Abstract
Abstract Epithelial ovarian cancer (EOC) is clinically heterogeneous, comprising different histological and biological subtypes. Despite tumor heterogeneity, patient stratification is lacking and targeted therapeutic options for EOC are limited. Epithelial-mesenchymal transition (EMT), an important developmental process that allows the conversion of epithelial cells to mesenchymal phenotype, has been implicated in contributing to the molecular heterogeneity in EOC. Emerging evidence suggests that EMT in EOC may be associated with tumor progression and metastasis. We aim to decipher the underlying EMT mechanisms by using a panel of 42 EMT-phenotyped EOC cell lines. We found that Grainyhead-like 2 (GRHL2), a transcription factor, was expressed exclusively in EOC cells with epithelial phenotype by using qPCR, ELISA and western blots. EOC tumors with Mesenchymal molecular subtype also showed a decrease in GRHL2 expression. These data suggest that GRHL2 is required for maintaining cell polarity or cell-cell adhesion. Therefore, manipulating the expression of GRHL2 might switch the EMT-related molecular subtypes in EOC. Here, we showed that knocking down of GRHL2 resulted in EMT changes in EOC cells with Epithelial molecular subtype, accompanied by an increase in cell motility and directional migration. GRHL2-deficient cells also showed a tendency to migrate individually instead of collectively, thus suggesting that GRHL2 might be required for collective cell migration. Knock-down of GRHL2 not only downregulates E-cadherin expression, but also interferes with the stability of E-cadherin at cell-cell junctions. Chromatin-immunoprecipitation sequencing (ChIP-seq) identified GRHL2 transcriptional targets that might be the downstream mediators for this molecular subtype switch. In conclusion, GRHL2 is an important regulator in maintaining the epithelial phenotype and crucial player in molecular heterogeneity in EOC. Citation Format: Vin Yee Chung, Meng Kang Wong, Kuee Theng Kuay, Tuan Zea Tan, Ernesto Guccione, Jean Paul Thiery, Ruby Yun-Ju Huang. Grainyhead-like 2 regulates molecular subtype switching in epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1058. doi:10.1158/1538-7445.AM2014-1058
Published Version
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