Clinical Significance of Frizzled Homolog 3 Protein in Colorectal Cancer Patients

Wong, Sze Chuen Cesar; He, Catherine Wan; Chan, Charles Ming Lok; Chan, Amanda; Wong, Heong Ting; Cheung, Moon‐Tong; Luk, Lewis Lai Yin; Au, Thomas Chi Chuen; Chiu, Man Kin; Yue, Brigette Buig; Chan, Anthony Tak Cheung

doi:10.1371/journal.pone.0079481

Cited by 24 publications

(24 citation statements)

References 28 publications

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“…27 An immunocytochemical study showed that FZD3 is strongly associated with CRC progression. 28 Additional studies on miR-4500 and its target genes may be helpful for understanding tumorigenesis. Collectively, similar to the let-7 family, the potential tumor suppressor miR-4500 may affect tumorigenesis by targeting many critical oncogenes.…”

Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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This study aimed to understand the exact function and potential mechanism of miR-4500 in colorectal cancer (CRC). In this study, the expression of miR-4500 was decreased in both CRC cells and tissues, and downregulated miR-4500 indicated advanced tumor stage and poor survival. By bisulfite sequencing analysis, we found that the CpG island in the promoter region of miR-4500 was hypermethylated in CRC cells and tissues compared with normal control cells and non-tumor tissues, respectively. Functionally, gain-and loss-of-function analyses indicated the tumor suppressor role of miR-4500: it suppressed cell proliferation, cell cycle progression, migration, and invasion. Predictive algorithms and experimental analyses identified HMGA2 as a direct target of miR-4500. Reintroducing HMGA2 impaired the inhibitory effects of miR-4500 on cell growth and motility. Clinically, higher HMGA2 protein expression in CRC tissues was associated with advanced tumor stage and poor survival. An inverse correlation was found between miR-4500 levels and HMGA2 protein expression. Taken together, this study provides the first evidence that miR-4500 functions as a novel tumor suppressor in the miR-4500/HMGA2 axis in colorectal carcinogenesis, and restoring miR-4500 expression might represent a promising therapeutic strategy for CRC.Abbreviations: CRC, Colorectal cancer; HMGA2, high mobility group AT-hook 2; 5-aza, 5-aza-2 0 -deoxycytidine

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Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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“…As a transmembrane receptor and activator of the Wnt/beta-catenin pathway, FZD3 interacts with Wnt and activates Dishevelled (DSH) to recruit other components of the destruction complex, thereby, reducing beta-catenin degradation. The blocked degradation of beta-catenin leads to an accumulation of beta-catenin in the nucleus and upregulation of oncogenic activity (22, 31). FZD3 is known to be overexpressed in CRC tissues and cell lines, and is highly correlated with CRC progression (31, 32).…”

Section: Discussionmentioning

confidence: 99%

“…The blocked degradation of beta-catenin leads to an accumulation of beta-catenin in the nucleus and upregulation of oncogenic activity (22, 31). FZD3 is known to be overexpressed in CRC tissues and cell lines, and is highly correlated with CRC progression (31, 32). …”

Section: Discussionmentioning

confidence: 99%

Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk

Hildebrandt

Reyes

Lin

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The Wnt/beta-catenin signaling pathway plays a key role in stem cell maintenance in the colorectum. Rare high penetrance genetic mutations in components of this pathway result in familial colorectal cancer, yet the impact of common, germline variants remains unknown. Methods We assessed 172 variants in 26 genes from the Wnt/beta-catenin pathway in 809 CRC cases and 814 healthy controls, followed by replication of the top findings in another 691 cases and 775 controls. In silico informatic tools were used to predict functional effects of variants. Results Eighteen SNPs in the pathway were significantly associated with CRC risk (P <0.05) in the discovery phase. We observed a significant dose-response increase in CRC risk by number of risk genotypes carried (P = 4.19 × 10−8). Gene-based analysis implicated CSNK1D (P = 0.014), FZD3 (P = 0.023), and APC (P = 0.027) as significant for CRC risk. In the replication phase, FZD3:rs11775139 remained significantly associated with reduced risk with a pooled OR of 0.85 (95% CI: 0.76–0.94, P = 0.001). Although borderline significant in the replication population, APC:rs2545162 was highly significant in the pooled analysis - OR: 1.42, 95% CI: 1.16–1.74, P =0.00085. Functional assessment identified several potential biological mechanisms underlying these associations. Conclusions Our findings suggest that common germline variants in the Wnt/beta-catenin pathway maybe involved in CRC development. Impact These variants may be informative in CRC risk assessment to identify individuals at increased risk who would be candidates for screening.

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“…Earlier studies have demonstrated the involvement of several Frizzled receptors, including FZD8, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, and FZD10 in different cancers. Though Frizzled receptors function as key components of the Wnt signaling pathway, the specific link with the ETS‐related transcription factor ERG is unknown.…”

Section: Discussionmentioning

confidence: 99%

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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Clinical Significance of Frizzled Homolog 3 Protein in Colorectal Cancer Patients

Cited by 24 publications

References 28 publications

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk

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

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