Unknown,Transcriptomics,Genomics,Proteomics

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RNAi profiling of human mammary epithelial cells - analysis of the effects of loss of E-cadherin and cell adhesion

ABSTRACT: Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contactsâan early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherinâs cell-cell adhesion and intracellular signaling functions. While the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness and anoikis-resistance. We find the E-cadherin binding partner ï¢-catenin to be necessary but not sufficient for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss-induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes. Experiment Overall Design: Gene expression changes induced by knockdown of E-cadherin, expression of dominant-negative E-cadherin and double knockdown of E-cadherin and Beta-catenin in immortalized human mammary epithelial cells Experiment Overall Design: Four groups, three biological replicates per group. shCntrl expressing cells are the control group

ORGANISM(S): Homo sapiens

SUBMITTER: Tamer Onder

PROVIDER: E-GEOD-9691 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: WNT signaling activation in colorectal cancers (CRCs) occurs mainly through APC inactivation or, more uncommonly, β-catenin activation. Both processes promote β-catenin nuclear accumulation, which transcriptionally up-regulates epithelial-to-mesenchymal transition (EMT)-related genes. Experimental Design: We investigated β-catenin localization, downstream gene expression, and phenotypic alterations in HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin localization and associated phenotypes in CRC tissues. Results: Wild-type β-catenin mainly localized at the cell membrane, whereas mutant showed predominantly nuclear localization; membranous, cytoplasmic, and nuclear localization was observed in HCT116-P cells. Microarray analysis revealed significant down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT cells. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT cells, although E-cadherin expression was unaffected. Altered expression of cell-cell junction-related molecules led to tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased migration and invasion activities of HCT116-WT, whereas AJ loss was required to further up-regulate these activities in HCT116-P. Immunohistochemistry analysis of 101 stage III CRC tissues revealed high nuclear β-catenin expression (≥30% of tumor cells) in 15 (14.9%) samples, low nuclear expression (1-29%) in 53 (52.5%) samples, and undetectable nuclear expression in 33 (32.6%) samples, with a trend toward more frequent down-regulation of Claudin-7 and E-cadherin, and increased metastasis in CRCs with high vs. low nuclear β-catenin. Conclusions: β-catenin activation and nuclear translocation induce EMT progression by modifying cell-cell junctions, and are associated with aggressive behaviors of CRCs.

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RNAi profiling of human mammary epithelial cells - analysis of the effects of loss of E-cadherin and cell adhesion

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