Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma

Xie, Fajun; Li, Haibo; Zhu, Ying; Qin, Yan; Dai, Yongdong; Zeng, Tingting; Chen, Leilei; Nie, Changjun; Tang, Hong; Li, Yan; Fu, Li; Guan, Xin Yuan

doi:10.1186/1471-2407-11-86

Cited by 33 publications

(23 citation statements)

References 30 publications

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“…In recent years, great progress has been made in studies on the pathogenesis of esophageal cancer at the molecular level. It has been confirmed that the genes related to esophageal cancer include P53, cyclin D1, VEGF, GPR39, Wnt-1 and cyclin E (13)(14)(15)(16)(17)(18). Cyclin E, a type of G1 cyclin, was first discovered by Koff et al in 1991 (19).…”

Section: R E T R a C T E D Discussionmentioning

confidence: 98%

Effects of cyclin E gene silencing on the proliferation of esophageal cancer cell lines, EC9706, Eca109 and KYSE30

Wang¹,

Li²,

Zang³

et al. 2013

Molecular Medicine Reports

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In order to observe the effects of cyclin E gene silencing by small interfering RNA (siRNA) on the growth, proliferation, invasion and apoptosis of esophageal cancer cell lines, including EC9706, Eca109 and KYSE30, siRNA vectors targeting cyclin E gene were constructed and then transfected into the EC9706, Eca109 and KYSE30 human esophageal cancer cell lines. Cyclin E mRNA and protein expression were determined by RT-PCR and western blotting. Cell proliferation and clonality were detected using a CCK-8 test and soft agar colony formation assay. Cell cycle distribution, apoptosis and invasion of EC9706, Eca109 and KYSE30 cells were evaluated with flow cytometry and a transwell culture system. After siRNA vectors targeting the cyclin E gene were transfected into EC9706, Eca109 and KYSE30 cell lines, compared with blank and negative control groups, the expression of cyclin E mRNA and protein (P<0.01), colony-forming units and the number of cells penetrating the transwell membrane (P<0.05) were significantly decreased, the cells in the S and G2/M phase were reduced, the cells in the G0/G1 phase were increased and the apoptosis rate was increased (P<0.01) in the experimental groups. Cyclin E gene silencing effectively inhibits growth, proliferation and invasion of esophageal cancer cells.

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Section: R E T R a C T E D Discussionmentioning

confidence: 98%

Effects of cyclin E gene silencing on the proliferation of esophageal cancer cell lines, EC9706, Eca109 and KYSE30

Wang¹,

Li²,

Zang³

et al. 2013

Molecular Medicine Reports

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“…For example, ZnR/GPR39 silencing in an esophageal squamous cell carcinoma (ESCC) cell line decreased cell proliferation and delayed the cells in the G1/S phase. 52 In addition, ZnR/GPR39 overexpression was detected in specimens of human ESCC and associated to the malignant development of this carcinoma, 52 but the role of Zn 2+ as the ligand of ZnR/GPR39 that promotes these tumorigenic processes remained elusive. Our results, however, do not support an oncogenic effect for ZnR/GPR39, as elevated levels of ZnR/GPR39 were found in differentiating Caco-2 cells compared with cells in the proliferative phase.…”

Section: Discussionmentioning

confidence: 99%

The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon

2014

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The intestinal epithelium is a renewable tissue that requires precise balance between proliferation and differentiation, an essential process for the formation of a tightly sealed barrier. Zinc deficiency impairs the integrity of the intestinal epithelial barrier and is associated with ulcerative and diarrheal pathologies, but the mechanisms underlying the role of Zn2+ are not well understood. Here, we determined a role of the colonocytic Zn2+ sensing receptor, ZnR/GPR39, in mediating Zn2+-dependent signaling and regulating the proliferation and differentiation of colonocytes. Silencing of ZnR/GPR39 expression attenuated Zn2+-dependent activation of ERK1/2 and AKT as well as downstream activation of mTOR/p70S6K, pathways that are linked with proliferation. Consistently, ZnR/GPR39 silencing inhibited HT29 and Caco-2 colonocyte proliferation, while not inducing caspase-3 cleavage. Remarkably, in differentiating HT29 colonocytes, silencing of ZnR/GPR39 expression inhibited alkaline phosphatase activity, a marker of differentiation. Furthermore, Caco-2 colonocytes showed elevated expression of ZnR/GPR39 during differentiation, whereas silencing of ZnR/GPR39 decreased monolayer transepithelial electrical resistance, suggesting compromised barrier formation. Indeed, silencing of ZnR/GPR39 or chelation of Zn2+ by the cell impermeable chelator CaEDTA was followed by impaired expression of the junctional proteins, that is, occludin, zonula-1 (ZO-1) and E-cadherin. Importantly, colon tissues of GPR39 knockout mice also showed a decrease in expression levels of ZO-1 and occludin compared with wildtype mice. Altogether, our results indicate that ZnR/GPR39 has a dual role in promoting proliferation of colonocytes and in controlling their differentiation. The latter is followed by ZnR/GPR39-dependent expression of tight junctional proteins, thereby leading to formation of a sealed intestinal epithelial barrier. Thus, ZnR/GPR39 may be a therapeutic target for promoting epithelial function and tight junction barrier integrity during ulcerative colon diseases.

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“…A score of 0 was considered negative; 2-3 was considered weak; 4-5 was considered moderate; and 6-7 was considered strong. For statisticalanalysis, 0-3 were counted as low expression, while 4-7 were counted as overexpression [14]. In half of the samples, staining was repeated twice to avoid technical errors, but similar results were obtained in these samples.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Expression of far upstream element (FUSE) binding protein 1 in human glioma is correlated with c‐Myc and cell proliferation

Ding

Liu

et al. 2013

Molecular Carcinogenesis

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Glioma is one of the most common type of primary intracranial tumor. Although great advances have been achieved in treatment of glioma, the underlying molecular mechanisms remain largely unknown. Previous studies demonstrated that FBP1 is a transcriptional regulator of c-Myc and acts as an important prognostic indicator in many cancers. Our study aimed to assess the expression and function of FBP1 in human glioma. Immunohistochemical and Western blot analysis were performed in human glioma and normal brain tissues. High FBP1 expression (located in cell nuclei) was observed in 70 samples and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between FBP1 and c-Myc (P = 0.005) and Ki-67 expression (P = 0.009). In a multivariate analysis, high FBP1 and c-Myc expressions were showed to be associated with poor prognosis in glioma. While in vitro, following serum stimulation of starved U87MG cells, the expression of FBP1 was upregulated, as well as c-Myc and PCNA. Moreover, knockdown of FBP1 by siRNA transfection diminished the expression of c-Myc and arrested cell growth at G1 phase. Collectively, our results shows that the expression of FBP1 is in close correlation with c-Myc level and cell proliferation in glioma and provides a potential strategy to develop FBP1 inhibitors as novel anti-tumor agents.

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Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma

Cited by 33 publications

References 30 publications

Effects of cyclin E gene silencing on the proliferation of esophageal cancer cell lines, EC9706, Eca109 and KYSE30

Effects of cyclin E gene silencing on the proliferation of esophageal cancer cell lines, EC9706, Eca109 and KYSE30

The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon

Expression of far upstream element (FUSE) binding protein 1 in human glioma is correlated with c‐Myc and cell proliferation

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