Roles of STAT3 and ZEB1 Proteins in E-cadherin Down-regulation and Human Colorectal Cancer Epithelial-Mesenchymal Transition

Xiong, Hua; Hong, Jie; Du, Wei; Lin, Yanwei; Ren, Linlin; Wang, Yingchao; Su, Wenyu; Wang, Jilin; Cui, Yun; Wang, Zhenhua; Fang, Jing‐Yuan

doi:10.1074/jbc.m111.295964

Cited by 265 publications

(205 citation statements)

References 49 publications

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“…The transcriptional suppressors of E-cadherin, Twist, Snail and ZEB1 have been identified as direct transcriptional targets of Stat3. 5,[37][38][39] It has also recently been shown that Stat3 activation through Ras signaling pathway was required for EMT in salivary epithelial cells, 40 and ectopic expression of Stat3C decreased the E-cadherin level in prostate epithelial cells. 41 Concomitant with transient reduction of the let-7 level after exposure to OSM, the expression of HMGA2 was instantly upregulated, accompanied by an increase in the levels of mesenchymal markers.…”

Section: Discussionmentioning

confidence: 95%

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

Guo¹,

Chen²,

Shi³

et al. 2013

Oncogene

178

164

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Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epigenetic transition was induced by OSM stimulation not only in breast cancer cell lines but also in MCF-7 xenografts in nude mice. The expression of miR-200 and let-7 family members in response to OSM stimulation was downregulated in a signal transducer and activator of transcription factor 3 (Stat3)-dependent manner, resulting in comprehensive alterations of the transcription factors and oncoproteins targeted by these microRNAs. Inhibition of Stat3 activation or the ectopic expression of let-7 and miR-200 effectively reversed the mesenchymal phenotype of breast cancer cells. Stat3 promotes the transcription of Lin-28 by directly binding to the Lin-28 promoter, resulting in the repression of let-7 expression and concomitant upregulation of the let-7 target, high-mobility group A protein 2 (HMGA2). Knock down of HMGA2 significantly impairs OSM-driven EMT. Our data indicate that downregulation of let-7 and miR-200 levels initiates and maintains OSM-induced EMT phenotypes, and HMGA2 acts as a master switch of OSM-induced EMT. These findings highlight the importance of Stat3-coordinated Lin-28B-let-7-HMGA2 and miR-200-ZEB1 circuits in the cytokine-mediated phenotypic reprogramming of breast cancer cells.

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Section: Discussionmentioning

confidence: 95%

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

Guo¹,

Chen²,

Shi³

et al. 2013

Oncogene

178

164

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“…Loss of E-cadherin is considered to be the most fundamental event during EMT (32). Deregulation in the expression of several genes or microRNAs has been reported to downregulate the expression of E-cadherin (33,34).…”

Section: Discussionmentioning

confidence: 99%

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

Liu

Qiao

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Ubiquitin-like with plant homeodomain (PHD) and RING-finger domain 1 (UHRF1) maintains methylation patterns following DNA replication and is expressed at high levels in various types of human cancer. UHRF1 has been identified as a novel oncogene involved in the pathogenesis of hepatocellular carcinoma. Previous studies have demonstrated that inhibition of the expression of UHRF1 suppresses the proliferation of cancer cells. However, the role of UHRF1 in human osteosarcoma has not been investigated. The present study examined the expression levels of UHRF1 and retinoblastoma 1 (Rb1) in human osteosarcoma cell lines by western blot analysis. Stable overexpression of UHRF1 or knockdown of Rb1 was achieved by lentiviral transfection. Subsequently, a Cell Counting Kit-8 assay and a cell invasion assay were performed to detect the biological functions of UHRF1 in vitro. The results of the present study demonstrated that UHRF1 promoted the proliferation of human osteosarcoma cells. The present study also reported that UHRF1 was able to enhance the invasion of osteosarcoma cells in a retinoblastoma 1 (Rb1)-dependent manner. UHRF1 promoted invasion in Rb1-positive osteosarcoma cells, but not in Saos-2 cells with homozygous loss of Rb1. Similarly, knockdown of Rb1 in Rb1-positive osteosarcoma cells enhanced levels of invasion and eliminated the regulation of invasion by UHRF1. UHRF1 was found to inhibit the mRNA and protein expression levels of Rb1. Furthermore, deletion of Rb1 was found to suppress the expression of E-cadherin and promote epithelial-to-mesenchymal transition (EMT). In addition, the overexpression of UHRF1 inhibited the expression of E-cadherin and promoted EMT via the suppression of Rb1. These data demonstrated that UHRF1 promotes osteosarcoma cell invasion by downregulating the expression of E-cadherin and increasing EMT in an Rb1-dependent manner.

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“…Western blot analysis was performed using standard techniques ( 47 ). An anti-GAPDH antibody was used as a control for whole-cell lysates.…”

Section: Western Blotmentioning

confidence: 99%

LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern

et al. 2016

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Long noncoding RNAs (lncRNA) play a role in carcinogenesis. However, the function of lncRNAs in human gastric cancer remains largely unknown. In this study, we identifi ed a novel lncRNA, GClnc1, which was upregulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in gastric cancer. GClnc1 affected gastric cancer cell proliferation, invasiveness, and metastasis in multiple gastric cancer models. Mechanistically, GClnc1 bound WDR5 (a key component of histone methyltransferase complex) and KAT2A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2A complexes, coordinated their localization, specifi ed the histone modifi cation pattern on the target genes, including SOD2 , and consequently altered gastric cancer cell biology. Thus, GClnc1 is mechanistically, functionally, and clinically oncogenic in gastric cancer. Targeting GClnc1 and its pathway may be meaningful for treating patients with gastric cancer. SIGNIFICANCE:This report documents a novel lncRNA, GClnc1, which may act as a scaffold to recruit the WDR5 and KAT2A complex and modify the transcription of target genes. This study reveals that GClnc1 is an oncogenic lncRNA in human gastric cancer. Cancer Discov; 6(7); 784-801.

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Roles of STAT3 and ZEB1 Proteins in E-cadherin Down-regulation and Human Colorectal Cancer Epithelial-Mesenchymal Transition

Cited by 265 publications

References 49 publications

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern

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