Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Chang, Tzu Hua; Tsai, Meng Feng; Su, Kang-Yi; Wu, Shang Gin; Huang, Chien-Chang; Yu, Sung-Liang; Yu, Yung Luen; Lan, Chou Chin; Yang, Chih Hsin; Lin, Shwu Bin; Wu, Chin Pyng; Shih, Jin‐Yuan; Yang, Pan Chyr

doi:10.1164/rccm.201009-1440oc

Cited by 148 publications

(138 citation statements)

References 36 publications

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“…The results of microarray and real-time RT-PCR showed an increase in cyclin D1 expression, which may explain how YWHAZ promotes cell proliferation and tumorigenesis. Another target gene of b-catenin, Slug, is an important transcription factor that promotes tumor growth, invasion, and drug resistance (8,42,43). On the basis of our current data, we also found enhanced expression of Slug in presence of YWHAZ expression.…”

Section: Discussionsupporting

confidence: 72%

A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

Chen

Chuang

Yang

et al. 2012

Molecular Cancer Research

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YWHAZ, also known as 14-3-3zeta, has been reportedly elevated in many human tumors, including non-small cell lung carcinoma (NSCLC) but little is known about its specific contribution to lung cancer malignancy. Through a combined array-based comparative genomic hybridization and expression microarray analysis, we identified YWHAZ as a potential metastasis enhancer in lung cancer. Ectopic expression of YWHAZ on low invasive cancer cells showed enhanced cell invasion, migration in vitro, and both the tumorigenic and metastatic potentials in vivo. Gene array analysis has indicated these changes associated with an elevation of pathways relevant to epithelial-mesenchymal transition (EMT), with an increase of cell protrusions and branchings. Conversely, knockdown of YWHAZ levels with siRNA or short hairpin RNA (shRNA) in invasive cancer cells led to a reversal of EMT. We observed that high levels of YWHAZ protein are capable of activating b-catenin-mediated transcription by facilitating the accumulation of b-catenin in cytosol and nucleus. Coimmunoprecipitation assays showed a decrease of ubiquitinated b-catenin in presence of the interaction between YWHAZ and b-catenin. This interaction resulted in disassociating b-catenin from the binding of b-TrCP leading to increase b-catenin stability. Using enforced expression of dominant-negative and -positive b-catenin mutants, we confirmed that S552 phosphorylation of b-catenin increases the b-catenin/YWHAZ complex formation, which is important in promoting cell invasiveness and the suppression of ubiquitnated b-catenin. This is the first demonstration showing YWHAZ through its complex with b-catenin in mediating lung cancer malignancy and b-catenin protein stability. Mol Cancer Res; 10(10); 1319-31. Ó2012 AACR. IntroductionLung cancer is a malignant tumor with a high incidence and mortality rate (1). Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers and has an overall 5-year survival rate of 10% to 15% (2). Metastasis is the main cause of treatment failure and cancer-related deaths. In carcinomas, metastasis is a multiple step process, the first of which is invasion (3). Cancer cells acquire their invasive capacity

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Section: Discussionsupporting

confidence: 72%

A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

Chen

Chuang

Yang

et al. 2012

Molecular Cancer Research

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“…Therefore the identification of new molecular mechanism of EGFR-TKIs and more effective treatments in NSCLC is extremely ultimate goal of cure and long-term control of NSCLC. Currently Chang et al (2011) [3] showed that Slug, the regulator of epithelial-mesenchymal transition (EMT) contributes to the resistance of EGFR-TKIs as gefitnib in NSCLC and [21] showed Notch-1 contributes to EGFR-TKIs acquired resistance in NSCLC, suggesting that Slug and Notch-1 might play a novel role in acquired resistance to gefitinib which could be reversed by inhibiting Slug and Notch-1 in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs expression profile of gefitinib resistant non-small cell lung cancer HCC827 cells

Quan¹,

Seong²

2016

V J Bio

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“…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%

“…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: 95%

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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Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Abstract: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.

Cited by 148 publications

References 36 publications

A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

MicroRNAs expression profile of gefitinib resistant non-small cell lung cancer HCC827 cells

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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