NF-kappaB and epithelial to mesenchymal transition of cancer [J]

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.26). 06/2008; 104(3):733-44. DOI: 10.1002/jcb.21695
Source: PubMed


During progression of an in situ to an invasive cancer, epithelial cells lose expression of proteins that promote cell-cell contact, and acquire mesenchymal markers, which promote cell migration and invasion. These events bear extensive similarities to the process of epithelial to mesenchymal transition (EMT), which has been recognized for several decades as critical feature of embryogenesis. The NF-kappaB family of transcription factors plays pivotal roles in both promoting and maintaining an invasive phenotype. After briefly describing the NF-kappaB family and its role in cancer, in this review we will first describe studies elucidating the functions of NF-kappaB in transcription of master regulator genes that repress an epithelial phenotype. In the second half, we discuss the roles of NF-kappaB in control of mesenchymal genes critical for promoting and maintaining an invasive phenotype. Overall, NF-kappaB is identified as a key target in prevention and in the treatment of invasive carcinomas.


Available from: David H Sherr, Sep 30, 2014
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    • "The induction of EMT can be triggered by transcription factors such as Snail, Slug, and Twist, which simultaneously repress the expression of genes that are required for the epithelial phenotype and induce the expression of genes required for mesenchymal properties [10]. The expression of these transcription factors is modulated by a number of signaling molecules, including nuclear factor kappa B (NF-κB) [10], [11]. NF-κB is a dimeric transcription factor composed of members of the Rel family, including RelA (p65) [12], [13]. "
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    ABSTRACT: Background Metastasis accounts for the most deaths in patients with hepatocellular carcinoma (HCC). Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown. Methods Immunohistochemistry was performed to determine the expression of RANK in HCC tissue (n = 398). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to examine the expression of RANK, E-cadherin, N-cadherin, vimentin, Snail, Slug, Twist and MMPs in HCC cells. Wound healing and Transwell assays were used to evaluate cell migration and invasion ability. Results We found that expression of RANK, the receptor of RANKL, was significantly higher in HCC tumor tissues than in peritumor liver tissues (p<0.001). Constitutive expression of RANK was detected in HCC cell lines, which can be up-regulated when HCC cells were stimulated with RANKL. Notably, in vitro experiments showed that activation of RANKL-RANK axis significantly promoted migration and invasion ability of HCC cells. In addition, RANKL stimulation increased the expression levels of N-cadherin, Snail, and Twist, while decreased the expression of E-cadherin, with concomitant activation of NF-κB signaling pathway. Moreover, administration of the NF-κB inhibitor attenuated RANKL-induced migration, invasion and epithelial-mesenchymal transition of HCC cells. Conclusions RANKL could potentiate migration and invasion ability of RANK-positive HCC cells through NF-κB pathway-mediated epithelial-mesenchymal transition, which means that RANKL-RANK axis could be a potential target for HCC therapy.
    PLoS ONE 09/2014; 9(9):e108507. DOI:10.1371/journal.pone.0108507 · 3.23 Impact Factor
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    • "The EMT phenotype is characterized by (1) the loss of cell-to-cell adhesion with the disintegration of tight, adherens, and gap junctions, and (2) a phenotypic change where cells shift from an ”epithelial” morphology to an elongated fibroblast-like morphology which is associated with increased motility and tumor invasion.(14) The process of EMT involves the up-regulation of mesenchymal markers such as vimentin, N-cadherin and fibronectin, and the down-regulation of epithelial adhesion molecules such as E-cadherin and cytokeratins.(15,16) EMT is triggered by the interplay of extracellular signals (such as collagen) and many secrete soluble factors such as Wnt, transforming growth factor-β (TGF-β), fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, and platelet-derived growth factors. "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a crucial role in cancer metastasis. In this study, we evaluated the effect of heat treatment on tumor growth factor-β1 (TGF-β1)-induced EMT in pancreatic cancer cells and tried to ascertain the mechanism related to any observed effects. Human pancreatic cancer cell lines (BxPC-3, PANC-1 and MIAPaCa-2) were stimulated by TGF-β1, and evaluated for morphological changes using immunofluorescence and EMT-related factors (i.e., E-cadherin, Vimentin, Snail or ZEB-1) using RT-PCR. To examine the effect of heat on EMT, the cancer cells were heat-treated at 43°C for 1 h then stimulated with TGF-β1. We then evaluated whether or not heat treatment changed the expression of EMT-related factors and cell migration and also whether Smad activation was inhibited in TGF-β signaling. After being treated with TGF-β1, pancreatic cancer cells resulted in EMT and cell migration was enhanced. Heat treatment inhibited TGF-β1-induced changes in morphology, inhibited the expression of EMT-related factors, and attenuated TGF-β1-induced migration in pancreatic cancer cells. Additionally, we observed that heat treatment blocked TGF-β1-induced phosphorylation of Smad2 in PANC-1 cells. Our results suggest that heat treatment can suppress TGF-β1-induced EMT and opens the possibility of a new therapeutic use of hyperthermia as a potential treatment for cancer metastasis.
    Journal of Clinical Biochemistry and Nutrition 07/2014; 55(1):56-61. DOI:10.3164/jcbn.14-8 · 2.19 Impact Factor
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    • "Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) is upregulated in human breast tumor cell lines, carcinogen transformed mammary epithelial cells, the majority of primary human and rodent breast tumor tissue samples [11]. It has been reported to be a central mediator of EMT in a mouse model of breast cancer progression [12], [13]. "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important parameter related to breast cancer survival. Among several microRNAs predicted to target EMT-related genes, miR-506 is a novel miRNA found to be significantly related to breast cancer patient survival in a meta-analysis. miR-506 suppressed the expression of mesenchymal genes such as Vimentin, Snai2, and CD151 in MDA-MB-231 human breast cancer cell line. Moreover, NF-κB bound to the upstream promoter region of miR-506 to suppress transcription. Overexpression of miR-506 inhibited TGFβ-induced EMT and suppressed adhesion, invasion, and migration of MDA-MB-231 cells. From these results, we concluded that miR-506 plays a key role in the process of EMT through posttranslational control of EMT-related genes.
    PLoS ONE 05/2013; 8(5):e64273. DOI:10.1371/journal.pone.0064273 · 3.23 Impact Factor
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