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Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [miRNA]

ABSTRACT: The significance of epithelial-to-mesenchymal transition (EMT)-inducing transcription factors in the onset of non-small cell lung cancer has not been resolved. Here, we report increased Snail expression in pulmonary premalignant lesions relative to histologically normal-appearing pulmonary epithelium. Utilizing immortalized human pulmonary epithelial cells and isogenic derivatives, we document Snail-dependent anchorage-independent growth of the epithelial cells in vitro, as well as transformation, primary tumor growth, and metastatic behavior in vivo. Epithelial splicing regulatory protein 1 (ESRP1) tumor suppressor silencing was a requirement for Snail-driven transformation in vivo, and we identified ESRP1 loss in Snail-expressing pulmonary premalignant lesions in situ. Snail drives these and other carcinogenic signaling programs in an ALDH+CD44+CD24- pulmonary stem cell subset in which ESRP1 and stemness-repressing micro-RNAs are inhibited.

ORGANISM(S): Mus musculus Rattus norvegicus Human gammaherpesvirus 8 JC polyomavirus Betapolyomavirus macacae Human immunodeficiency virus 1 Homo sapiens Murid gammaherpesvirus 4 Human betaherpesvirus 5 Human alphaherpesvirus 1 Betapolyomavirus hominis human gammaherpesvirus 4 Murid betaherpesvirus 1

PROVIDER: GSE108136 | GEO | 2017/12/16

SECONDARY ACCESSION(S): PRJNA422652

REPOSITORIES: GEO

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Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [mRNA]

Project description:The significance of epithelial-to-mesenchymal transition (EMT)-inducing transcription factors in the onset of non-small cell lung cancer has not been resolved. Here, we report increased Snail expression in pulmonary premalignant lesions relative to histologically normal-appearing pulmonary epithelium. Utilizing immortalized human pulmonary epithelial cells and isogenic derivatives, we document Snail-dependent anchorage-independent growth of the epithelial cells in vitro, as well as transformation, primary tumor growth, and metastatic behavior in vivo. Epithelial splicing regulatory protein 1 (ESRP1) tumor suppressor silencing was a requirement for Snail-driven transformation in vivo, and we identified ESRP1 loss in Snail-expressing pulmonary premalignant lesions in situ. Snail drives these and other carcinogenic signaling programs in an ALDH+CD44+CD24- pulmonary stem cell subset in which ESRP1 and stemness-repressing micro-RNAs are inhibited.

2017-12-16 | GSE108135 | GEO

Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells

Project description:Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells

| PRJNA422566 | ENA

Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [miRNA]

Project description:Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [miRNA]

| PRJNA422652 | ENA

Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [mRNA]

Project description:Snail-dependent epithelial splicing regulatory protein 1 (ESRP1) silencing drives malignant transformation of human pulmonary epithelial cells [mRNA]

| PRJNA422653 | ENA

Transcriptomic Analysis of PNN- and ESRP1-regulation in Human Corneal Epithelial Cells

Project description:Pnn depletion in developing mouse corneal epithelium led to disrupted alternative splicing of multiple ESRP-regulated epithelial-type exons. In human corneal epithelial cells (HCET), ESRP1 and PNN displayed close localization in and around nuclear speckles and their physical association in protein complexes was identified. In this study, gene expression profiling was performed to identify PNN- and ESRP1-regulated alternative pre-mRNA splicing in human corneal epithelial cells. Immortalized human corneal epithelial cells harboring doxycycline-inducible shRNA against PNN or ESRP1 were created. Whole transcriptome array analysis on ESRP1 or PNN knockdown HCET cells revealed clear alterations in transcript level and splicing pattern of specific subsets of genes with significant overlaps in their candidate targets. Our data suggest that ESRP1 and PNN modulate alternative splicing of a specific subset of exons, but not general splicing events. ESRP1 and PNN may together participate in the regulation of epithelial-specific splicing program in a genome-wide fashion. Parental HCET, shRNA-PNN HCET, and shRNA-ESRP1 HCET cells were cultured for 3 days with/without doxycycline. Total RNA was isolated from four biological replicates of each sample group and then subjected to hGlue3_0 transcriptome array analysis.

2013-01-24 | E-GEOD-41996 | biostudies-arrayexpress

Transcriptomic Analysis of PNN- and ESRP1-regulation in Human Corneal Epithelial Cells

2013-01-24 | GSE41996 | GEO

Dynamic Chromatin Modification Sustains Epithelial-Mesenchymal Transition following Inducible Expression of Snail-1 (ChIP-chip)

2013-12-18 | GSE52591 | GEO

Dynamic Chromatin Modification Sustains Epithelial-Mesenchymal Transition following Inducible Expression of Snail-1 (gene expression)

2013-12-18 | GSE52592 | GEO

Dynamic Chromatin Modification Sustains Epithelial-Mesenchymal Transition following Inducible Expression of Snail-1 (ChIP-chip)

Project description:Epithelial-Mesenchymal Transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. Following Snail-1 induction, epithelial markers were repressed within 6 hours and mesenchymal genes induced at 24 hours. Snail-1 binding to its target promoters was transient (6-48 hours) despite continued protein expression and it was followed by both transient and long-lasting chromatin changes. To generate a potent reversible EMT-inducing stimulus, we created a Snail-1 retroviral expression construct, using a fused estrogen receptor (ER) response element to mediate regulation by exogenous 4-hydroxy-tamoxifen (4-OHT). Since Snail-1 protein stability and nuclear localization are suppressed by GSK3-beta-mediated phosphorylation, we substituted the six targeted amino acids (ER-Snail-1(6SA)), thus conferring constitutive activity to the induced protein (Zhou et al., 2004, Pubmed ID 15448698). Infection of non-transformed, immortalized human mammary epithelial MCF10A cells with ER-Snail-1(6SA), followed by treatment with 4-OHT, triggered morphological and biomarker characteristics of EMT. At 0, 6, 48 and 120 hours after beginning exposure to 4-OHT in ethanol (or, for controls, ethanol only) we ChIPed Snail-1 and 6 histone marks. We perfomed two replicates of each, except we only had one replicate of H3K27Me3 at 6 hours.

2013-12-18 | E-GEOD-52591 | biostudies-arrayexpress

The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

Project description:Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are recently discovered epithelial-specific RNA-binding proteins that promote splicing of the epithelial variant of the FGFR2, ENAH, CD44, and CTNND1 transcripts. To catalogue a larger set of splicing events under the regulation of the ESRPs, we profiled splicing changes induced by RNA interference-mediated knockdown of ESRP1 and ESRP2 expression in a human epithelial cell line using the splicing-sensitive Affymetrix Exon ST1.0 Arrays. Analysis of the microarray data using the previously described MADS tool resulted in the identification of over a hundred candidate ESRP-regulated splicing events. We were able to independently validate 37 of these targets by RT-PCR. The ESRP-regulated events encompass all known types of alternative splicing events. Importantly, a number of these regulated splicing events occur in gene transcripts that encode proteins with well-described roles in the regulation of actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration. In sum, this work reveals a novel list of transcripts differentially spliced in epithelial and mesenchymal cells, implying that coordinated alternative splicing plays a critical role in determination of cell type identity. Keywords: control / knockdown comparison Short interfering knockdown of ESRP1 and ESRP2 in human PNT2 prostatic epithelium cells was performed as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). The efficiency of ESRP1 and ESRP2 knockdown was monitored by quantitative RT-PCR as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). In all cases the efficiency of the knockdown was close to 80%. We conducted Exon array profiling on RNAs from four siESRP1/2-treated samples and four siGFP controls.

2010-08-18 | E-GEOD-17468 | biostudies-arrayexpress

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