Effect of downregulation of ZEB1 on vimentin expression, tumour migration and tumourigenicity of melanoma B16F10 cells and CSCs

Dou, Jun; He, Xue; Liu, Yurong; Wang, Yaqian; Zhao, Fengshu; Wang, Xiaoying; Chen, Dengyu; Shi, Fangfang; Wang, Jing

doi:10.1002/cbin.10223

Cited by 32 publications

(23 citation statements)

References 30 publications

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“…Probably as a result of the reduced expression of EMT associated genes, cells with CHKα suppression exhibit fewer phenotypic properties of mesenchymal cells, since we detected significantly reduced invasiveness and clonogenicity in shCHKα cells (Figure 6). Concisely, ZEB1, ZEB2, and TWIST1 have all been described to promote invasion, and clonogenicity in GBM and other tumors [12, 43–48]. Additionally we found increased CHKα expression on the infiltrative leading edge of GBMs as compared to tumor parenchyma, indicating CHKα expression is associated with invasive properties of the tumor cells in GBM patients (Supplementary Figure S3).…”

Section: Discussionsupporting

confidence: 61%

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

et al. 2016

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Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy.

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Section: Discussionsupporting

confidence: 61%

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

et al. 2016

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“…On immunoblots, the downregulation of IGF-1 was associated with higher levels of the epithelial marker E-cadherin, and lower levels of the mesenchymal marker N-cadherin (Figure 3A). Levels of zinc finger E-box-binding protein 1 (ZEB1), a major driver of the EMT process in melanoma cells [28–30], were also significantly lower in the C10 clone (Figure 3A). These results were supported by flow cytometry analysis, which showed markedly lower levels of the mesenchymal markers CD29, CD44 and CD105 in the C10 clone than in control and parental cells (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Our results show that IGF-1 plays a critical role in EMT in B16-F10 cells. Indeed, IGF-1 downregulation resulted in morphological changes, an upregulation of epithelial marker expression, and a downregulation of mesenchymal markers (N-cadherin, CD29, CD44 and CD105) and ZEB1, which is essential for EMT induction in B16-F10 cells [28–30]. Indeed, one of the roles of ZEB1 is to regulate the expression of E-cadherin, a key molecule in the maintenance of epithelial cell characteristics [45], as its loss may enhance the invasive and metastatic behavior of melanoma cells [46].…”

Section: Discussionmentioning

confidence: 99%

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IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process

et al. 2016

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Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.

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“…Increasing evidences indicated that ZEB1 closely related with the biological behaviors of tumors, such as invasion and metastasis, stemness of cancer stem cells, tumor angiogenesis and chemosensitivity, which largely contributes to tumors initiation and progression (12,13,(31)(32)(33). Several miRNAs also had been showed to take part in ZEB1 regulation, and therefore adjusted of its function in occurrence and development of tumors.…”

Section: Discussionmentioning

confidence: 99%

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1

Sun

et al. 2015

Japanese Journal of Clinical Oncology

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Objective: Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. Methods: The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptasepolymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. Results: We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-boxbinding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. Conclusions: miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.

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Effect of downregulation of ZEB1 on vimentin expression, tumour migration and tumourigenicity of melanoma B16F10 cells and CSCs

Cited by 32 publications

References 30 publications

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1

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