Knockdown of ZEB1, a master epithelial-to-mesenchymal transition (EMT) gene, suppresses anchorage-independent cell growth of lung cancer cells

Takeyama, Yoshihiro; Sato, Mitsuo; Horio, Mihoko; Hase, Takashi; Yoshida, Kenya; Yokoyama, Toshihiko; Nakashima, Hitoshi; Hashimoto, Naozumi; Sekido, Yoshitaka; Gazdar, Adi F.; Minna, John D.; Kondo, Masashi; Hasegawa, Yoshinori

doi:10.1016/j.canlet.2010.04.008

Cited by 132 publications

(136 citation statements)

References 39 publications

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“…The acquirement of this invasive potential of tumor cells through EMT is interrelated with the formation of migratory, mesenchymal cells with loose cell-cell contacts and apico-basolateral polarity (21). EMT also leads to upregulation of anti-apoptotic signals rendering the cells more tumorigenic and less responsive to treatment (22,23).…”

Section: Epithelial To Mesenchymal Transition (Emt)mentioning

confidence: 99%

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The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and resistance to lung cancer therapy Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The 5-year survival remains at 10-15% despite advances in treatment options.Erlotinib, a TKI targeting EGFR, was initially explored as a second-line treatment in NSCLC patients progressing on standard chemotherapy. Survival was prolonged compared to placebo (1). However, erlotinib was soon discovered to be especially efficient in patients with a mutation in the tyrosine kinase domain of EGFR. These patients are nowThe role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Correspondence to: Anders Lade Nielsen. Department of Biomedicine, Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark.Email: aln@biomed.au.dk.Abstract: Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFRdirected tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs.Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.Keywords: Epidermal growth factor receptor (EGFR); epithelial to mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI)

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Section: Epithelial To Mesenchymal Transition (Emt)mentioning

confidence: 99%

“…Cooccurring induction of EMT may result in generation of mesenchymal-like cells which have a growth and survival advantage do to the lack of E-cadherin expression and through the anti-apoptotic effect of the EMT factors SNAIL, SLUG and ZEB1 (22,23,49).…”

Section: Molecular Mechanisms For Emt Induction Related To Egfr-tki Rmentioning

confidence: 99%

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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“…TGFBI mediates cell adhesion by interacting with collagens, fibronectin and integrins, which are major components of the DM. 43,44 TGF-b, which induces the TGFBI protein, has a reported role in the regulation of TCF4 and ZEB1 through signaling pathways in EMT. 26 Mutations in TGFBI cause some human corneal dystrophies, but have not been reported to cause FED.…”

Section: Association Of Tcf4 and Clu Polymorphisms With Fedmentioning

confidence: 99%

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

et al. 2012

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Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, b-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P¼5.25Â10 À15 , OR¼4.05), rs9954153 (P¼3.37Â10 À7 , OR¼2.58), rs2286812 (P¼4.23Â10 À6 , OR¼2.55) and rs17595731 (P¼3.57Â10 À5 , OR¼3.79)), CLU (rs17466684; P¼0.003, OR¼1.85) and one haplotype of TGFBI SNPs (P¼0.011, OR¼2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism.

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“…EMT in cancer refers to a dynamic cellular process during which cells lose cellular polarity and attain a mesenchymal-like or fibroblastoid phenotype at the primary site of tumor [11]. Among the molecular changes are loss of E-cadherin, occludin, and β 4-integrin with gain of vimentin, fibronectin, N-cadherin, and α -smooth muscle actin [13, 14] (Fig. 1).…”

Section: Epithelial-to-mesenchymal Transition: Explanations For Tumormentioning

confidence: 99%

“…ZEB1 functions in anchorage-independent growth in non-small cell lung carcinoma [13]. TGF- β is also a major player in EMT, and this cytokine is particularly important based on its dual role in breast cancer [15, 17].…”

Section: Epithelial-to-mesenchymal Transition: Explanations For Tumormentioning

confidence: 99%

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

Patel

Dave²,

Murthy³

et al. 2010

Oncol Rev

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Among all cancers, malignancies of the breast are the second leading cause of cancer death in the United States after carcinoma of the lung. One of the major factors considered when assessing the prognosis of breast cancer patients is whether the tumor has metastasized to distant organs. Although the exact phenotype of the malignant cells responsible for metastasis and dormancy is still unknown, growing evidence has revealed that they may have stem cell-like properties that may account for resistance to chemotherapy and radiation. One process that has been attributed to primary tumor metastasis is the epithelial-to-mesenchymal transition. In this review, we specifically discuss breast cancer dissemination to the bone marrow and factors that ultimately serve to shelter and promote tumor growth, including the complex relationship between mesenchymal stem cells (MSCs) and various aspects of the immune system, carcinoma-associated fibroblasts, and the diverse components of the tumor microenvironment. A better understanding of the journey from the primary tumor site to the bone marrow and subsequently the oncoprotective role of MSCs and other factors within that microenvironment can potentially lead to development of novel therapeutic targets.

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Knockdown of ZEB1, a master epithelial-to-mesenchymal transition (EMT) gene, suppresses anchorage-independent cell growth of lung cancer cells

Cited by 132 publications

References 39 publications

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

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