Gene Summary

Gene:NFATC1; nuclear factor of activated T cells 1
Aliases: NFAT2, NFATc, NF-ATC, NF-ATc1.2
Summary:The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes. [provided by RefSeq, Jul 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear factor of activated T-cells, cytoplasmic 1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NFATC1 (cancer-related)

Zuo J, Yu H, Xie P, et al.
miR-454-3p exerts tumor-suppressive functions by down-regulation of NFATc2 in glioblastoma.
Gene. 2019; 710:233-239 [PubMed] Related Publications
Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor. Numerous studies have demonstrated that aberrant microRNAs (miRNAs) expression is involved in various pathogenesis events in GBM. miR-454-3p has been found to be downregulated in GBM, however, the role and underlying mechanism has not been fully investigated. The expression levels of miR-454-3p in GBM clinical tissues and cultured cell lines were measured by qRT-PCR. To evaluate the role of miR-454-3p in GBM, GBM cells were transfected with miR-454-3p inhibitor (anti-miR-454-3p)/control inhibitor (anti-miR-NC) or miR-454-3p mimic/control mimic (miR-NC). Online prediction algorithm Targetscan was used to predict the target genes of miR-454-3p. The dual luciferase reporter gene assay was performed to confirm whether nuclear factor of activated T cells c2 (NFATc2) was a direct biological target of miR-454-3p. We found that miR-454-3p expression was significantly decreased in both GBM tissues and cultured cell lines. Overexpression of miR-454-3p by transfection with miR-454-3p mimic suppressed cell proliferation and induced apoptosis of GBM cells. Nuclear factor of activated T cells c2 (NFATc2) was predicted as a target gene of miR-454-3p. We found that NFATc2 expression was significantly increased in both GBM tissues and cultured cell lines. Besides, expression levels of miR-454-3p were negatively associated with NFATc2 expression in GBM tissues. NFATc2 knockdown in GBM cells obviously inhibited cell proliferation and elevated apoptosis. Luciferase reporter assay revealed that NFATc2 was a target gene of miR-454-3p. miR-454-3p overexpression suppressed the NFATc2 expression, while inhibition of miR-454-3p induced the NFATc2 expression. Suppression of NFATc2 blocked the effects of miR-454-3p inhibitor on cell proliferation and apoptosis in GBM cells. The results indicated that miR-454-3p executed the tumor suppressive activity via downregulating NFATc2 in GBM.

Duan Y, Tan Z, Yang M, et al.
PC-3-Derived Exosomes Inhibit Osteoclast Differentiation by Downregulating miR-214 and Blocking NF-
Biomed Res Int. 2019; 2019:8650846 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is a serious disease that can invade bone tissues. These bone metastases can greatly decrease a patient's quality of life, pose a financial burden, and even result in death. In recent years, tumor cell-secreted microvesicles have been identified and proposed to be a key factor in cell interaction. However, the impact of cancer-derived exosomes on bone cells remains unclear. Herein, we isolated exosomes from prostate cancer cell line PC-3 and investigated their effects on human osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) staining. The potential mechanism was evaluated by qRT-PCR, western blotting, and microRNA transfection experiments. The results showed that PC-3-derived exosomes dramatically inhibited osteoclast differentiation. Marker genes of mature osteoclasts, including CTSK, NFATc1, ACP5, and miR-214, were all downregulated in the presence of PC-3 exosomes. Furthermore, transfection experiments showed that miR-214 downregulation severely impaired osteoclast differentiation, whereas overexpression of miR-214 promoted differentiation. Furthermore, we demonstrated that PC-3-derived exosomes block the NF-

Koelsche C, Kriegsmann M, Kommoss FKF, et al.
DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.
J Cancer Res Clin Oncol. 2019; 145(5):1273-1281 [PubMed] Related Publications
PURPOSE: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS.
METHODS: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas.
RESULTS: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively.
CONCLUSION: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.

Liu Y, Liang T, Qiu X, et al.
Down-Regulation of Nfatc1 Suppresses Proliferation, Migration, Invasion, and Warburg Effect in Prostate Cancer Cells.
Med Sci Monit. 2019; 25:1572-1581 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Prostate cancer (PCa), accounting for 28% of all male cancer cases, is the second leading cause of cancer-related death among men. NFATc1, belonging to the NFAT family, is overexpressed in PCa and is correlated with the risk of recurrence after radical prostatectomy. MATERIAL AND METHODS In the present study, the expression of NFATc, c-myc, and PKM2 in PCa cells was regulated by lentiviruses and then detected by real-time PCR and Western blot analysis. Further, proliferation, invasion, and migration assays were performed. The glucose consumption and lactate production were assessed by biochemical detection. RESULTS We found that NFATc1 down-regulation significantly suppressed the proliferation and Warburg effect of PCa cells, concurrent with a decrease of c-myc and PKM2 expression. Likewise, the abilities of migration and invasion were also inhibited in NFATc1-silenced PCa cells. In addition, NFATc1 down-regulation-induced inhibition of cell proliferation, migration, invasion, and Warburg effect were counteracted by up-regulation of c-myc or PKM2. The expression of PKM2 was positively regulated by NFATc1 and c-myc expression. CONCLUSIONS These results indicate that NFATc1 down-regulation can suppress the proliferation, Warburg effect, and migration and invasion abilities of PCa cells, probably by regulating c-myc and PKM2 expression. NFATc1 may be a potential therapeutic target for PCa and could be used as a diagnosis or prognosis indicator of PCa.

Wu L, Zhang D, Zhou L, et al.
FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis.
EBioMedicine. 2019; 41:384-394 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC).
METHODS: Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay.
FINDINGS: Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan-Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca
INTERPRETATION: FUNDC1 might promote BC progression by activating the Ca

Zhang J, Zheng ZQ, Yuan YW, et al.
NFAT1 Hypermethylation Promotes Epithelial-Mesenchymal Transition and Metastasis in Nasopharyngeal Carcinoma by Activating ITGA6 Transcription.
Neoplasia. 2019; 21(3):311-321 [PubMed] Free Access to Full Article Related Publications
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.

Wang G, Wang YZ, Yu Y, Wang JJ
Inhibitory ASIC2-mediated calcineurin/NFAT against colorectal cancer by triterpenoids extracted from Rhus chinensis Mill.
J Ethnopharmacol. 2019; 235:255-267 [PubMed] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: Studies have shown that the etiology and pathogenesis of colorectal cancer are closely related to the tumor microenvironment, and the cancer tissue is still in the state of "energy deficit" and has to promote energy generation through high glycolysis. Rhus chinensis Mill is a Chinese herbal medicine used to treat various types of solid tumors in China. Colorectal cancer (CRC) is a heterogeneous disease group caused by abnormal changes in glucose metabolism resulted in lactic acid production, which remodels acidosis.
AIM OF THE STUDY: Although previous studies have shown that the active compounds of Rhus chinensis Mill. can inhibit the proliferation of tumor cells, whether its triterpenoids could effectively regulate glycolysis involved in CRC have not been systematically investigated.
MATERIALS AND METHODS: In this study, the extraction of triterpenoids extract from Rhus chinensis Mill. was obtained, and cell viability assay, the percentage of apoptosis for CRC cells were counted, and matrigel invasion assay and production of lactic acid and glucose uptake assay was determined. we further examined the expression of the key glycolytic enzymes and acid-sending ion channel (ASIC) family members of SW620 cells, and some key proteins in the glycolytic pathway were further verified.
RESULTS: Notably, triterpenoids (TER) of Rhus chinensis Mill. showed effective anti-proliferative activity and significantly altered protein levels associated with CRC cell survival and glycolysis metabolism. TER could down-regulate the expression of ASIC2, in CRC SW620 cell line. Most importantly, the levels of ASIC2 and calcineurin/nuclear factor of activated T cells (NFAT) were also down-regulated by TER. Furthermore, inhibition of activated the ASIC2-mediated calcineurin/NFAT1 pathway and target gene transcript expression of MMP-2 and MMP-9 in parallel to reduce, and resulted in the reduced invasion ability by TER treatment.
CONCLUSION: The potential pathways and targets that involved in glycolysis to excert the anti-CRC effects of main compounds in triterpenoids of Rhus chinensis Mill. were predicted by network pharmacology methods. Our findings thus provided rational evidence that inhibition of the ASIC2-induced calcineurin/NFAT pathway by triterpenoids in Rhus chinensis Mill. profoundly suppressed cell growth and invasion in CRC, which target alternative glycolysis in colorectal tumor cells, may be a useful adjuvant therapy in the treatment of colorectal cancer.

Malsy M, Graf B, Almstedt K
The active role of the transcription factor Sp1 in NFATc2-mediated gene regulation in pancreatic cancer.
BMC Biochem. 2019; 20(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body. The oncogenic potential of pancreatic cancer is mainly characterized by extremely rapid growth triggered by the activation of oncogenic signaling cascades, which suggests a change in the regulation of important transcription factors. Amongst others, NFAT transcription factors are assumed to play a central role in the carcinogenesis of pancreatic cancer. Recent research has shown the importance of the transcription factor Sp1 in the transcriptional activity of NFATc2 in pancreatic cancer. However, the role of the interaction between these two binding partners remains unclear. The current study investigated the role of Sp1 proteins in the expression of NFATc2 target genes and identified new target genes and their function in cells. A further objective was the domain of the Sp1 protein that mediates interaction with NFATc2. The involvement of Sp1 proteins in NFATc2 target genes was shown by means of a gene expression profile analysis, and the results were confirmed by quantitative RT-PCR. The functional impact of this interaction was shown in a thymidine incorporation assay. A second objective was the physical interaction between NFATc2 and different Sp1 deletion mutants that was investigated by means of immunoprecipitation.
RESULTS: In pancreatic cancer, the proto-oncogene c-Fos, the tumor necrosis factor TNF-alpha, and the adhesion molecule integrin beta-3 are target genes of the interaction between Sp1 and NFATc2. Loss of just one transcription factor inhibits oncogenic complex formation and expression of cell cycle-regulating genes, thus verifiably decreasing the carcinogenic effect. The current study also showed the interaction between the transcription factor NFATc2 and the N-terminal domain of Sp1 in pancreatic cancer cells. Sp1 increases the activity of NFATc2 in the NFAT-responsive promoter.
CONCLUSIONS: The regulation of gene promotors during transcription is a rather complex process because of the involvement of many proteins that - as transcription factors or co-factors - regulate promotor activity as required and control cell function. NFATc2 and Sp1 seem to play a key role in the progression of pancreatic cancer.

Fuchs AR, Märklin M, Heitmann JS, et al.
A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia.
J Vis Exp. 2018; (142) [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant B cell clones and represents the most common leukemia in western countries. The majority of CLL patients show an indolent course of the disease as well as an anergic phenotype of their leukemia cells, referring to a B cell receptor unresponsive to external stimulation. We have recently shown that the transcription factor NFAT2 is a crucial regulator of anergy in CLL. A major challenge in the analysis of the role of a transcription factor in different diseases is the identification of its specific target genes. This is of great significance for the elucidation of pathogenetic mechanisms and potential therapeutic interventions. Chromatin immunoprecipitation (ChIP) is a classic technique to demonstrate protein-DNA interactions and can, therefore, be used to identify direct target genes of transcription factors in mammalian cells. Here, ChIP was used to identify LCK as a direct target gene of NFAT2 in human CLL cells. DNA and associated proteins are crosslinked using formaldehyde and subsequently sheared by sonication into DNA fragments of approximately 200-500 base pairs (bp). Cross-linked DNA fragments associated with NFAT2 are then selectively immunoprecipitated from cell debris using an αNFAT2 antibody. After purification, associated DNA fragments are detected via quantitative real-time PCR (qRT-PCR). DNA sequences with evident enrichment represent regions of the genome which are targeted by NFAT2 in vivo. Appropriate shearing of the DNA and the selection of the required antibody are particularly crucial for the successful application of this method. This protocol is ideal for the demonstration of direct interactions of NFAT2 with target genes. Its major limitation is the difficulty to employ ChIP in large-scale assays analyzing the target genes of multiple transcription factors in intact organisms.

Moayedi Y, Greenberg SA, Jenkins BA, et al.
Camphor white oil induces tumor regression through cytotoxic T cell-dependent mechanisms.
Mol Carcinog. 2019; 58(5):722-734 [PubMed] Related Publications
Bioactive derivatives from the camphor laurel tree, Cinnamomum camphora, are posited to exhibit chemopreventive properties but the efficacy and mechanism of these natural products are not fully understood. We tested an essential-oil derivative, camphor white oil (CWO), for anti-tumor activity in a mouse model of keratinocyte-derived skin cancer. Daily topical treatment with CWO induced dramatic regression of pre-malignant skin tumors and a two-fold reduction in cutaneous squamous cell carcinomas. We next investigated underlying cellular and molecular mechanisms. In cultured keratinocytes, CWO stimulated calcium signaling, resulting in calcineurin-dependent activation of nuclear factor of activated T cells (NFAT). In vivo, CWO induced transcriptional changes in immune-related genes identified by RNA-sequencing, resulting in cytotoxic T cell-dependent tumor regression. Finally, we identified chemical constituents of CWO that recapitulated effects of the admixture. Together, these studies identify T cell-mediated tumor regression as a mechanism through which a plant-derived essential oil diminishes established tumor burden.

Lin Y, Yuan Q, Qian F, et al.
Polymorphism rs4787951 in IL-4R contributes to the increased risk of renal cell carcinoma in a Chinese population.
Gene. 2019; 685:242-247 [PubMed] Related Publications
OBJECTIVE: Interleukins are important molecules involved in tumor formation. In this study, the association between renal cell carcinoma (RCC) risk and single nucleotide polymorphisms (SNPs) on IL-4/IL-13/IL-4R was assessed.
METHODS: We recruited 620/623 cases/controls and conducted a case-control study. Five tagSNPs (i.e., IL-4R rs8832, IL-4R rs4787951, IL-13 rs1881457, IL-13 rs2066960 and IL-13 rs2069744) were selected. Odds ratios (ORs) with their 95% confidence intervals (CIs) were obtained to appraise the association between SNPs and RCC susceptibility. Luciferase report assay and EMSA were conducted to investigate whether SNPs could affect binding affinity of transcription factors to target genes.
RESULTS: IL-4R rs4787951T>C was significantly associated with RCC susceptibility. Individuals carrying CC genotypes had a significant increment in RCC risk compared with TT genotype carriers (adjusted OR = 1.57, 95% CI = 1.07-2.28, P = 0.020). By stratified analyses, more pronounced association was found in the female, diabetic or without smoking, drinking and hypertension group. Besides, SNP rs4787951 could influence the binding affinity of IL-4R to transcription factors. Sequence surrounding allele T was prone to bind transcription factor NFATc.
CONCLUSIONS: This study revealed that IL-4R rs4787951T>C was associated with susceptibility of RCC and could be a predictive biomarker for RCC risk.

Liu H, Yang L, Qi M, Zhang J
NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) play substantial roles in tumor growth, invasion, and metastasis. Nuclear factor of activated T cell (NFAT1) has been shown to promote melanoma growth and metastasis

Shakhova I, Li Y, Yu F, et al.
PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma.
Mol Carcinog. 2019; 58(3):426-435 [PubMed] Related Publications
We previously identified a gain-of-function mutation in PPP3CB in a neuroblastoma (NB) with MYCN amplification. Here we investigated the functional and clinical role of PPP3CB in NB. High PPP3CB expression was an independent indicator predicting poor prognosis of NB. Overexpression of wildtype or mutated PPP3CB (PPP3CBmut) promoted cell growth, but PPP3CB knockdown decreased cell growth in NB cells. Forced expressions of PPP3CB and PPP3CBmut activated NFAT2 and NFAT4 transcription factors and inhibited GSK3β activity, resulting in the increase in the expressions of c-Myc, MYCN, and β-catenin, which were downregulated in response to PPP3CB knockdown. Treatment with calcineurin inhibitor cyclosporin A (CsA) or FK506 suppressed cell proliferation and induced apoptotic cell death in both MYCN-amplified and MYCN-non-amplified NB cell lines. Expression of PPP3CB protein was decreased in response to two calcineurin inhibitors. c-Myc, MYCN, and β-catenin were downregulated at the mRNA and protein levels in CsA or FK506-treated NB cells. Our data indicate that elevated expression of PPP3CB and the expression of its constitutively active mutant contribute to the aggressive behavior of NB tumors and therefore suggest that inhibition of calcineurin activity might have therapeutic potential for high-risk NB.

Kawahara T, Ishiguro Y, Ohtake S, et al.
PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer.
BMC Urol. 2018; 18(1):97 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bladder cancers have been characterized as a tumor group in which the immunological response is relatively well preserved. Programmed death ligand 1 (PD-L1, B7-H1, CD274) has been shown to be expressed in several malignancies, including bladder cancer. However, the clinicopathological impact of this biomarker has not yet been established. In the present study, a quantitative real-time polymerase chain reaction (qPCR) was performed using paired normal and cancerous bladder cancer tissue to investigate PD-1/PD-L1 gene expression.
METHODS: We examined the mRNA expression of PD-1/PD-L1 by a qPCR using 58 pairs of normal and cancerous human bladder tissue specimens. We also examined the correlation with the expressions of the STAT1 and NFAT genes, which are thought to be upstream and downstream of the PD-L1 pathway, respectively.
RESULTS: There were no significant differences between normal and cancerous tissue in the expression of the PD-1 and PD-L1 genes (p = 0.724 and p = 0.102, respectively). However, PD-1 and PD-L1 were both more highly expressed in high-grade bladder cancer than in low-grade bladder cancer (p < 0.050 and p < 0.010). PD-L1 was positively correlated with the expressions of both the STAT1 (r = 0.681, p < 0.001) and the NFATc1 genes (r = 0.444. p < 0.001).
CONCLUSIONS: PD-1 and PD-L1 might be a new biomarker that correlates with the pathological grade of bladder cancer. PD-L1 might function as a mediator of stage progression in bladder cancer and STAT1-NFAT pathway might associate this function.

Bai H, Zhu H, Yan Q, et al.
TRPV2-induced Ca
Cell Commun Signal. 2018; 16(1):68 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Myeloma bone disease (MBD) can cause bone destruction and increase the level of Ca
METHODS: To investigate the expression of TRPV2 in MM, we analyzed publicly available MM data sets and performed immunohistochemistry in MM patients. The correlations between TRPV2 expression levels and osteoclast-related cytokines were analyzed. Fluo-4 staining and ELISA assays were used to assess the regulated function of TRPV2 in intracellular Ca
RESULTS: The functional expression of TRPV2, involved in the osteolysis through gating the calcium influx, was changed in the MM cells cultured in a high Ca
CONCLUSIONS: Our study uncovers the possible roles of TRPV2, which enhances MBD, suggesting that targeting osteocyte-MM cells interactions through blockade of TRPV2 channel may provide a promising treatment strategy in MM.

Hattori Y, Sentani K, Shinmei S, et al.
Clinicopathological significance of RCAN2 production in gastric carcinoma.
Histopathology. 2019; 74(3):430-442 [PubMed] Related Publications
AIMS: Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Genes expressed only in cancer tissue may be useful biomarkers for cancer diagnosis and therapeutics. The aims of the present study were to analyse regulator of calcineurin 2 (RCAN2) in a large number of GCs, and to investigate how these expression patterns correlate with clinicopathological parameters and various markers.
METHODS AND RESULTS: An immunohistochemical analysis of RCAN2 in 207 GC tissue samples showed that 110 (53%) GCs were positive for RCAN2. RCAN2-positive GCs were more advanced in terms of TNM classification and tumour stage than RCAN2-negative GCs. Furthermore, RCAN2 was an independent prognostic classifier for GC patients. The cell growth and invasiveness of RCAN2 small interfering RNA (siRNA)-transfected GC cell lines were less than those of the negative control siRNA-transfected cell lines, whereas those of RCAN2-transfected cells were significantly increased as compared with those of empty vector-transfected cells. RCAN2 siRNA inhibits the phosphorylation of AKT and p44/p42 (ERK1/2). RCAN2 was colocalised with EGFR, nuclear β-catenin, MMP7, laminin-γ2, VEGF-A, and VEGF-C.
CONCLUSION: These results suggest that RCAN2 is involved in tumour progression and is an independent prognostic classifier in patients with GC.

Li L, Zhang J, Chen J, et al.
B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.
Blood. 2018; 132(17):1805-1817 [PubMed] Free Access to Full Article Related Publications
Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1

Chetsawang J, Nudmamud-Thanoi S, Phonchai R, et al.
Methamphetamine toxicity-induced calcineurin activation, nuclear translocation of nuclear factor of activated T-cells and elevation of cyclooxygenase 2 levels are averted by calpastatin overexpression in neuroblastoma SH-SY5Y cells.
Neurotoxicology. 2018; 67:287-295 [PubMed] Related Publications
Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca

Jang JE, Kim HP, Han SW, et al.
NFATC3-PLA2G15 Fusion Transcript Identified by RNA Sequencing Promotes Tumor Invasion and Proliferation in Colorectal Cancer Cell Lines.
Cancer Res Treat. 2019; 51(1):391-401 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study was designed to identify novel fusion transcripts (FTs) and their functional significance in colorectal cancer (CRC) lines.
Materials and Methods: We performed paired-end RNA sequencing of 28 CRC cell lines. FT candidates were identified using TopHat-fusion, ChimeraScan, and FusionMap tools and further experimental validation was conducted through reverse transcription-polymerase chain reaction and Sanger sequencing. FT was depleted in human CRC line and the effects on cell proliferation, cell migration, and cell invasion were analyzed.
RESULTS: One thousand three hundred eighty FT candidates were detected through bioinformatics filtering. We selected six candidate FTs, including four inter-chromosomal and two intrachromosomal FTs and each FT was found in at least one of the 28 cell lines. Moreover, when we tested 19 pairs of CRC tumor and adjacent normal tissue samples, NFATC3-PLA2G15 FT was found in two. Knockdown of NFATC3-PLA2G15 using siRNA reduced mRNA expression of epithelial-mesenchymal transition (EMT) markers such as vimentin, twist, and fibronectin and increased mesenchymal-epithelial transition markers of E-cadherin, claudin-1, and FOXC2 in colo-320 cell line harboring NFATC3-PLA2G15 FT. The NFATC3-PLA2G15 knockdown also inhibited invasion, colony formation capacity, and cell proliferation.
CONCLUSION: These results suggest that that NFATC3-PLA2G15 FTs may contribute to tumor progression by enhancing invasion by EMT and proliferation.

Sundaramoorthy S, Devanand P, Ryu MS, et al.
J Cancer Res Clin Oncol. 2018; 144(8):1445-1462 [PubMed] Related Publications
PURPOSE: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21
METHODS: Transduction of adenovirus carrying TIS21
RESULTS: We observed that TIS21

Liu X, Wan X, Kan H, et al.
Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis.
Eur J Pharmacol. 2018; 832:1-10 [PubMed] Related Publications
In colon cancer, hypoxia promotes metastasis and angiogenesis, but little is known about the mediators of these effects. Here, we reported that expression of Orai1 is up-regulated in colon cancer cells in response to hypoxia, and the increase in Orai1 is mediated by Notch1 pathway. We also showed upregulation of Orai1 contributes to hypoxia-induced invasion and angiogenesis, and inhibition or downregulation of Orai1 reverses these effects. Mechanistic study revealed that upregulation of Orai1 by hypoxia potentiates store-operated Ca

Pudova EA, Kudryavtseva AV, Fedorova MS, et al.
HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer.
BMC Genomics. 2018; 19(Suppl 3):113 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is a common cancer worldwide. The main cause of death in CRC includes tumor progression and metastasis. At molecular level, these processes may be triggered by epithelial-mesenchymal transition (EMT) and necessitates specific alterations in cell metabolism. Although several EMT-related metabolic changes have been described in CRC, the mechanism is still poorly understood.
RESULTS: Using CrossHub software, we analyzed RNA-Seq expression profile data of CRC derived from The Cancer Genome Atlas (TCGA) project. Correlation analysis between the change in the expression of genes involved in glycolysis and EMT was performed. We obtained the set of genes with significant correlation coefficients, which included 21 EMT-related genes and a single glycolytic gene, HK3. The mRNA level of these genes was measured in 78 paired colorectal cancer samples by quantitative polymerase chain reaction (qPCR). Upregulation of HK3 and deregulation of 11 genes (COL1A1, TWIST1, NFATC1, GLIPR2, SFPR1, FLNA, GREM1, SFRP2, ZEB2, SPP1, and RARRES1) involved in EMT were found. The results of correlation study showed that the expression of HK3 demonstrated a strong correlation with 7 of the 21 examined genes (ZEB2, GREM1, TGFB3, TGFB1, SNAI2, TWIST1, and COL1A1) in CRC.
CONCLUSIONS: Upregulation of HK3 is associated with EMT in CRC and may be a crucial metabolic adaptation for rapid proliferation, survival, and metastases of CRC cells.

Pan Y, Yoon S, Sun J, et al.
Mechanogenetics for the remote and noninvasive control of cancer immunotherapy.
Proc Natl Acad Sci U S A. 2018; 115(5):992-997 [PubMed] Free Access to Full Article Related Publications
While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities. We have further engineered the Jurkat T-cell line and primary T cells (peripheral blood mononuclear cells) to remotely sense the ultrasound wave and transduce it into transcriptional activation for the CAR expression to recognize and eradicate target tumor cells. This approach is modular and can be extended for remote-controlled activation of different cell types with high spatiotemporal precision for therapeutic applications.

Zhao X, Liu J, Feng L, et al.
Anti-angiogenic effects of Qingdu granule on breast cancer through inhibiting NFAT signaling pathway.
J Ethnopharmacol. 2018; 222:261-269 [PubMed] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: Qingdu granule (QDG), a traditional Chinese herbal prescription, had anti-tumor effect on breast cancer. However the underlying mechanism of QDG was unclear.
THE AIM OF THIS STUDY: The present study aimed to investigate whether QDG could inhibit angiogenesis of breast cancer via acting on nuclear factor of activated T-cells (NFAT) signaling pathway. This was implicated in human umbilical vein endothelial cells (HUVECs) in vitro and breast cancer xenograft model in vivo.
RESULTS: The results showed that, QDG significantly inhibited HUVEC migration and tube formation. It downregulated NFATc3 gene expression, decreased NFATc3 protein amount, and reduced the ratio of NFATc3 nuclear translocation in HUVECs. In breast cancer xenograft model, QDG treatment significantly suppressed tumor growth, inhibited VEGF release, and decreased microvessel density. QDG reduced protein expressions of VEGF, VEGFR2 and NFATc3.
CONCLUSION: The results suggested that QDG showed anti-angiogenic effects of breast cancer both in vitro and in vivo. The mechanism might be partially associated with inhibiting NFAT signaling pathway.

Bond J, Tran Quang C, Hypolite G, et al.
Novel Intergenically Spliced Chimera,
Mol Cancer Res. 2018; 16(3):470-475 [PubMed] Related Publications
Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically spliced chimeric RNAs (ISC) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA sequencing was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens (

Liu X, Wang T, Wang Y, et al.
Orai1 is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative breast cancers.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(4 Pt A):975-986 [PubMed] Related Publications
It is believed that hypoxia stimulates triple-negative breast cancers (TNBCs) metastasis, which is associated with a poor prognosis. However, the underlying mechanism remains unclear. Here, we demonstrated that hypoxia up-regulates both the levels of Orai1 and Notch1, and the increase in Orai1 is mediated by Notch1 signaling in TNBCs. Functionally, Orai1 caused a sustained elevation of intracellular Ca

Jiang Y, Han S, Cheng W, et al.
NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of glioma.
Cell Commun Signal. 2017; 15(1):54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We previously demonstrated that the local immune status correlated with the glioma prognosis. Interleukin-6 (IL6) was identified as an important local immune-related risk marker related to unfavourable prognosis. In this study, we further investigated the role and regulation of IL6 signalling in glioma.
METHODS: The expression and prognostic value of IL6 and the IL6 receptor (IL6R) were explored in The Cancer Genome Atlas (TCGA) and REMBRANDT databases and clinical samples. Functional effects of genetic knockdown and overexpression of IL6R or IL6 stimulation were examined in vitro and in tumours in vivo. The effects of the nuclear factor of activated T cells-1 (NFAT1) on the promoter activities of IL6R and IL6 were also examined.
RESULTS: High IL6- and IL6R-expression were significantly associated with mesenchymal subtype and IDH-wildtype gliomas, and were predictors of poor survival. Knockdown of IL6R decreased cell proliferation, invasion and neurosphere formation in vitro, and inhibited tumorigenesis in vivo. IL6R overexpression or IL6 stimulation enhanced the invasion and growth of glioma cells. TCGA database searching revealed that IL6- and IL6R-expression were correlated with that of NFAT1. In glioma cells, NFAT1 enhanced the promoter activities of IL6R and IL6, and upregulated the expression of both IL6R and IL6.
CONCLUSION: NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of gliomas, emphasizing the role of immunomodulatory factors in glioma malignant progression.

Kato I, Furuya M, Matsuo K, et al.
Giant cell tumours of bone treated with denosumab: histological, immunohistochemical and H3F3A mutation analyses.
Histopathology. 2018; 72(6):914-922 [PubMed] Related Publications
AIMS: Denosumab, a human monoclonal antibody directed against the receptor activator of nuclear factor-κB ligand (RANKL), is a therapeutic agent for giant cell tumour of bone (GCTB). Although some studies have reported that denosumab shrinks tumours and induces bone formation, the actual effects of RANKL suppression on GCTB remain unclear. A mutation in the H3 histone family member 3A gene (H3F3A) was recently identified as a genetic signature for GCTB. The aim of this study was to investigate the histopathological features and H3F3A mutation status of GCTBs treated with denosumab.
METHODS AND RESULTS: Nine biopsy-diagnosed patients with GCTB, who underwent curettage after neoadjuvant denosumab therapy, were reviewed. Immunohistochemistry for NFATc1 (an osteoclast marker), RUNX2 (an osteoblast marker) and histone H3.3 G34W (G34W, a GCTB marker) was performed; furthermore, H3F3A mutation status was examined with direct sequencing. Before therapy, GCTBs comprised NFATc1+ and RUNX2+ cells. All cases were G34W+ and contained H3F3A mutations. After therapy, the osteoclast-like giant cells disappeared. Areas of slender spindle cell proliferation and reticular woven bone that were NFATc1- and RUNX2+ replaced the lesions in various proportions. However, all post-therapy lesions still contained many G34W+ cells and harboured H3F3A mutations. Immunofluorescence double staining revealed that RUNX2+ mononuclear cells coexpressed G34W in pre-therapy and post-therapy lesions. Two patients experienced radiologically detected local recurrence within 2 years.
CONCLUSIONS: Denosumab therapy effectively decreases the number of osteoclastic cells in GCTBs. However, the neoplastic cells with H3F3A mutation survive denosumab treatment and undergo dramatic histological changes in response to this agent.

Agüera-González S, Burton OT, Vázquez-Chávez E, et al.
Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization.
Cell Rep. 2017; 21(1):181-194 [PubMed] Related Publications
Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.

Märklin M, Heitmann JS, Fuchs AR, et al.
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.
Nat Commun. 2017; 8(1):755 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

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