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.

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Available from: David H Sherr, Sep 30, 2014
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    • "However, it remains to be studied. The transcription factor NFκB regulates the expression of several proteins that mediate the EMT process, such as Snail1/ 2, Twist1/2, ZEB1, vimentin, MMP-9, and MT1-MMP, which induces MMP-2 activation[34]. MMPs are involved in the EMT process because elevated levels of MMPs are able to induce EMT in the tumor microenvironment, whereas EMT process itself promotes MMP secretion. Moreover, MMPs are able to generate activated stroma-like cells that promote cancer progression[35,36]. "
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    ABSTRACT: Extracellular vesicles (EVs) mediate many stages of tumor progression including angiogenesis, escape from immune surveillance, and extracellular matrix degradation. We studied whether EVs from plasma of women with breast cancer are able to induce an epithelial-mesenchymal transition (EMT) process in mammary epithelial cells MCF10A. Our findings demonstrate that EVs from plasma of breast cancer patients induce a downregulation of E-cadherin expression and an increase of vimentin and N-cadherin expression. Moreover, EVs induce migration and invasion, as well as an increase of NFκB-DNA binding activity and MMP-2 and MMP-9 secretions. In summary, our findings demonstrate, for the first time, that EVs from breast cancer patients induce an EMT-like process in human mammary non-tumorigenic epithelial cells MCF10A.
    Full-text · Article · Jul 2015 · Tumor Biology
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    • "MnSOD may also contribute to the genetic program of EMT by producing H 2 O 2 . This ROS is able to activate NF-κB, which plays a central role in the genetic program of EMT, by inducing directly or indirectly the expression of a family of zinc finger transcription factors, including Snail, Slug, Twist, and Zeb1 and Zeb2123124125. These actors are typical of EMT because they repress epithelial gene expression, as the best-studied cases, E-cadherin and γ-catenin, promote the loss of epithelial cell adhesion and polarity [116]. "
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    ABSTRACT: Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently and reliable predictive biological markers and are a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O2-) and hydrogen peroxide (H2O2). Particularly, they report how these ROS may activate some signalling pathways involved in breast tumor growth. Emerging understanding of these findings provides an interesting framework for guiding translational research and suggests to define precisely the clinical interest of MnSOD, as prognostic and/or predicting marker in breast cancer, by associating with some regulators involved in SOD2 gene regulation and other well known biomarkers, in addition to the typical clinical parameters.
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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.
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