3170

FOXA2

The Forkhead Box A2 (FOXA2) transcription factor is required for embryonic development and for normal functions of multiple adult tissues, in which the maintained expression of FOXA2 is usually related to preventing the progression of malignant transformation. In this study, we found that FOXA2 prevented the epithelial to mesenchymal transition (EMT) in human breast cancer. We observed a strong correlation between the expression levels of FOXA2 and the epithelial phenotype. Knockdown of FOXA2 promoted the mesenchymal phenotype, whereas stable overexpression of FOXA2 attenuated EMT in breast cancer cells. FOXA2 was found to endogenously bind to and stimulate the promoter of E-cadherin that is crucial for epithelial phenotype of the tumor cells. Meanwhile, FOXA2 prevented EMT of breast cancer cells by repressing the expression of EMT-related transcription factor ZEB2 through recruiting a transcriptional corepressor TLE3 to the ZEB2 promoter. The stable overexpression of FOXA2 abolished metastasis of breast cancer cells in vivo. This study confirmed that FOXA2 inhibited EMT in breast cancer cells by regulating the transcription of EMT-related genes such as E-cadherin and ZEB2.CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved.

Emerging evidence indicates that the long noncoding RNAs extensively participate in cancer progression. Nevertheless, the molecular pathogenesis of how these lncRNAs regulate tumorigenesis has not been fully elucidated especially in hepatocellular carcinoma (HCC). Here, we sought to define the role of a novel lncRNA named lncRNA-NEF in modulating epithelial to mesenchymal transition (EMT) in HCC. It was found that the lncRNA-NEF was transcriptionally activated by EMT suppressor FOXA2 and frequently downregulated in HCC cell lines as well as clinical specimens. Although enhanced expression of lncRNA-NEF did not affect tumor cell growth, ectopic expression of lncRNA-NEF significantly suppressed EMT program and cell migration. Animal studies validated that lncRNA-NEF alleviated in vivo tumor metastasis and protected mice from tumor-induced mortality. Interestingly, we verified that lncRNA-NEF acted as a novel activator of its neighbor gene FOXA2, which formed a positive feedback loop. Subsequent studies revealed that lncRNA-NEF physically interacted with beta-catenin to increase the binding of GSK3beta with beta-catenin and therefore promoted the inhibitory phosphorylation of beta-catenin, leading to the suppression on Wnt/beta-catenin signaling and activation of FOXA2 expression. Hence, our findings illustrated a novel feedback loop including FOXA2 and its neighboring gene lncRNA-NEF, which might provide mechanistic insights into the metastatic progress of HCC.

Endometrial cancer is the most common gynecological cancer. epithelial-mesenchymal transition (EMT) plays a critical role in tumor invasion and metastasis, which limits the success of treatment. Here, we investigated the roles of forkhead box A2 (FOXA2) and microRNA-200a (miR-200a) in regulating the EMT of endometrial cancer cells RL95-2. Empty vector or FOXA2 was stably transfected into RL95-2 cells. MTT assay measured cell proliferation, apoptosis assay measured apoptosis, Transwell invasion assay measured cell invasion, and Western blot measured the protein expression of FOXA2, E-cadherin, and vimentin. ChIP assay determined the binding of FOXA2 to E-cadherin promoter. For miR-200a analysis, the cells with stable FOXA2 expression were transfected with miR-negative control or miR-200a. Forced expression of FOXA2 decreased the proliferation and invasion, and increased the apoptosis of RL95-2 cells. FOXA2 also affected the EMT-associated proteins: FOXA2 increased the protein expression of E-cadherin and decreased the expression of vimentin. Moreover, FOXA2 positively regulated the promoter of E-cadherin in RL95-2 cells. Luciferase reporter assay identified FOXA2 as a target of miR-200a, which negatively regulated FOXA2. Western blot results showed that overexpression of miR-200a decreased the expression of E-cadherin but increased the expression of vimentin in the endometrial cancer cells by downregulating FOXA2 expression. FOXA2 may act as a tumor suppressor and inhibit EMT of endometrial cancer cells. FOXA2 expression is controlled by miR-200a, which promotes EMT of the endometrial cancer cells.