Overexpression of EB1 in human esophageal squamous cell carcinoma (ESCC) may promote cellular growth by activating β-catenin/TCF pathway

Wang, Yihua; Zhou, Xiaobo; Zhu, Hongxia; Liu, Shuang; Zhou, Cuiqi; Guo, Zhiyong; Xue, Liyan; Lü, Ning; Quan, Lanping; Bai, Jinfeng; Zhan, Qimin; Xu, Nuo

doi:10.1038/sj.onc.1208819

Cited by 72 publications

(76 citation statements)

References 20 publications

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“…The Wnt/b-catenin signaling pathway is essential for embryonic development and aberrant activation has been associated with the progression of many cancer types, including ESCC (5,6). Pairedlike homeodomain transcription factor 2 (PITX2) is a member of the bicoid-related homeodomain family and a downstream effecter of Wnt signaling, which activates the expression of target genes required for cell proliferation and survival (7).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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Purpose: We previously reported the oncogenic role of pairedlike homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain-and lossof-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3b/b-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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“…For example, end-binding protein 1 (EB1) over-expression may contribute to the development of ESCC by activating the ß-catenin/TCF pathway (2). Another report demonstrated that the Notch1 signaling pathway is activated in ESCC, and that it can inhibit cell proliferation and induce apoptosis in human ESCC cells (3).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of altered expression of SDC2 and CYR61 in esophageal squamous cell carcinoma

Huang

Di²,

Xu³

et al. 2009

Oncol Rep

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Abstract. The transforming growth factor ß (TGF-ß) signaling pathway plays an important role in growth and development, and is critically involved in the genesis and development of tumors. Syndecan-2 (SDC2) and Cysteine-rich 61 (CYR61) are important genes in this pathway and SDC2 is known to be a significant upstream regulator of TGF-ß signaling. However, the roles of SDC2 and CYR61 in the development of esophageal squamous cell carcinoma (ESCC) remain unclear. In the present study, we investigated the relationship between SDC2 and CYR61 mRNA expression levels and disease prognosis in patients with ESCC. The mRNA expression of SDC2 and CYR61 was detected by quantitative real-time RT-PCR in 77 tissue specimens. Quantitative realtime RT-PCR showed that SDC2 and CYR61 mRNA expression levels were aberrant in ESCC tissue (P<0.01) and that SDC2 mRNA expression was significantly associated with tumor size (P=0.024) in ESCC. CYR61 mRNA expression was significantly associated with regional lymph node metastasis (P=0.034) and tumor size (P=0.03). A positive correlation between SDC2 and CYR61 (r=0.770; P<0.001) mRNA expression was observed. Moreover, we observed significant associations between altered expression of SDC2/CYR61 and regional lymph node metastasis (P=0.009) and TNM stages (P=0.033). Aberrant mRNA expression of CYR61 and SDC2/CYR61 (P=0.005 and P=0.026, respectively) were significantly associated with patient survival time. The multivariate Cox regression analysis showed that SDC2 and CYR61 were independent prognostic factors for survival. Our findings suggest that SDC2 may act as an a upstream regulator of the TGF-ß signaling pathway and regulate the expression of downstream target genes. Moreover, SDC2 and CYR61 expression affect the severity of cancer, and the survival of patients with ESCC. Importantly, we report that SDC2 and CYR61 are significant, independent prognostic factors for survival in ESCC. These findings may have implications for targeted therapies in patients with ESCC.

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“…The importance of this interaction in carcinogenesis is shown by the finding that mutation of the APC tumor suppressor that disrupts its interaction with EB1 occurs commonly in the familial and sporadic colon cancers (Su et al, 1995). A recent finding has indicated that EB1 is overexpressed in many human esophageal squamous cell carcinoma (ESCC), and may play a role in the development of ESCC by affecting APC function and activating the b-catenin/TCF pathway (Wang et al, 2005). Recently, an APC homolog APC2 has been identified and shown to be predominantly expressed in the central nervous system (Nakagawa et al, 1998;van Es et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

p53 downstream target DDA3 is a novel microtubule-associated protein that interacts with end-binding protein EB3 and activates β-catenin pathway

Chang

Sun

et al. 2007

Oncogene

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We have previously identified mouse DDA3 as a p53-inducible gene. To explore the functional role of DDA3, we screened a mouse brain cDNA library by the yeast two-hybrid assay, and identified the microtubule plus-end binding protein EB3 as a DDA3-interacting protein.Binding of DDA3 to EB3 was verified by glutathione S-transferase (GST) pull-down assay and subcellular colocalization; co-immunoprecipitation further indicated that interaction of these two proteins within cells required intact microtubules. Domains of DDA3-EB3 interaction were mapped by GST pull-down assay to amino acids 118-241 and 242-329 of DDA3 and the N-and C-termini of EB3. Immunofluorescence analysis revealed colocalization of DDA3 with microtubules in various cell phases, and regions encompassing aa 118-241 and 242-329 contained microtubule-interacting and bundling activities. In vitro microtubule-binding assay showed that DDA3 and EB3 associated directly with microtubules, and cooperated with each other for microtubule binding. In addition, DDA3 bound to the EB3 interacting partner adenomatous polyposis coli 2 (APC2), a homolog of the tumor suppressor APC, which is a component of the b-catenin destruction complex. Ectopic expression of DDA3 and EB3 enhanced b-catenin-dependent transactivation and cyclin D1 production, whereas knockdown of endogenous DDA3 or EB3 inhibited b-catenin-mediated transactivation and the ability of cells to form colonies. Together, our results identify DDA3 as a novel microtubule-associated protein that binds to EB3, and implicate DDA3 and EB3 in the b-catenin-mediated growth signaling.

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Overexpression of EB1 in human esophageal squamous cell carcinoma (ESCC) may promote cellular growth by activating β-catenin/TCF pathway

Cited by 72 publications

References 20 publications

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Prognostic significance of altered expression of SDC2 and CYR61 in esophageal squamous cell carcinoma

p53 downstream target DDA3 is a novel microtubule-associated protein that interacts with end-binding protein EB3 and activates β-catenin pathway

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