Ye-Seul Kim

Role of the epithelial–mesenchymal transition and its effects on embryonic stem cells

The epithelial–mesenchymal transition (EMT) is important for embryonic development and the formation of various tissues or organs. However, EMT dysfunction in normal cells leads to diseases, such as cancer or fibrosis. During the EMT, epithelial cells are converted into more invasive and active mesenchymal cells. E-box-binding proteins, including Snail, ZEB and helix–loop–helix family members, serve as EMT-activating transcription factors. These transcription factors repress the expression of epithelial markers, for example, E-cadherin, rearrange the cytoskeleton and promote the expression of mesenchymal markers, such as vimentin, fibronectin and other EMT-activating transcription factors. Signaling pathways that induce EMT, including transforming growth factor-β, Wnt/glycogen synthase kinase-3β, Notch and receptor tyrosine kinase signaling pathways, interact with each other for the regulation of this process. Although the mechanism(s) underlying EMT in cancer or embryonic development have been identified, the mechanism(s) in embryonic stem cells (ESCs) remain unclear. In this review, we describe the underlying mechanisms of important EMT factors, indicating a precise role for EMT in ESCs, and characterize the relationship between EMT and ESCs.

Bisphenol A and Nonylphenol Have the Potential to Stimulate the Migration of Ovarian Cancer Cells by Inducing Epithelial–Mesenchymal Transition via an Estrogen Receptor Dependent Pathway

Epithelial-mesenchymal transition (EMT) is an important process appearing in embryo development and tumor migration or progression, which is influenced by 17β-estradiol (E2). Bisphenol A (BPA) and nonylphenol (NP) are suspected as endocrine disrupting chemicals (EDCs) because they can exert estrogenic properties. In this study, we examined whether E2, BPA, and NP can lead to the EMT process in BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To confirm the effect of E2, BPA, and NP, BG-1 cells were cultured under treatment with E2, BPA, or NP, and the alteration of EMT markers such as vimentin was examined at mRNA levels by using real-time and reverse-transcription (RT)-PCR. The expressions of snail, slug, and vimentin were enhanced by the treatment of E2, BPA, or NP compared to a control (DMSO). In protein levels, vimentin protein was increased by E2 and two EDCs, while E-cadherin was decreased. In addition, the expression of snail protein was enhanced by the treatment of E2 and the two EDCs in comparison with that of the control. Since EMT response in cancer cells can affect metastasis, we also performed a scratch assay and Western blot assay to show the migration ability caused by E2, BPA, or NP. Consequently, E2, BPA, and NP enhanced the migration capability of BG-1 cells and increased the expression of MMP-9 protein. Furthermore, to examine whether EMT and migration of BG-1 cancer cells are induced by BPA or NP via the ER dependent pathway, we cotreated the cells with ER-antagonist, ICI 182,780, in the presence of E2, BPA, or NP. As a result, the expressions of E-cadherin, vimentin, snail, and slug were reversed following treatment with an ER antagonist. Moreover, we confirmed that ICI 182,780 reduced the migration ability of BPA and NP to the control level. Taken together, these results indicate that BPA and NP, the potential EDCs, may have the ability to influence ovarian cancer metastasis via regulating EMT markers and migration in ER-expressing BG-1 ovarian cancer cells.

Genistein suppressed epithelial-mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-β signaling pathway.

BACKGROUND Epithelial-mesenchymal transition (EMT), which is activated by 17β-estradiol (E2) in estrogen-responsive cancers, is an important process in tumor migration or progression. As typical endocrine disrupting chemicals (EDCs), bisphenol A (BPA) and nonylphenol (NP) have a potential to promote EMT and migration of estrogen-responsive cancers. On the contrary, genistein (GEN) as a phytoestrogen is known to have chemopreventive effects in diverse cancers. METHODS In the present study, the effects of BPA and GEN on EMT and the migration of BG-1 ovarian cancer cells and the underlying mechanism were investigated. ICI 182,780, an estrogen receptor (ER) antagonist, was co-treated with E2 or BPA or NP to BG-1 cells to identify the relevance of ER signaling in EMT and migration. RESULTS As results, E2 and BPA upregulated the protein expression of vimentin, cathepsin D, and MMP-2, but downregulated the protein expression of E-cadherin via ER signaling pathway, suggesting that E2 and BPA promote EMT and cell migration related gene expressions. However, the increased protein expressions of vimentin, cathepsin D, and MMP-2 by E2, BPA, or NP were reduced by the co-treatment of GEN. In a scratch assay, the migration capability of BG-1 cells was enhanced by E2, BPA, and NP via ER signaling but reversed by the co-treatment of GEN. In the protein expression of SnoN and Smad3, E2, BPA, and NP upregulated SnoN, a negative regulator of TGF-β signaling, and downregulated pSmad3, a transcription factor in the downstream pathway of TGF-β signaling pathway, suggesting that E2, BPA, and NP simultaneously lead to the downregualtion of TGF-β signaling in the process of induction of EMT and migration of BG-1 cells via ER signaling. On the other hand, the co-treatment of GEN reversed the downregulation of TGF-β signaling by estrogenic chemicals. CONCLUSION Taken together, GEN suppressed EMT and migration capacities of BG-1 ovarian cancer cells enhanced by E2, BPA, and NP via ER signaling and the downregulation of TGF-β signal.

Alteration of epithelial-mesenchymal transition markers in human normal ovaries and neoplastic ovarian cancers

Most ovarian cancers originate in the ovarian surface epithelium (OSE). Ovarian cancers might undergo epithelial-mesenchymal transition (EMT) in response to various mediators or regulators such as EMT-inducing factors. In this study, ovarian tumor specimens from patients were analyzed to demonstrate alteration of EMT-related markers according to benign and malignant types of ovarian cancers. In the three ovarian cancer cell lines, OVCAR-3, SKOV-3, and BG-1, the expression of epithelial (E-cadherin) and mesenchymal (vimentin) cell markers was identified by RNA and protein analysis. OVCAR-3 and BG-1 cells strongly expressed E-cadherin as well as morphological features such as epithelial cells, but vimentin was not observed. In contrast to these cancer cells, SKOV-3 showed a phenotype typical of mesenchymal cells. Alteration of EMT markers and EMT-related transcriptional factors were confirmed in clinical ovarian tissue samples obtained from 74 patients. E-cadherin was expressed in 57.1% of benign tumors, while vimentin was expressed in 83.3% of normal ovaries by immunohistochemistry (IHC) analysis of E-cadherin and vimentin revealed the phenomenon in the tissue specimens. Evaluation of the EMT-associated transcriptional factors Snail, Slug, and Twist revealed that Snail was overexpressed by 7.1-fold in malignant ovarian cancer compared to normal ovaries or benign tumors. Although expression levels of other factors were higher in benign and malignant ovarian tumors, they were not closely correlated with the aforementioned ovarian cancer types. Overall, Snail may affect the EMT process in ovarian cancer development and upregulation of Snail expression followed by the downregulation of E-cadherin enhances the invasiveness of ovarian cancer.

Gene therapy strategies using engineered stem cells for treating gynecologic and breast cancer patients (Review)

There are three types of stem cells: embryonic stem (ES) cells, adult stem (AS) cells and induced pluripotent stem (iPS) cells. These stem cells have many benefits including the potential ability to differentiate into various organs. In addition, engineered stem cells (GESTECs) designed for delivering therapeutic genes may be capable of treating human diseases including malignant cancers. Stem cells have been found to possess the potential for serving as novel delivery vehicles for therapeutic or suicide genes to primary or metastatic cancer formation sites as a part of gene-directed enzyme/prodrug combination therapy (GEPT). Given the advantageous properties of stem cells, tissue-derived stem cells are emerging as a new tool for anticancer therapy combined with prodrugs. In this review, the effects of GESTECs with different origins, i.e., neural, amniotic membrane and amniotic fluid, introduced to treat patients with diverse types of gynecologic and breast cancers are discussed. Data from the literature indicate the therapeutic potential of these cells as a part of gene therapy strategies to selectively target malignancies in women at clinically terminal stages.

Trends in blood pressure and prevalence of hypertension in Korean adults based on the 1998–2014 KNHANES

Purpose To investigate trends in blood pressure (BP) and hypertension prevalence in Korea. Materials and Methods Based on the Korean National Health and Nutrition Examination Survey (KNHANES) I (1998), II (2001), III (2005), IV (2007–2009), V (2010–2012), and VI (2013–2014), 56077 participants (23974 men and 32103 women) were included. Results Mean systolic BP (SBP) and diastolic BP (DBP) decreased in both sexes (male SBP: 128.1 to 120.2 mm Hg, male DBP: 82.0 to 78.5 mm Hg; female SBP: 125.7 to 116.0 mm Hg and female DBP: 77.4 to 73.2 mm Hg from the KNHANES I–VI). The age-standardized prevalence of hypertension was significantly decreased in both sexes (male; 33.3% to 30.3%, female; 28.7% to 22.7%, all p for trend <0.001). Regardless of taking anti-hypertensive medication or not, SBP and DBP declined universally in both sexes. Compared to the KNHANES I, the odds ratios (95% confidence intervals) of the KNHANES II to VI for less-than-normotensive and less-than-hypertensive BP increased in both sexes. Conclusion Mean BP levels in both sexes and hypertension prevalence showed downward trends during the 16-year period.