Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT - β-catenin - TCF signaling pathway

Terasaki, Harumi; Saitoh, Tetsuroh; Shiokawa, K.; Katoh, Masaru

doi:10.3892/ijmm.9.2.107

Cited by 57 publications

(62 citation statements)

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“…1D). Consistent with the notion that fzd10 transduces the Wnt/-catenin pathway (Terasaki et al, 2002;Momoi et al, 2003;Wang et al, 2005), the expression of specific targets of this pathway were inhibited, as demonstrated by depletion of sp5l from DFCs in DFC fzd10 MO embryos (Fig. 1F, arrow) and downregulation of axin2 in the brain, neural tube and tail bud region in fzd10 morphants ( Fig.…”

Section: Resultssupporting

confidence: 66%

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

2012

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SUMMARYCilia are essential for normal development. The composition and assembly of cilia has been well characterized, but the signaling and transcriptional pathways that govern ciliogenesis remain poorly studied. Here, we report that Wnt/-catenin signaling directly regulates ciliogenic transcription factor foxj1a expression and ciliogenesis in zebrafish Kupffer's vesicle (KV). We show that Wnt signaling acts temporally and KV cell-autonomously to control left-right (LR) axis determination and ciliogenesis. Specifically, reduction of Wnt signaling leads to a disruption of LR patterning, shorter and fewer cilia, a loss of cilia motility and a downregulation of foxj1a expression. However, these phenotypes can be rescued by KV-targeted overexpression of foxj1a. In comparison to the FGF pathway that has been previously implicated in the control of ciliogenesis, our epistatic studies suggest a more downstream function of Wnt signaling in the regulation of foxj1a expression and ciliogenesis in KV. Importantly, enhancer analysis reveals that KV-specific expression of foxj1a requires the presence of putative Lef1/Tcf binding sites, indicating that Wnt signaling activates foxj1a transcription directly. We also find that impaired Wnt signaling leads to kidney cysts and otolith disorganization, which can be attributed to a loss of foxj1 expression and disrupted ciliogenesis in the developing pronephric ducts and otic vesicles. Together, our data reveal a novel role of Wnt/-catenin signaling upstream of ciliogenesis, which might be a general developmental mechanism beyond KV. Moreover, our results also prompt a hypothesis that certain developmental effects of the Wnt/-catenin pathway are due to the activation of Foxj1 and cilia formation. KEY WORDS: Wnt/-catenin signaling, Ciliogenesis, Foxj1, Kupffer's vesicle ZebrafishWnt/-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer's vesicle

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Section: Resultssupporting

confidence: 66%

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

2012

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“…For instance, FZD10 activates the non-canonical Wnt/JNK pathway in synovial sarcoma cell 34 and enhances their anchorage-independent growth. On the other hand, FZD10 can activate the canonical Wnt/b-catenin/TCF signalling pathway in colorectal cancer cells 44 . Herein, we show that FZD10 overexpression in breast cancer cells due to reduced BRMS1L level leads to aberrant activation of canonical Wnt signalling and thus induces EMT in these cells.…”

Section: Discussionmentioning

confidence: 99%

BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10

Gong

et al. 2014

Nat Commun

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BRMS1L (breast cancer metastasis suppressor 1 like, BRMS1-like) is a component of Sin3A-histone deacetylase (HDAC) co-repressor complex that suppresses target gene transcription. Here we show that reduced BRMS1L in breast cancer tissues is associated with metastasis and poor patient survival. Functionally, BRMS1L inhibits breast cancer cells migration and invasion by inhibiting epithelial-mesenchymal transition. These effects are mediated by epigenetic silencing of FZD10, a receptor for Wnt signalling, through HDAC1 recruitment and histone H3K9 deacetylation at the promoter. Consequently, BRMS1L-induced FZD10 silencing inhibits aberrant activation of WNT3-FZD10-b-catenin signalling. Furthermore, BRMS1L is a target of miR-106b and miR-106b upregulation leads to BRMS1L reduction in breast cancer cells. RNA interference-mediated silencing of BRMS1L expression promotes metastasis of breast cancer xenografts in immunocompromised mice, whereas ectopic BRMS1L expression inhibits metastasis. Therefore, BRMS1L provides an epigenetic regulation of Wnt signalling in breast cancer cells and acts as a breast cancer metastasis suppressor.

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“…(12) Using a specific monoclonal antibody directed against FZD10, we analyzed expression patterns of FZD10 in colonic polyps, primary CRCs, and metastatic liver lesions to elucidate the role of FZD10 in the progression of CRCs. In addition, we examined the relationship between expression patterns of FZD10 and β-catenin, which is the main signal transducer of the canonical Wnt pathway.…”

mentioning

confidence: 99%

“…(10,11) Although FZD10 protein expression patterns in tumor tissues were not demonstrated, and the precise biological behavior of FZD10 with regard to tumorigenesis of CRCs remains obscure, the up-regulation of FZD10 mRNA was observed in two out of 11 cases with primary CRCs. (12) Using a specific monoclonal antibody directed against FZD10, we analyzed expression patterns of FZD10 in colonic polyps, primary CRCs, and metastatic liver lesions to elucidate the role of FZD10 in the progression of CRCs. In addition, we examined the relationship between expression patterns of FZD10 and β-catenin, which is the main signal transducer of the canonical Wnt pathway.…”

mentioning

confidence: 99%

Inverse correlation of the up‐regulation of FZD10 expression and the activation of β‐catenin in synchronous colorectal tumors

et al. 2009

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T he Wnt signal pathway is an essential signal pathway for multicellular organisms with diverse biological consequences. A large number of components are involved in signal transduction, one of which is the Frizzled homolog protein (FZD) that serves as a seven-pass transmembrane receptor for Wnt ligands. So far 10 members of FZD family genes have been identified based on structural and functional homologies. Colorectal cancers (CRCs) are prototype tumors and the Wnt signal pathway is profoundly involved in CRC pathogenesis. There are two major intracellular pathways of Wnt signal transduction: canonical and non-canonical pathways. In the early stages of CRC progression, Wnt signal activation frequently appears due to genetic alterations of molecules in the Wnt canonical pathway including Adenomatous polyposis coli (APC) and β-catenin, resulting in the stabilization and nuclear translocation of β-catenin with the subsequent transcriptional activation of Wnt target genes.(1-6) In contrast to extensive studies related to downstream events of Wnt signal transduction, little attention has been paid to the specificity of FZD receptors in CRCs, although there have been a few reports demonstrating the up-regulation of FZD1 and FZD2 in poorly differentiated CRCs,and FZD7 expression in colon cancer cell lines with APC or β-catenin mutations. (8) We previously demonstrated that FZD10, the latest cloned member of the FZD family, was specifically up-regulated in synovial sarcomas based upon a genome-wide analysis of gene-expression profiles in soft-tissue sarcomas.(9) Since FZD10 is located in plasma membranes and its expression is very low or absent in vital organs, we focused on this molecule as a likely candidate for antibody-based therapy, and demonstrated the therapeutic potential of antibodies directed against FZD10 in synovial sarcomas.(10,11) Although FZD10 protein expression patterns in tumor tissues were not demonstrated, and the precise biological behavior of FZD10 with regard to tumorigenesis of CRCs remains obscure, the up-regulation of FZD10 mRNA was observed in two out of 11 cases with primary CRCs. (12) Using a specific monoclonal antibody directed against FZD10, we analyzed expression patterns of FZD10 in colonic polyps, primary CRCs, and metastatic liver lesions to elucidate the role of FZD10 in the progression of CRCs. In addition, we examined the relationship between expression patterns of FZD10 and β-catenin, which is the main signal transducer of the canonical Wnt pathway. Materials and MethodsTissue samples and cell lines. Tissue samples were obtained from 104 CRC patients that had undergone surgical curative resection at the Department of Surgery, Kyoto University Hospital during 1999-2001 (Table 1). All samples were approved for analysis by the ethics committee of the Faculty of Medicine of Kyoto University. Formalin-fixed and paraffin-embedded samples were obtained from all patients, and were subdivided into the three following groups: (1) only primary tumor samples were available in 57 cases; (2) p...

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Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT - β-catenin - TCF signaling pathway

Cited by 57 publications

References 0 publications

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10

Inverse correlation of the up‐regulation of FZD10 expression and the activation of β‐catenin in synchronous colorectal tumors

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