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| Entity | Familial Exudative Vitreoretinopathy (FEVR) |
| Note | Familial Exudative Vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by incomplete development of the retinal vasculature.
It is possible to distinguish two forms of FEVR: one with dominant autosomal inheritance and one with X-linked recessive inheritance (Gilmour DF., 2015).
Autosomal inheritance has been associated with mutation of FZD4, LRP5 or Tetraspanin 12 (TSPAN12) genes, while X-linked recessive inheritance is due to mutation of Norrin gene (NPD) that it is also involved in other ocular disease.
Several FZD4 mutations were connected with FEVR, many of which were found in the extracellular portion of the protein. Kaykas et al., have shown how some FZD4 mutations in FEVR lead to the retention of mutated protein within the endoplasmic reticulum (ER), where it is recognized by endoplasmic-reticulum-associated protein degradation (ERAD) and degraded, not allowing its exposure on the plasma membrane. They also demonstrated that oligomerization of mutants and wild-type FZD4 in the ER reduces the FZD4 function by preventing a sufficient amount of FZD4 from reaching the cell membrane and inhibits its signaling. This dominant-negative effect can partly explain the pathological mechanism that causes the disease phenotype, in patients with heterozygous FZD4 mutations. Mutations that do not cause retention in ER of mutated protein, induce a conformational modification of the CRD FZD4 that doesn't permit the biding to its ligands or downstream targets. |
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| Entity | Acute myeloid leukemia (AML) |
| Note | It was demonstrated that FZD4 represents one of the mechanism of canonical or non canonical Wnt signaling activation in the pathogenesis of AML. Recently microarray analysis confirmed a higher expression of FZD4 in primary AML blast cells. (Beghini A. et al., 2012).
Tickenbrock, A. et al, also showed FZD4 overexpression in primary AML blasts, both in the presence or absence of FLT3 mutations. They also showed a canonical Wnt pathway activation due at specific WNT3A/FZD4 interaction, that leads to the stabilization of β-catenin and induces higher resistance against apoptosis. It was observed an involvement of FZD4 in differentiation of AML cell line mediated by 6-benzylthioinosine (6-BT) treatment. 6-BT treatment results in downregulation of canonical Wnt molecules and up-regulation of transcriptional level of the non canonical Wnt ligand Wnt5a and receptors FZD2, FZD4, FZD5, resulting in activation of Wnt/Ca2+ pathway ( Zang S. et al., 2014). |
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| Entity | Non small cell lung cancer (NSCLC) |
| Note | Recently several studies have reported that single nucleotide polymorphisms (SNPs) of FZD4 gene can influence recurrence and survival of early stage NSCLC patients treated with only surgery or in combination with chemotherapy.
miR-related SNP (rs713065) in the 3?UTR region of FZD4 gene is associated with decreased risk of death in early stage NSCLC patients treated with only surgery, while it is related to increased risk of death in patients treated with surgery plus chemotherapy (Pu X. et al., 2013). This FZD4-miR-SNP specifically interacts with MIR204 which acts as a tumor suppressor and inhibits the expression of FZD4 and transduction of Wnt/βcatenin signalling (Lin J. et al, 2017).) This FZD4-miR-SNP specifically interacts with miR-204 which acts as a tumor suppressor and inhibits the expression of FZD4 and transduction of Wnt/βcatenin signalling (Lin J. et al, 2017).
Coscio A. et al, demonstrated that miR-SNP (rs10898564) of FZD4 is most significantly associated with increased recurrence and death risk in NSCLC patients treated with only surgery but not in patients treated with surgery and chemotherapy. These reports suggest a potential role of FZD4-SNPs as predictive biomarkers for both recurrence and survival in early stage NSCLC patients. |
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| Entity | Prostate cancer |
| Note | In prostate cancer cells have been shown activation of Wnt signalling through FZD4 leading to epithelial-to-mesenchymal transition (EMT) and loss of cell adhesion (Gupta S. et al., 2010; Acevedo VD et al., 2007). |
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| Entity | Breast cancer |
| Note | Recently Lazzaroni F. et al. evidenced an autocrine activation of Wnt signalling in breast cancer cell line model. In MCF7 cell line model they identified the WNT10B/FZD4 interacting complex using the in situ proximity ligation assay and a dose dependent reduction of WNT10B/FZD4 complex after the treatment with pharmacological inhibitor of porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins. |
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| Entity | Liver cancer |
| Note | It was revealed that Let7b microRNA inhibit Wnt/β-catenin signaling pathway via downregulation of FZD4 in liver cancer cell, resulting in a reduction of proliferation, invasion, migration of liver cancer cells and reduction in the amount of cancer stem cells in liver (Cai H.et al 2017). |
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| Entity | Glioblastoma |
| Note | Microarray analysis in U87R4 invasive glioblastoma cell line reported an overexpression of FZD4, which actives Wnt/β catenin signalling pathway and promotes stemness and invasiveness of glioblastoma cells. (Jin X. et al. 2011). |
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| Entity | Medulloblastoma |
| Note | Recently evidences showed an involvement of Norrin/FZD4 signaling pathway in the cerebellar tumor medulloblastoma (MB) initiation. In this tumor, Norrin/FZD4 pathway acts as anti-tumor signal in the preneoplastic niche, in fact loss of function of Norrin/FZD4 signaling in the endothelian cells promotes the formation of preneoplastic lesion of MB and their progression to malignancies (Bassett E. et al., 2016). |
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| Entity | Bladder cancer |
| Note | FZD4 is a target of miR-493 in the bladder cancer. It was observed a down-regulated expression of miR-493 in the bladder cancer tissue in comparison with normal bladder tissue. MIR493 transfection in the T24 or J82 bladder cancer cell line inhibits FZD4 and Rho4 expression, resulting in the inhibition of cell motility and migration
These results, suggested that miR-493 represent a new tumor suppressor in the bladder cancer (Ueno K. et al., 2012). |
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| Entity | Melanoma |
| Note | It was reported that in melanoma cells Wnt signalling activation through FZD4 promotes tumor cell invasion and metastasis. WNT5a binds FZD4/LRP6 receptor complex and actives the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 ( ARF6), leading to the disruption of N-cadherin-βcatenin complex and accumulation of nuclear βcatenin, which increases the transcription of its target genes and stimulates melanoma invasion (Grossman A. et al., 2013) |
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| Entity | Chronic Myeloid Leukemia |
| Note | Agarwal P. et al., revealed a role of FZD4 in Wnt-mediated regulation of CML progenitor growth and their resistance to tyrosine kinase inhibitor (TKI) treatment. Silencing of FZD4 expression in combination with Nilotinib (NIL) treatment reduces Wnt signalling activation and the colony forming capacity of CML cells. |
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| Entity | Colorectal cancer |
| Note | Expression of FZD4 in colorectal cancer and its binding with the Norrin ligand, produced by the same cells and endothelial tumor cells, activates β-catenin signalling and regulates angiogenesis in the colorectal cancer microenvironment (K. Platinus et al. 2014). |
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| Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition |
| Acevedo VD, Gangula RD, Freeman KW, Li R, Zhang Y, Wang F, Ayala GE, Peterson LE, Ittmann M, Spencer DM |
| Cancer Cell 2007 Dec;12(6):559-71 |
| PMID 18068632 |
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| Agarwal P, Zhang B, Ho Y, Cook A, Li L, Mikhail FM, Wang Y, McLaughlin ME, Bhatia R |
| Blood 2017 Feb 23;129(8):1008-1020 |
| PMID 28011678 |
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| Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation |
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| Neoplasia 2012 Dec;14(12):1236-48 |
| PMID 23308055 |
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| Let7b modulates the Wnt/β-catenin pathway in liver cancer cells via downregulated Frizzled4 |
| Cai H, Chen Y, Yang X, Ma S, Wang Q, Zhang Y, Niu X, Ding G, Yuan Y |
| Tumour Biol 2017 Jul;39(7):1010428317716076 |
| PMID 28671046 |
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| Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4 |
| Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ |
| Science 2003 Sep 5;301(5638):1391-4 |
| PMID 12958364 |
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| Wnt/beta-catenin signaling in development and disease |
| Clevers H |
| Cell 2006 Nov 3;127(3):469-80 |
| PMID 17081971 |
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| Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients |
| Coscio A, Chang DW, Roth JA, Ye Y, Gu J, Yang P, Wu X |
| Carcinogenesis 2014 Jun;35(6):1284-91 |
| PMID 24517998 |
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| Familial exudative vitreoretinopathy and related retinopathies |
| Gilmour DF |
| Eye (Lond) 2015 Jan;29(1):1-14 |
| PMID 25323851 |
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| The small GTPase ARF6 stimulates β-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis |
| Grossmann AH, Yoo JH, Clancy J, Sorensen LK, Sedgwick A, Tong Z, Ostanin K, Rogers A, Grossmann KF, Tripp SR, Thomas KR, D'Souza-Schorey C, Odelberg SJ, Li DY |
| Sci Signal 2013 Mar 5;6(265):ra14 |
| PMID 23462101 |
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| FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells |
| Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, Rantala J, Alanen K, Nees M, Kallioniemi O |
| Cancer Res 2010 Sep 1;70(17):6735-45 |
| PMID 20713528 |
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| Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation |
| Jin X, Jeon HY, Joo KM, Kim JK, Jin J, Kim SH, Kang BG, Beck S, Lee SJ, Kim JK, Park AK, Park WY, Choi YJ, Nam DH, Kim H |
| Cancer Res 2011 Apr 15;71(8):3066-75 |
| PMID 21363911 |
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| Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization |
| Kaykas A, Yang-Snyder J, Héroux M, Shah KV, Bouvier M, Moon RT |
| Nat Cell Biol 2004 Jan;6(1):52-8 |
| PMID 14688793 |
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| Kondo H, Hayashi H, Oshima K, Tahira T, Hayashi K |
| Br J Ophthalmol 2003 Oct;87(10):1291-5 |
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| Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukaemia |
| Lazzaroni F, Del Giacco L, Biasci D, Turrini M, Prosperi L, Brusamolino R, Cairoli R, Beghini A |
| Sci Rep 2016 Nov 17;6:37201 |
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| Sci Rep 2017 Aug 22;7(1):9029 |
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| Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development |
| Mazzotta S, Neves C, Bonner RJ, Bernardo AS, Docherty K, Hoppler S |
| Stem Cell Reports 2016 Oct 11;7(4):764-776 |
| PMID 27641648 |
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| A novel signaling pathway regulates colon cancer angiogenesis through Norrin |
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| Sci Rep 2014 Jul 9;4:5630 |
| PMID 25005225 |
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| MicroRNA-related genetic variants associated with clinical outcomes in early-stage non-small cell lung cancer patients |
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| Cancer Res 2013 Mar 15;73(6):1867-75 |
| PMID 23378343 |
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| Hum Mutat 2005 Aug;26(2):104-12 |
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| Nat Genet 2002 Oct;32(2):326-30 |
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| FZD4S, a splicing variant of frizzled-4, encodes a soluble-type positive regulator of the WNT signaling pathway |
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| Biochem Biophys Res Commun 2001 Apr 6;282(3):750-6 |
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| Schulte G |
| LXXX The class Frizzled receptors |
| PMID 21079039 |
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| Activation of Wnt signalling in acute myeloid leukemia by induction of Frizzled-4 |
| Tickenbrock L, Hehn S, Sargin B, Choudhary C, Bäumer N, Buerger H, Schulte B, Müller O, Berdel WE, Müller-Tidow C, Serve H |
| Int J Oncol 2008 Dec;33(6):1215-21 |
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| Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by downregulating RhoC and FZD4 |
| Ueno K, Hirata H, Majid S, Yamamura S, Shahryari V, Tabatabai ZL, Hinoda Y, Dahiya R |
| Mol Cancer Ther 2012 Jan;11(1):244-53 |
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| Wnt signaling is involved in 6-benzylthioinosine-induced AML cell differentiation |
| Zang S, Liu N, Wang H, Wald DN, Shao N, Zhang J, Ma D, Ji C, Tse W |
| BMC Cancer 2014 Nov 27;14:886 |
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