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      NFATc1 Promotes Prostate Tumorigenesis and Overcomes PTEN Loss-Induced Senescence

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          Abstract

          Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive due to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found upregulation of Nuclear Factor of Activated T Cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1β, IL6, and SPP1 (Osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten-null–driven prostate tumorigenesis by overcoming the PTEN loss–induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

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          Most cited references41

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          Inflammation and prostate cancer: the role of interleukin 6 (IL-6).

          Environmental and genetic aspects are reflected in the development of prostate cancer. In this context, there is growing evidence that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumour microenvironment. One of the best surrogates of chronic inflammation in prostate cancer is interleukin 6 (IL-6). Serum IL-6 levels are elevated in patients with untreated metastatic or castration-resistant prostate cancer (CRPC) and correlate negatively with tumour survival and response to chemotherapy. Via multiple signal pathways including the Janus tyrosine family kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, the extracellular signal-regulated kinase 1 and 2 (ERK1/2)-mitogen activated protein kinase (MAPK) pathway, and the phosphoinositide 3-kinase (PI3-K) pathway, IL-6 is able to promote prostate cancer cell proliferation and inhibit apoptosis in vitro and in vivo. IL-6 is associated with aggressive prostate cancer phenotype and may be involved in the metastatic process through regulation of epithelial-mesenchymal transition (EMT) and homing of cancer cells to the bone. A substantial body of evidence suggests that IL-6 plays a major role in the transition from hormone-dependent to CRPC, most notably through accessory activation of the androgen receptor. Collectively, these data have stimulated the development of agents targeting IL-6 signalling pathways. A chimeric anti-IL-6 monoclonal antibody has been tested in clinical trials, with mixed results.
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            The role of NFAT transcription factors in integrin-mediated carcinoma invasion.

            Integrins, receptors for extracellular matrix ligands, are critical regulators of the invasive phenotype. Specifically, the alpha(6)beta(4) integrin has been linked with epithelial cell motility, cellular survival and carcinoma invasion, hallmarks of metastatic tumours. Previous studies have also shown that antagonists of the NFAT (nuclear factor of activated T-cells) family of transcription factors exhibit strong anti-tumour-promoting activity. This suggests that NFAT may function in tumour metastasis. Here, we investigate the involvement of NFAT in promoting carcinoma invasion downstream of the alpha(6)beta(4) integrin. We provide evidence that both NFAT1, and the recently identified NFAT5 isoform, are expressed in invasive human ductal breast carcinomas and participate in promoting carcinoma invasion using cell lines derived from human breast and colon carcinomas. NFAT1 and NFAT5 activity correlates with the expression of the alpha(6)beta(4) integrin. In addition, the transcriptional activity of NFAT5 is induced by alpha(6)beta(4) clustering in the presence of chemo-attractants, resulting in enhanced cell migration. These observations show that NFATs are targets of alpha(6)beta(4) integrin signalling and are involved in promoting carcinoma invasion, highlighting a novel function for this family of transcription factors in human cancer.
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              Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction

              Here we describe a triple transgenic mouse system, which combines the tissue specificity of any Cre-transgenic line with the inducibility of the reverse tetracycline transactivator (rtTA)/tetracycline-responsive element (tet-O)-driven transgenes. To ensure reliable rtTA expression in a broad range of cell types, we have targeted the rtTA transgene into the ROSA26 locus. The rtTA expression, however, is conditional to a Cre recombinase-mediated excision of a STOP region from the ROSA26 locus. We demonstrate the utility of this technology through the inducible expression of the vascular endothelial growth factor (VEGF-A) during embryonic development and postnatally in adult mice. Our results of adult induction recapitulate several different hepatic and immune cell pathological phenotypes associated with increased systemic VEGF-A protein levels. This system will be useful for studying genes in which temporal control of expression is necessary for the discovery of the full spectrum of functions. The presented approach abrogates the need to generate tissue-specific rtTA transgenes for tissues where well-characterized Cre lines already exist.
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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                31 August 2016
                19 October 2015
                23 June 2016
                23 December 2016
                : 35
                : 25
                : 3282-3292
                Affiliations
                [1 ]Department of Medicine, Washington University, St. Louis, MO, 63110, USA
                [2 ]Department of Pathology and Immunology, Washington University, St. Louis, MO, 63110, USA
                [3 ]The Genome Institute, Washington University, St. Louis, MO, 63110, USA
                [4 ]Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
                [5 ]Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA
                [7 ]Department of Surgery, Washington University, St. Louis, MO, 63110, USA
                [8 ]Department of Structural and Cellular Biology, Tulane University, New Orleans, LA, 70112, USA
                [9 ]Department of Cell Biology and Physiology, Washington University, St. Louis, MO, 63110, USA
                Author notes
                [* ]Corresponding Author: Feng Chen, Department of Medicine, Campus Box 8126, Washington University School of Medicine, St. Louis, MO 63110, USA. Phone: (314) 362-3162; Fax: (314) 362-8237; fchen@ 123456dom.wustl.edu
                [6]

                Current Address: Department of Pathology, Yale University, New Haven, CT, 06520, USA.

                Article
                NIHMS721932
                10.1038/onc.2015.389
                5012433
                26477312
                993f3612-51aa-4193-9fd4-793927a58246

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                Categories
                Article

                Oncology & Radiotherapy
                nfat,prostate cancer,pten,senescence,microenvironment
                Oncology & Radiotherapy
                nfat, prostate cancer, pten, senescence, microenvironment

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