Natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA517828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8506730.fastq.gz | Fastqsanger.gz | |||
| SRR8506731.fastq.gz | Fastqsanger.gz | |||
| SRR8506732.fastq.gz | Fastqsanger.gz | |||
| SRR8506733.fastq.gz | Fastqsanger.gz | |||
| SRR8506734.fastq.gz | Fastqsanger.gz |
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Project description:Cancer predisposing allelic variants have shown to be notoriously difficult to identify by conventional GWA studies. Searching for preferential co-occurrence with defined somatically acquired oncogenic lesions can significantly contribute to the identification of such alleles1. We here show that a natural Wnt-7b allelic variant in the mouse, which is not associated with increased tumour susceptibility, strongly synergizes with loss of the Cdkn2ab tumour suppressor locus in cancer development. Previously, we reported that Cdkn2ab-/- mice, generated from 129P2 ES cells develop skin carcinomas 2. The incidence of these carcinomas dropped gradually in the course of backcrossing to the FVB/N background suggesting that one or more 129P2 alleles cooperate with Cdkn2ab deficiency in skin carcinogenesis. Here we show that this skin cancer phenotype is linked to a 20Mb region of 129P2 chromosome 15 harboring the Wnt7b and Pdgfb genes. Both Wnt7b and Pdgfb are preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis showed enrichment of H3K27-Ac, a mark for active enhancers, in the 5’ region of the Wnt7b 129P2 gene. Moreover, the Wnt7b 129P2 allele appeared sufficient to cause in vitro transformation and anchorage-independent growth of Cdkn2ab deficient cell lines. Further we show that Wnt7b contributes to transformation through Cdk6 activation. Our observations imply that normally occurring variations in Wnt expression can elicit transformation of cells upon Cdkn2ab locus loss and point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of Wnt signaling in check. Consequently, it will be worthwhile to explore whether human tumours that show loss of CDKN2ab are associated with distinct allelic variants causing enhanced WNT signaling.
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Project description:Cdkn2ab knockout mice, generated from 129P2 ES cells develop skin carcinomas. Here we show that the incidence of these carcinomas drops gradually in the course of backcrossing to the FVB/N background. Microsatellite analyses indicate that this cancer phenotype is linked to a 20 Mb region of 129P2 chromosome 15 harboring the Wnt7b gene, which is preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis shows enrichment of H3K27-Ac, a mark for active enhancers, in the 5' region of the Wnt7b 129P2 gene. The Wnt7b 129P2 allele appears sufficient to cause in vitro transformation of Cdkn2ab-deficient cell lines primarily through CDK6 activation. These results point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of WNT signaling in check and illustrate that GWAS-based searches for cancer predisposing allelic variants can be enhanced by including defined somatically acquired lesions as an additional input.
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Project description:The adult stem cell marker Lgr5 and its close relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. Conditional deletion of the two genes in the gut impairs expression of Wnt target genes and results in rapid demise of intestinal crypts, thus phenocopying the effects of Wnt pathway inhibition. By mass-spectrometry, we find that Lgr4 and Lgr5 associate with the endogenous Wnt co-receptors Frizzled-5/7 and Lrp5/6 in HEK293 cells and in colorectal cancer cells. We also find that soluble Rspondin1, a Wnt pathway agonist, specifically binds to endogenous Lgr4 on HEK293 cells. In these cells, soluble Rspondin1 potently enhances canonical Wnt signals initiated by Wnt3A. Removal of Lgr4 does not affect Wnt3A-induced signals, but abrogates the Rspondin1-mediated enhancement of these signals, a phenomenon rescued by re-expression of Lgr4, -5 or -6. Rspondin1 and can be rescued by Wnt pathway activation. Lgr4/5/6 are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble Rspondin proteins.
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Project description:MicroRNAs (miRNAs) participate in many biological processes and have emerged as key players in carcinogenesis. In order to identify changes in miRNAs specific for betelquid-associated oral squamous cell carcinoma (OSCC), we investigated the expression profiles of 858 miRNAs in a panel of 40 pairs of OSCC specimens and their matched non-tumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared to the matched tissue. Among these miRNAs, 19 downregulated miRNAs located in the chromosome 14q32.2 miRNA cluster region were analyzed. This miRNA cluster resides within a parentally imprinted region known to be important in development and growth. The re-expression of miR-329 and miR-410from this cluster significantly reduced OSCC cell proliferation and invasion and downregulated Wnt-7b, an activator of the Wnt/b-catenin pathway. Furthermore, the expression of those 2 miRNAs was restored by 5-aza-2′-deoxycytidine treatment and the expression levels of the 2 miRNAs were inversely correlated with the hypermethylation of the Meg-3 promoter in OSCC cells. Specifically, arecoline, a major betel nut alkaloid, reduces miR-329 and miR-410 expression. Our results thus provide a novel molecular insight into how betel quid may contribute to oral carcinogenesis through the epigenetic silencing of tumor suppressor miRNAs targeting the Wnt/b-catenin signaling pathway. Total RNA was obtained from 40 pairs of OSCC patients with tumor specimens and their adjacent non-tumorous epithelia.
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