Dataset Information

E-cadherin can limit the transforming properties of activating ?-catenin mutations.

ABSTRACT: Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in ?-catenin (CTNNB1). We have compared the dynamics and the potency of ?-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ?-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of ?-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ?-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:?-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ?-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ?-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ?-catenin.

SUBMITTER: Huels DJ

PROVIDER: S-EPMC4570519 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

E-cadherin can limit the transforming properties of activating β-catenin mutations.

Huels David J DJ Ridgway Rachel A RA Radulescu Sorina S Leushacke Marc M Campbell Andrew D AD Biswas Sujata S Leedham Simon S Serra Stefano S Chetty Runjan R Moreaux Guenievre G Parry Lee L Matthews James J Song Fei F Hedley Ann A Kalna Gabriela G Ceteci Fatih F Reed Karen R KR Meniel Valerie S VS Maguire Aoife A Doyle Brendan B Söderberg Ola O Barker Nick N Watson Alastair A Larue Lionel L Clarke Alan R AR Sansom Owen J OJ

The EMBO journal 20150803 18

Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve Wnt deregulation and acquire a cryp ...[more]

PMID: 26240067

Similar Datasets

Project description:Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear. Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism. Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3β signaling and facilitate β-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting β-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo. Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.

Project description:Background: Homeobox cut like 1 (CUX1), which often presents aberrated expression in many cancer cells, exerts a crucial role in tumorigenesis. Evidence describing CUX1 in gliomagenesis is scarce, and the effects of CUX1 on the Wnt/β-catenin pathway have not been reported. Our study aimed to explore the biological functions and molecular mechanisms involved in CUX1 activity in glioma. Methods: Datasets for bioinformatics analysis were obtained from the GEO, TCGA, CGGA, GTEX and CCLE databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CUX1 among glioma and brain tissues. CUX1 knockdown and overexpression vectors were transfected into glioma cell lines, the CCK-8, clone formation assay, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the cell cycle. WB and immunofluorescence (IF) assays were used to explore changes in cell cycle-related and Wnt/β-catenin signaling protein levels. Results: Overexpression of CUX1 was identified in glioma tissues, and especially in glioblastoma (GBM), when compared to normal controls and correlated with poor prognosis. In comparison with untreated cells, TJ905 glioma cells overexpressing CUX1 showed higher proliferation and invasion abilities and S phase cell-cycle arrest, while the knockdown of CUX1 suppressed cell invasive ability and induced G1 phase arrest. Active Wnt/β-catenin signaling was enriched and clustered in a CUX1-associated GSEA/GSVA analysis. IF and WB assays indicated that CUX1 regulated the distribution of Axin2/β-catenin in glioma cells and regulated the expression of proteins downstream of the Wnt/β-catenin signaling pathway, suggesting that CUX1 served as an upstream positive regulator of the Wnt/β-catenin pathway. Finally, the knockdown of Axin2 or β-catenin could reverse the tumor-promoting effects caused by CUX1 overexpression, suggesting that CUX1 induced gliomagenesis and malignant phenotype by activating the Wnt/β-catenin signaling pathway. Conclusion: Our data suggested that the transcription factor CUX1 could be a novel therapeutic target for glioma with gene therapy.

Dataset Information

E-cadherin can limit the transforming properties of activating ?-catenin mutations.

Publications

E-cadherin can limit the transforming properties of activating β-catenin mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure