LEF1 regulates glioblastoma cell proliferation, migration, invasion, and cancer stem-like cell self-renewal

Gao, Xingchun; Mi, Yajing; Ma, Yue; Jin, Wei‐Lin

doi:10.1007/s13277-014-2466-z

Cited by 47 publications

(45 citation statements)

References 27 publications

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“…A previous study stated that Wnt caused elevated LEF1 expression in a β-catenin-independent and LEF1-dependent manner [40], which supports our finding of β-catenin-independent LEF1 repression by mangiferin in HCC cells. LEF1 related signalling is a multi-targeted regulatory mechanism in which the aberrant activation of LEF1 results in cancer development by promoting processes such as invasion, proliferation, and self-renewal of cancer cells [28,41,42]. Our molecular finding that mangiferin represses LEF1 target genes accords with these previous studies, especially given our cellular finding mangiferin restricted HCC cell proliferation, migration, and chemotactic properties.…”

Section: Discussionsupporting

confidence: 88%

Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma

Tan

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The development of hepatocellular carcinoma (HCC) is a complex process which involves deregulation of multiple signalling pathways. The hyper-activation of Wnt signalling promotes sustained expansion, invasion, and neovascularization of HCC. Mangiferin, a natural small molecule present in Mangifera indica L. has been shown to inactivate β-catenin, which is an indispensable regulator in Wnt pathway. Our study aimed to determine whether mangiferin has any inhibitory effect on HCC and examine how it modulates Wnt signalling. Methods: The tumour inhibitory effect of mangiferin was examined by in vitro cellular models and an in vivo orthotopic HCC implantation model. The genes responsible for mangiferin-mediated anti-HCC were delineated by polymerase chain reaction (PCR) microarray. The expression of target genes was further determined by quantitative PCR and immuno-blotting assays. The binding capacity of Wilms’ tumour 1 (WT1) to the lymphoid enhancer-binding factor 1 (LEF1) promoter was confirmed by chromatin immunoprecipitation-qPCR. Results: Oral administration of mangiferin inhibited orthotopic tumour growth. Cellular investigations confirmed the dose-dependent inhibition of mangiferin on HCC expansion and invasion. PCR array combined with Gene Ontology analysis revealed that the Wnt pathway was the predominant target of mangiferin and LEF1 was the most reduced gene in the Wnt pathway. Overexpression of LEF1 diminished repression of Wnt signalling and reduced proliferation activity in mangiferin-treated HCC cells. The mangiferin-mediated down-regulation of LEF1 was independent of β-catenin but associated with WT1 protein. WT1 knock-in in HCC cells further enhanced LEF1 expression. Chromatin immunoprecipitation assays revealed that the mangiferin induced repression of LEF1 was associated with decreased occupancy of WT1 on the LEF1 promoter. Conclusion: Our study identifies a novel mechanism of hepatocellular carcinoma inhibition through β-catenin-independent Wnt signalling, which is regulated by WT1-associated LEF1 repression. The study also highlights mangiferin as a promising Wnt inhibitor for HCC treatment.

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Section: Discussionsupporting

confidence: 88%

Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma

Tan

Wang

et al. 2018

Cell Physiol Biochem

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“…We detected downregulation of PCNA in 5637 and UMUC-3 cells knocked down for HMGB3. MMP2, which can degrade collagen IV, the major extracellular matrix component of the basement membrane, is implicated in nonphysiological tissue invasion and migration [23]. We found that the protein level of MMP2 was decreased in HMGB3-silenced 5637 and UMUC-3 cells.…”

Section: Discussionmentioning

confidence: 68%

Overexpression of HMGB3 protein promotes cell proliferation, migration and is associated with poor prognosis in urinary bladder cancer patients

Cai

Zhao

et al. 2015

Tumor Biol.

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Human urinary bladder cancer (UBC) is the fourth most common cancer and the eighth most common cause of cancer death in the USA. High mobility group box 3 (HMGB3), a member of a family of proteins containing one or more high mobility group DNA binding motifs, was reported to be overexpressed in a variety of human cancers. However, the expression and role of HMGB3 in human UBC remains unclear. Here, we found that UBC patients had upregulated HMGB at both mRNA and protein levels. Immunochemistry (IHC) evaluation of HMGB3 expression in 113 UBC clinical specimens showed that high expression of HMGB3 had positive correlation with UBC tumor size (P = 0.019), tumor WHO grade (P = 0.031), stage (P = 0.028), and lymph node metastasis (P = 0.017). Moreover, patients with higher HMGB3 expression showed a poorer overall survival rate than those with relatively low HMGB3 (P = 0.0079, log-rank test). Multivariate analysis revealed that HMGB3 expression is an independent prognostic marker. The UBC cancer cell proliferation and migration ability were measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and wound healing assays, respectively. RNA interference of HMGB3 in UBC cell lines inhibited cancer cell growth and migration, along with the downregulation of PCNA and MMP2 protein levels. In sum, our data suggests HMGB3 may serve as an important oncoprotein and indicate that overexpression of HMGB3 in UBC could be used as a potential prognostic marker.

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“…3,68 Although most studies have addressed canonical WNT signaling, several studies have indicated the involvement of both canonical and non-canonical WNT signaling. 22,83 WNT SIGNALING IN GBM INVASION Tumor metastasis is a major factor contributing to tumorassociated death. Epithelial-mesenchymal transition (EMT) is a critical process that enables cancer cells of epithelial origin to metastasize to distal organs.…”

Section: Wnt Signaling In Gbm Stem Cells (Gscs)mentioning

confidence: 99%

WNT signaling in glioblastoma and therapeutic opportunities

Lee

Ahn

et al. 2016

Laboratory Investigation

220

182

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WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross-talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials.

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LEF1 regulates glioblastoma cell proliferation, migration, invasion, and cancer stem-like cell self-renewal

Cited by 47 publications

References 27 publications

Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma

Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma

Overexpression of HMGB3 protein promotes cell proliferation, migration and is associated with poor prognosis in urinary bladder cancer patients

WNT signaling in glioblastoma and therapeutic opportunities

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