Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer

Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 09/2011; 10(17):2865-73. DOI: 10.4161/cc.10.17.17188
Source: PubMed


Epithelial-mesenchymal transition (EMT) is an essential developmental program that becomes reactivated in adult tissues to promote the progression of cancer. EMT has been largely studied by examining the beginning epithelial state or the ending mesenchymal state without studying the intermediate stages. Recent studies using trophoblast stem (TS) cells paused in EMT have defined the molecular and epigenetic mechanisms responsible for modulating the intermediate "metastable" stages of EMT. Targeted inactivation of MAP3K4, knockdown of CBP, or overexpression of SNAI1 in TS cells induced similar metastable phenotypes. These TS cells exhibited epigenetic changes in the histone acetylation landscape that cause loss of epithelial maintenance while preserving self-renewal and multipotency. A similar phenotype was found in claudin-low breast cancer cells with properties of EMT and stemness. This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer.

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Available from: Amy N Abell, Apr 28, 2014
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    • "Cytoskeletal remodeling occurs in these cells and the cells subsequently obtain a mesenchymal-like phenotype. These changes increase the invasive capacity of tumor cells and enhance their degree of malignancy (5). The major molecular characteristics of EMT are the downregulation of the epithelial cell markers, E-cadherin and β-catenin, and upregulation of the markers of mesenchymal phenotype, vimentin, fibronectin and N-cadherin. "
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    ABSTRACT: The aim of the present study was to investigate the impact of the WW domain-containing oxidoreductase (WWOX) gene on the mechanisms underlying epithelial-mesenchymal transition (EMT) in human ovarian cancer stem cells. Western blot analysis was performed to detect the differences in the expression of the EMT markers, E-cadherin, β-catenin, N-cadherin, vimentin and fibronectin, between human ovarian cancer stem cells and the human epithelial ovarian carcinoma cell line, HO-8910. A pcDNA3.1-WWOX eukaryotic expression vector was subsequently transfected into the ovarian cancer stem cells (recombinant plasmid group) or an empty plasmid (empty plasmid group) and non-transfected ovarian cancer stem cells (blank control group) served as the controls. Following the transfection of the WWOX gene, methyl thiazolyl tetrazolium cell viability and Transwell(®) invasion assays, and western blot analysis were performed to detect changes in the proliferative capability and invasive capacity of ovarian cancer stem cells, as well as the expression of EMT markers and regulatory factors, Elf5 and Snail. The expression levels of E-cadherin and β-catenin in the ovarian cancer stem cells were identified to be significantly lower than those in the HO-8910 cells, whereas the expression levels of N-cadherin, vimentin and fibronectin in the ovarian cancer stem cells were found to be significantly higher than those in the HO-8910 cells. At each time point, the cellular proliferative capacity of the recombinant plasmid group was observed to be significantly lower than that of the empty plasmid or blank control groups (P<0.05 vs. the controls). The number of penetrating cells in the recombinant plasmid, empty plasmid and the blank control groups were 105.5±3.1, 199.7±3.4 and 191.4±4.1, respectively (mean ± standard error of the mean; P<0.05 vs. the controls). In addition, the protein expression of E-cadherin, β-catenin and Elf5 in the recombinant plasmid group was found to be significantly higher than that in the other two groups, whereas the protein expression of N-cadherin, vimentin, fibronectin and Snail in the recombinant plasmid group was significantly lower than that in the other two groups. An EMT exists in ovarian cancer stem cells, and the WWOX gene inhibits the cellular proliferation of ovarian cancer stem cells and reduces their invasive capability. Therefore, the WWOX gene may reverse the EMT in ovarian cancer stem cells by regulating the expression of the EMT regulatory factors, Elf5 and Snail.
    Oncology letters 07/2014; 8(1):426-430. DOI:10.3892/ol.2014.2063 · 1.55 Impact Factor
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    • "In contrast, SIRT3 was reported to suppress tumor growth via induction of growth arrest and apoptosis in colorectal carcinoma, osteosarcoma cells, ovarian cancer, prostate cancer, suggesting that SIRT3 is tumor suppressor in these cancers [9]. Several published papers demonstrated a tumor suppressor role for SIRT3 via the ability of SIRT3 to negatively regulate ROS (reactive oxygen species) and HIF1-α (hypoxia inducible factor-1 α) [44, 45]. However, the exact mechanisms how SIRT3 is involved in cancer are largely unclear. "
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    ABSTRACT: The Skp2 (S-phase kinase associated protein 2) oncoprotein is often highly expressed in various types of human cancers. However, the mechanistic basis of its oncogenic function, as well as the upstream regulatory pathway(s) that control Skp2 activities remains not fully understood. Recently, we reported that p300 acetylates Skp2 at two conserved lysine residues K68 and K71 within its NLS (Nuclear localization signal). This modification leads to increased Skp2 stability and cytoplasmic translocation, thus contributing to elevated Skp2 oncogenic potential. Moreover, we found that the SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes p300-mediated Skp2 acetylation. Furthermore, we showed that Skp2 governs E-cadherin ubiquitination and degradation in the cytosol. Consistent with this, we observed an inverse correlation between Skp2 and E-cadherin expression in clinical breast tumor samples. Therefore, our work elucidates a novel acetylation-dependent regulatory mechanism for Skp2 oncogenic functions.
    Oncotarget 11/2012; 3(11):1294-300. DOI:10.18632/oncotarget.740 · 6.36 Impact Factor
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    • "EMT is a biologic process that allows epithelial cells to undergo multiple biochemical changes that acquire a mesenchymal cell phenotype with an enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and increased production of ECM components (Kalluri, 2009; Yilmaz and Christofori, 2009). CSCs have been hypothesized to be the disseminating subpopulation and supported by accumulating evidence that CSCs also express EMT markers, and more importantly, induction of EMT in transformed epithelial cells promotes the generation of CSCs (Yang et al., 2004; Mani et al., 2008; Floor et al., 2011; Jordan et al., 2011; Wu, 2011; Wu and Yang, 2011; Krantz et al., 2012). For example, in colon cancer, nuclear accumulation of β-catenin, the feature of Wnt signaling activation and stem cell signaling, is found at the invasive front of the primary tumor (Fodde and Brabletz, 2007). "
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    ABSTRACT: Tumor cells can persist undetectably for an extended period of time in primary tumors and in disseminated cancer cells. Very little is known about why and how these tumors persist for extended periods of time and then evolve to malignancy. The discovery of cancer stem cells (CSCs) in human tumors challenges our current understanding of tumor recurrence, drug resistance, and metastasis, and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Although overlapping molecules and pathways have been reported to regulate the stem-like phenotype of CSCs and metastasis, accumulated evidence has suggested additional clonal diversity within the stem-like cancer cell subpopulation. This review will describe the current hypothesis linking CSCs and metastasis and summarize mechanisms important for metastatic CSCs to re-initiate tumors in the secondary sites. A better understanding of CSCs' contribution to clinical tumor dormancy and metastasis will provide new therapeutic revenues to eradicate metastatic tumors and significantly reduce the mortality of cancer patients.
    Frontiers in Endocrinology 10/2012; 3:125. DOI:10.3389/fendo.2012.00125
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