Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

Wu, Wen-Sheng; You, Ren-In; Cheng, Chuan-Chu; Lee, Ming-Che; Lin, Teng-Yi; Hu, Chi-Tan

doi:10.1038/s41598-017-18101-7

Cited by 72 publications

(71 citation statements)

References 40 publications

(53 reference statements)

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“…ZEB1 induces the promotion of EMT and in combination with other factors triggers metastasis [ 25 ] and is highly expressed in aggressive cancer cell lines [ 1 ] and the overexpression of the protein may be an indicator of poor prognosis in breast, pancreatic, and lung cancer [ 21 ]. What is more, a mutual regulation between SNAI1 and ZEB1 has been recently identified [ 25 ]; SNAI1, acting as a primary EMT regulator, may enhance expression of other transcription factors, including ZEB1 and TWIST [ 27 ]. In metastatic cell nucleus, ZEB1 and TWIST1 proteins prevent E-cadherin gene transcription [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Caffeic Acid and Metformin Inhibit Invasive Phenotype Induced by TGF-β1 in C-4I and HTB-35/SiHa Human Cervical Squamous Carcinoma Cells by Acting on Different Molecular Targets

Tyszka-Czochara

Lasota

Majka

2018

IJMS

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During the progression of epithelial cancer, the cells may lose epithelial markers and gain mesenchymal phenotype via Epithelial-Mesenchymal Transition (EMT). Such transformation of epithelial cancer cells to mesenchymal-like characteristic benefits plasticity and supports their ability to migrate. The aim of this study was to evaluate the influence of natural compound Caffeic Acid (CA) alone and in combination with antidiabetic drug Metformin (Met) on metastatic progression of two human cervical squamous cell cancer lines, C-4I and HTB-35/SiHa cells. EMT program was triggered by exposition of both epithelial cell lines to TGF-β1. Gene expression patterns related to epithelial/mesenchymal phenotype were evaluated by Real-Time PCR analysis and the protein amount was detected by western blot. The treatment of human squamous cancer cells with CA and with Met, suppressed the motility of cells and the effect depended on a particular cell line. Both compounds regulated the EMT process in C4-I and HTB-35 cells by interfering with different molecular targets. In TGF-β1-stimulated C4-I cells, CA suppressed the expression of mesenchymal transcription factor SNAI1 which resulted in enhanced expression of epithelial markers E-cadherin, Occludin and Claudin. Additionally, CA blocked MMP-9 and upregulated TIMP-1 expression, a specific inhibitor of MMP-9. In HTB-35 cells stimulated with TGF-β1, Met decreased the expression of Vimentin. By suppressing hypoxia master regulator HIF-1α, Met caused downregulation of CAIX, an enzyme involved in metastasis of aggressive malignant cells. In this study we showed that CA and Met inhibited EMT process in cancer cells via different mechanisms. However, when applied together, compounds exerted the greater effect on EMT than each compound alone. This is the first report revealing that CA alone and co-treated with Met may reverse mesenchymal phenotype of TGF-β1-treated cervical tumor cells and we believe that the use of the two small molecules may be considered as a potential therapeutic approach for metastatic cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Caffeic Acid and Metformin Inhibit Invasive Phenotype Induced by TGF-β1 in C-4I and HTB-35/SiHa Human Cervical Squamous Carcinoma Cells by Acting on Different Molecular Targets

Tyszka-Czochara

Lasota

Majka

2018

IJMS

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“…Kukoamine A significantly reduced the expression of mesenchymal markers such as snail, vimentin, and N‐cadherin and increased the expression of epithelial markers such as E‐cadherin and subsequently inhibited the migration of human GBM U251 and WJ1 cells . Jorda et al indicated that snail bound to the promoter region and enhanced the expression of MMP‐9 in Madin Darby canine kidney epithelial cells and Hep G2 cells. Snail also upregulated the expression of MMP‐2 in hepatocellular carcinoma cells .…”

Section: Discussionmentioning

confidence: 99%

Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms

Chen

Chang

Wang

et al. 2018

Environmental Toxicology

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Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin.Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin.Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38.Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.

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“…Next, we deciphered the generic emergent properties of an extended gene regulatory network involving SNAIL, SLUG, ZEB1, miR-200 and E-cadherin (CDH1) (Fig 4A). At a transcriptional level, ZEB1, SNAIL and SLUG can all repress E-cadherin [Batlle et al, 2000;Sterneck et al, 2020;Mooney et al, 2016], and SNAIL and SLUG can activate ZEB1 [Wels et al, 2011;Wu et al, 2017]. Further, SLUG is known to self-activate [Kumar et al, 2015], but SNAIL selfinhibits [Peiró et al, 2006].…”

Section: The Role Of Slug In Stabilizing Hybrid E/m State Is a Functimentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) – an EMT-inducing transcription factor – can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

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Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

Cited by 72 publications

References 40 publications

Caffeic Acid and Metformin Inhibit Invasive Phenotype Induced by TGF-β1 in C-4I and HTB-35/SiHa Human Cervical Squamous Carcinoma Cells by Acting on Different Molecular Targets

Caffeic Acid and Metformin Inhibit Invasive Phenotype Induced by TGF-β1 in C-4I and HTB-35/SiHa Human Cervical Squamous Carcinoma Cells by Acting on Different Molecular Targets

Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

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