receptors, like FZD4, was shown to be a direct target of ERG in PCa .…”

Section: Discussionsupporting

confidence: 63%

“…Wnt signaling activates diverse responses including cell proliferation, migration, polarity, metastasis, and maintenance of stemness. Studies show that Wnt2 signaling is activated through FZD8 in non‐small cell lung cancer (NSCLC), and FZD8 is a major Wnt11 receptor in PCa . Activation of canonical WNT signaling results in β‐catenin stabilization and translocation to the nucleus, where it promotes expression of Wnt target genes, such as LEF1 and AXIN2.…”

Section: Discussionmentioning

confidence: 99%

“…FZD4 knockdown in the VCaP cell lines induces beta (1)‐integrin and E‐cadherin expression, while overexpression shows an inverse effect on these molecules, suggesting modulation of epithelial‐mesenchymal transition (EMT) by FZD4. A recent study showed evidence that Frizzled‐8 (FZD8) is a major Wnt11 receptor, involved in the expression of EMT‐related genes, and TGF‐β/Smad‐dependent signaling in PCa …”

Section: Introductionmentioning

confidence: 99%

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Wnt receptor Frizzled 8 is a target of ERG in prostate cancer

et al. 2018

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Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men. Many molecular changes have been detailed during PCa progression. The gene encoding the transcription factor ERG shows recurrent rearrangement, resulting in the overexpression of ERG in the majority of prostate cancers. Overexpression of ERG plays a critical role in prostate oncogenesis and development of metastatic disease. Among the downstream effectors of ERG, Frizzled family member FZD4 has been shown to be a target of ERG. Frizzled-8 (FZD8) has been shown to be involved in PCa bone metastasis. In the present study, we show that the expression of FZD8 is directly correlated with ERG expression in PCa. Furthermore, we show that ERG directly targets and activates FZD8 by binding to its promoter. This activation is specific to ETS transcription factor ERG and not ETV1. We propose that ERG overexpression in PCa leads to induction of Frizzled family member FZD8, which is known to activate the Wnt pathway. Taken together, these findings uncover a novel mechanism for PCa metastasis, and indicate that FZD8 may represent a potential therapeutic target for PCa.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wnt receptor Frizzled 8 is a target of ERG in prostate cancer

et al. 2018

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“…EMT is an initial transition stage toward cancer progression. EMT is a trigger of cancer cell migration, invasion, and metastasis (Murillo‐Garzón et al, ). EMT is induced in a cell through loss of epithelial proteins such as E‐cadherin and attaining mesenchymal proteins such as vimentin and N‐cadherin.…”

Section: Mapk Involvement In Emt Invasion and Metastasismentioning

confidence: 99%

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

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Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

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“…1B), it will be lipidated by a special palmitoyl transferase-porcupine [34], further modified by Wntless in the Golgi and finally secreted by exocytosis [35,36]. Frizzled (FZD) receptors, the principal receptors for Wnts, consist of seven-transmembrane proteins and cysteine-rich domain (CRD) in the N-terminal [37,38]. Low-density lipoprotein receptor-related proteins (LRPs), the co-receptors of FZDs, are long single-pass transmembrane proteins.…”

Section: Canonical Wnt Pathway Activation Mechanismmentioning

confidence: 99%