Diverse Targets of β-Catenin during the Epithelial–Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse

Chang, Yi‐Wen; Su, Ying-Jhen; Hsiao, Michael; Wei, Kuo‐Chen; Lin, Wei-Hsin; Liang, Chi-Lung; Chen, Shin‐Cheh; Lee, Jia-Lin

doi:10.1158/0008-5472.can-14-3265

Cited by 77 publications

(72 citation statements)

References 47 publications

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“…However, the mechanistic relationship between EMT and the Wnt/β-catenin pathway is not entirely clear. Chromatin immunoprecipitation with high-throughput sequencing indicated that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-catenin/Twist1/TCF4 complex, which then binds to cancer stem cell-related gene promoters [32]. In our study, we found that C/EBPα suppressed β-catenin/TCF/LEF complex transcriptional activity and downregulated levels of β-catenin and its downstream targets.…”

Section: Discussionmentioning

confidence: 49%

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

Lu¹,

Du²,

Yao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor that plays essential roles in tumor progression. Although decreased or absent C/EBPα expression in many cancers suggests a possible role for C/EBPα as a tumor suppressor, the functions of C/EBPα in lung adenocarcinoma remain unclear. Methods: Here, C/EBPα expression levels in 26 lung adenocarcinoma and para-carcinoma tissue samples were detected by qRT-PCR and immunohistochemistry. Cell transwell assays, wound healing assay and three-dimensional spheroid invasion assay were performed to assess the effects of C/EBPα on migration and invasion in lung adenocarcinoma cells in vitro. Western blotting was applied to analyze the potential mechanisms. Results: C/EBPα was found to be decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues. Overexpression of C/EBPα significantly inhibited the migration and invasion of lung adenocarcinoma cells. In addition, C/EBPα overexpression suppressed the epithelial–mesenchymal transition (EMT) that was characterized by a gain of epithelial and loss of mesenchymal markers. Further study showed that C/EBPα suppressed the transcription of β-catenin and downregulated the levels of its downstream targets. Conclusion: Our data suggest that C/EBPα inhibits lung adenocarcinoma cell invasion and migration by suppressing β-catenin-mediated EMT in vitro. Thus, C/EBPα may be helpful as a potential target for treatment of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 49%

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

Lu¹,

Du²,

Yao³

et al. 2017

Cell Physiol Biochem

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“…LGR5 potentiates Wnt/β-catenin pathway in BCSCs and is required for the maintenance of spheroid-derived CD44+/CD24− BCSCs [245]. During EMT, β-catenin binds to Twist1 to increases the transcriptional activity of β-catenin/TCF4 complex by binding to the promoter DNA of ABCG2, a cancer stemness marker [246]. …”

Section: Her2 Promotes Stemness Signaling Pathwaysmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

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“…β-catenin, one key protein in Wnt signaling, separates from the degradation complex and then accumulates in the cytoplasm, translocates into nucleus subsequently to sensitize the Wnt pathway during Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review) carcinoma progression. In the presence of downregulation of E-cadherin and Wnt signals activation, both cytoplasmic and nuclear levels of β-catenin increase where it interacts with cell growth and EMT (7,8). MicroRNAs are small noncoding molecules with 19-25 nucleotides that bind to 3'UTR of target mRNAs with complementary base pairing to inhibit their translation or speed up decomposition.…”

Section: Introductionmentioning

confidence: 99%

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

Zhuang

Jiang

et al. 2016

International Journal of Oncology

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Abstract. Gastric cancer (GC) is the third primary cause of cancer-related mortality and one of the most common type of malignant diseases worldwide. Despite remarkable progress in multimodality therapy, advanced GC with high aggressiveness always ends in treatment failure. Epithelialmesenchymal transition (EMT) has been widely recognized to be a key process associating with GC evolution, during which cancer cells go through phenotypic variations and acquire the capability of migration and invasion. Wnt/β-catenin pathway has established itself as an EMT regulative signaling due to its maintenance of epithelial integrity as well as tight adherens junctions while mutations of its components will lead to GC initiation and diffusion. The E-cadherin/β-catenin complex plays an important role in stabilizing β-catenin at cell membrane while disruption of this compound gives rise to nuclear translocation of β-catenin, which accounts for upregulation of EMT biomarkers and unfavorable prognosis. Additionally, several microRNAs positively or negatively modify EMT by reciprocally acting with certain target genes of Wnt/β-catenin pathway in GC. Thus, this review centers on the strong associations between Wnt/β-catenin pathway and microRNAs during alteration of EMT in GC, which may induce advantageous therapeutic strategies for human gastric cancer.

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Diverse Targets of β-Catenin during the Epithelial–Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse

Cited by 77 publications

References 47 publications

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

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