Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Grainyhead-like 2 (GRHL2) maintains the epithelial status of ovarian cancer through miR-200-ZEB1 regulatory networks (expression)

ABSTRACT: Epithelial ovarian cancer (EOC) is clinically heterogeneous, comprising different histological and biological subtypes. Multiple studies have implicated epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, to contribute significantly to this molecular heterogeneity of EOC. From gene expression analyses of a collection of EMT-characterized EOC cell lines, we found that the expression of the transcription factor Grainyhead-like 2 (GRHL2) correlates with E-cadherin expression and the epithelial phenotype. EOC tumors with lower levels of GRHL2 are associated with the Mes (mesenchymal) molecular subtype and show poorer overall survival in patients. Here, we demonstrate that shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype resulted in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, we identified a variety of target genes regulated by GRHL2, including protein-coding and non-coding genes. Our data suggest that GRHL2 maintains the epithelial phenotype of EOC cells through the regulatory networks of miR-200b/a, ZEB1 and E-cadherin. These findings support GRHL2 as a crucial player in the molecular heterogeneity of EOC. 7 samples were analyzed (shNon control in duplicates; shGRHL2 #10 in duplicates, shGRHL2 #12 in triplicates)

ORGANISM(S): Homo sapiens

SUBMITTER: Tuan Zea Tan

PROVIDER: E-GEOD-71017 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification.

Chung Vin Yee VY Tan Tuan Zea TZ Tan Ming M Wong Meng Kang MK Kuay Kuee Theng KT Yang Zhe Z Ye Jieru J Muller Julius J Koh Cheryl M CM Guccione Ernesto E Thiery Jean Paul JP Huang Ruby Yun-Ju RY

Scientific reports 20160218

Epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, has been implicated to contribute to the molecular heterogeneity of epithelial ovarian cancer (EOC). Here we report that a transcription factor--Grainyhead-like 2 (GRHL2) maintains the epithelial phenotype. EOC tumours with lower GRHL2 levels are associated with the Mes/Mesenchymal molecular subtype and a poorer overall survival. shRNA-mediated knockdown of GRHL ...[more]

PMID: 26887977

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Project description:Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies. It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Previously, we identified the mannose receptor LY75 (DEC205/CD205) gene as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. LY75 has been identified as a putative antigen-uptake receptor, which is expressed abundantly on dendritic cells, which are specialist antigen presenting cells to T lymphocytes for the initiation of an immune response. The implication of LY75 in EOC tumorigenesis is currently unknown. Here we show that LY75 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Importantly, shRNA-mediated LY75 knockout in the mesenchymal EOC cells (SKOV3) led to mesenchymal to epithelial transition (MET), associated with overexpression of epithelial markers E-cadherin and EPCAM and loss of expression of mesenchymal markers Fibronectin, N-cadherin Snail1 and Twist1. In addition, LY75 suppression significantly inhibited EOC cell migration and invasion in vitro. However, LY75 knockdown led to enhanced tumor cell dissemination and significantly increased lethality in vivo, in xenograft model of advanced peritoneal EOC. Thus, our findings indicate that LY75 could play an essential role in the mesenchymal-to-epithelial transition (MET) of EOC cells and support the hypothesis that, while epithelial-to-mesenchymal transition (EMT) enables the invasiveness of tumor cells, a MET-associated epithelial phenotype could be essential for their metastatic colonization. To better understand the molecular mechanisms of LY75 gene action in epithelial ovarian cancer (EOC), we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon LY75 suppression in SKOV3 EOC cells. We compared the gene expression of the previously selected shRNA-mediated LY75-knockdown clones sh-S3 and sh-S6 against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for each of the LY75-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

Dataset Information

Grainyhead-like 2 (GRHL2) maintains the epithelial status of ovarian cancer through miR-200-ZEB1 regulatory networks (expression)

Publications

GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification.

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