Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial–mesenchymal transition and stemness

Wu, Kaijie; Ning, Zhongyun; Zeng, Jin; Fan, Jinhai; Zhou, Jiancheng; Zhang, Tingting; Zhang, Linlin; Chen, Yule; Gao, Yang; Wang, Bin; Guo, Peng; Li, Lei; Wang, Xinyang; He, Dalin

doi:10.1016/j.cellsig.2013.08.028

Cited by 104 publications

(88 citation statements)

References 53 publications

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“…In contrast, ZEB2 expression is significantly higher in infiltrating carcinoma than high-grade urothelial carcinoma [24]. It has been suggested that ZEB1 expression is regulated by nuclear β -catenin upon stimulation [49]. In bladder cancer, β -catenin signaling cascades can be activated by various routes.…”

Section: Bladder and Renal Cancermentioning

confidence: 99%

“…In bladder cancer, β -catenin signaling cascades can be activated by various routes. In which, many evidence pointed to the glycogen synthase kinase 3 β - (GSK3 β -) ZEB1 cascade which was triggered through phosphatidylinositol 3-kinase (PI3 K)/Akt pathways [49–51]. Further, noncoding RNA including microRNA-23b and long noncoding RNA MALAT-1 has also been suggested to be the transcriptional regulator of ZEB1 and ZEB2 in bladder cancers [52, 53].…”

Section: Bladder and Renal Cancermentioning

confidence: 99%

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Transcription Regulation of E-Cadherin by Zinc Finger E-Box Binding Homeobox Proteins in Solid Tumors

Wong

Gao

Chan

2014

BioMed Research International

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Downregulation of E-cadherin in solid tumors with regional migration and systematic metastasis is well recognized. In view of its significance in tumorigenesis and solid cancer progression, studies on the regulatory mechanisms are important for the development of target treatment and prediction of clinical behavior for cancer patients. The vertebrate zinc finger E-box binding homeobox (ZEB) protein family comprises 2 major members: ZEB1 and ZEB2. Both contain the motif for specific binding to multiple enhancer boxes (E-boxes) located within the short-range transcription regulatory regions of the E-cadherin gene. Binding of ZEB1 and ZEB2 to the spaced E-cadherin E-boxes has been implicated in the regulation of E-cadherin expression in multiple human cancers. The widespread functions of ZEB proteins in human malignancies indicate their significance. Given the significance of E-cadherin in the solid tumors, a deeper understanding of the functional role of ZEB proteins in solid tumors could provide insights in the design of target therapy against the migratory nature of solid cancers.

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Section: Bladder and Renal Cancermentioning

confidence: 99%

Section: Bladder and Renal Cancermentioning

confidence: 99%

Transcription Regulation of E-Cadherin by Zinc Finger E-Box Binding Homeobox Proteins in Solid Tumors

Wong

Gao

Chan

2014

BioMed Research International

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“…Thus, CD44 is thought to be a biomarker for cancer stem cells (CSCs) [47]. Functional studies have shown that CD44 is involved in tumorigenesis and metastasis in many cancer types such as colon [48–50], bladder [51], gastric [52], breast, [53], and GBM [54]. Recently, overexpression of CD44 was associated with significantly worse overall survival in breast cancer patients [55].…”

Section: Discussionmentioning

confidence: 99%

Computational analysis of the mesenchymal signature landscape in gliomas

et al. 2017

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BackgroundEpithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting.ResultsComputational analysis of 275 glioma samples from “The Cancer Genome Atlas” was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway - Extracellular matrix organization - was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53–8.33), after controlling for known prognostic factors (age, and glioma grade). The signature’s significance was validated in an independent data set. The putative stem cell marker CD44 was biologically validated in glioma cell lines and brain tissue samples.ConclusionsOur results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0252-7) contains supplementary material, which is available to authorized users.

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“…Recent studies have found that SIL has strong antitumor activities toward a variety of epithelium-derived tumors, such as prostate,2 colon,1 bladder,13 breast,14 ovarian,15 and lung cancers 3,4. This study analyzed the impacts of SIL on the proliferation of ACC-M cells, and the results revealed that SIL could inhibit the proliferation of ACC-M cells in time- and dose-dependent manner, particularly when treated with 160 µg/mL of SIL for 72 hours, the inhibition rate of 93% suggested that SIL had significant inhibitory activities toward ACC.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of silibinin on proliferation and lung metastasis of human high metastasis cell line of salivary gland adenoid cystic carcinoma via autophagy induction

Jiang¹,

Jin²,

Jiang³

et al. 2016

OTT

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ObjectiveTo investigate the possible mechanisms and effects of silibinin (SIL) on the proliferation and lung metastasis of human lung high metastasis cell line of salivary gland adenoid cystic carcinoma (ACC-M).MethodsA methyl thiazolyl tetrazolium assay was performed to detect the inhibitory effects of SIL on the proliferation of ACC-M cells in vitro. Fluorescence microscopy and transmission electron microscopy were used to observe the autophagic process. Western blot was performed to detect the expression of microtube-related protein 1 light-chain 3 (LC3). An experimental adenoid cystic carcinoma (ACC) lung metastasis model was established in nude mice to detect the impacts of SIL on lung weight and lung cancer nodules. Immunohistochemistry was used to detect the expressions of LC3 in human ACC samples and normal salivary gland tissue samples.ResultsSIL inhibited the proliferation of ACC-M cells in a dose- and time-dependent manner, and inductively increased the autophagic bodies in ACC-M cells. Furthermore, SIL could increase the expression of LC3 in ACC-M cells and promote the conversion of LC3-I into LC3-II in a dose- and time-dependent manner. In the ACC lung metastasis model, the lung weight and left and right lung nodules in the SIL-treated group were significantly less than those in the control group (P<0.05). The expressions of LC3-I and LC3-II as well as the positive expression rate of LC3 (80%) significantly increased, but the positive expression of LC3 in human ACC (42.22%) reduced significantly.ConclusionSIL could inhibit the proliferation and lung metastasis of ACC-M cells by possibly inducing tumor cells autophagy.

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Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial–mesenchymal transition and stemness

Cited by 104 publications

References 53 publications

Transcription Regulation of E-Cadherin by Zinc Finger E-Box Binding Homeobox Proteins in Solid Tumors

Transcription Regulation of E-Cadherin by Zinc Finger E-Box Binding Homeobox Proteins in Solid Tumors

Computational analysis of the mesenchymal signature landscape in gliomas

Inhibitory effects of silibinin on proliferation and lung metastasis of human high metastasis cell line of salivary gland adenoid cystic carcinoma via autophagy induction

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