EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

Haslehurst, Alexandria; Koti, Madhuri; Dharsee, Moyez; Nuin, Paulo; Evans, Ken; Geraci, Joseph; Childs, Timothy; Chen, Jian; Li, Jieran; Weberpals, Johanne I.; Davey, Scott; Squire, Jeremy A.; Park, Paul C.; Feilotter, Harriet

doi:10.1186/1471-2407-12-91

Cited by 343 publications

(290 citation statements)

References 46 publications

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“…Previous studies reported that cancer cells could acquire new traits such as enhanced proliferation and drug resistance through EMT (Sarkar et al, 2009;Singh and Settleman, 2010;Haslehurst et al, 2012). We also found that ltDSCs had higher colony forming ability than parental cells.…”

Section: Ltdscs Were More Malignant Compared To Parental Cellssupporting

confidence: 70%

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

Han

Ji²,

Dong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and plays an important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 h treatment of anti-cancer drug doxorubicin could induce EMT in human gastric cancer BGC-823 cells. However, the long term effects of this transient drug treatment were unknown. In this study we found that after 48 h treatment with 0.1 μg/ml doxorubicin, most cells died during next week, while a minor population of cells survived and formed colonies. We propagated the surviving cells in drug free medium and found that these long term cultured drug survival cells (abbreviated as ltDSCs) retained a mesenchymal-like cell morphology, and expressed high levels of EMT-related molecules such as vimentin, twist and β-catenin. The expression of chromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We further demonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNA suppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were more drug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involved in the EMT of ltDSCs.

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Section: Ltdscs Were More Malignant Compared To Parental Cellssupporting

confidence: 70%

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

Han

Ji²,

Dong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…In another study, overexpression of Snail was shown to be correlated with a higher state or to be a marker of poor prognosis in malignancies because it confers resistance to apoptosis induced by DNA damage (36,37). In ovarian cancer cell lines, upregulation of Snail and Slug has been correlated with resistance to radiation and paclitaxel and shown to participate directly in p53-mediated pro-survival signaling (38). Twist has been found to be expressed at high levels in a number of human cancers, including those of the breast, prostate, esophagus, and uterus, and is associated with EMT and intravasation (39).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

et al. 2014

International Journal of Oncology

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Abstract. 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 typical phenotype 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 western blot analysis 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. IntroductionEpithelial-mesenchymal transition (EMT) is a critical process in cell differentiation, morphogenesis, growth and change of function (1). EMT is a cellular mechanism recognized as a central feature of normal physiological development such as organogenesis during embryonic development and wound healing (2). Several developmental milestones, including gastrulation, neural crest formation, and heart morphogenesis, rely on the plastic transition between epithelial cells and mesenchymal cells (3). However, dysregulated EMT appears to occur in cancer progression and metastasis, as well as the pathogenesis of chronic degenerative fibrotic disorders in several organs (4). Epithelial and mesenchymal cells differ in function and characteristics. Epithelial cells are closely adjoined by specialized membrane structures such as desmosomes, as well as tight, adherent, and gap junctions, and have apical-basolateral polarization (5). Conversely, mesenchymal cells do not form an organized cell layer, nor do they have the same apical-basolateral organization, polarization of the cell surface molecules (6). In culture, epithelial cells grow in clusters, whereas mesenchymal cells have a spindle shaped and fibroblast-like morphology (7). During the EMT process, epithelial cells are removed of cellular polarity and epithelial cell-cell as well a...

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“…Luo et al (27) reported that the expression of EGFL7 in gastric cancer cells promotes the epithelial-to-mesenchymal transition (EMT) and tumor metastasis by epidermal growth factor receptor (EGFR)-mediated protein kinase B (AKT) phosphorylation, which subsequently activates Snail and suppresses the transcription of E-cadherin. Numerous studies have demonstrated that increased EMT may lead to chemoresistance in bladder, lung, breast and ovarian cancers (28)(29)(30)(31)(32). In addition, Vega et al (33) reported that Snail inhibits the cell cycle and confers resistance to TGF-β-induced cell death, consistent with Snail activating the Mek/Frk and PI3K/Akt survival pathways.…”

Section: Introductionmentioning

confidence: 80%

“…The second hypothesis was that the promotion of EMT by EGFL7 may induce the development of tumor cell resistance to chemotherapy; EMT is regulated by EGFR-mediated AKT phosphorylation induced by EGFL7, which then activates Snail and the subsequent suppression of E-cadherin transcription (27). Numerous studies have previously reported that EMT may have a function in acquired chemoresistance (28)(29)(30)(31)(32). The third hypothesis considered that EGFL7 may have a role in the development of tumor chemoresistance through an increased resistance to cell apoptosis induced by the activation of Snail.…”

Section: No Of Patients --------------------------------------------mentioning

confidence: 99%

Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer

et al. 2016

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Abstract. Neoadjuvant chemotherapy (NAC) followed by hysterectomy may be effective for the treatment of locally advanced uterine cervical cancer and improve patient prognosis. It is important to identify markers that are able to predict whether NAC may be successful. Epidermal growth factor-like domain 7 (EGFL7) regulates vascular sprouting in blood vessel formation. In numerous types of human cancer, EGFL7 is upregulated and inhibits endothelial cell adhesion molecules, decreasing vascular tightness and, thus, increasing vascular permeability. It is considered that the overexpression of EGFL7 is able to inhibit drug delivery, resistance to apoptosis and the epithelial-to-mesenchymal transition. In the current study, 63 patients with locally advanced uterine cervical cancer were reviewed and classified as stage IIIA-IIIB using the International Federation of Gynecology and Obstetrics criteria. These patients (aged <70 years) were treated at

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EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

Cited by 343 publications

References 46 publications

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

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

Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer

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