|Year : 2014 | Volume
| Issue : 7 | Page : 83-88
Wnt5a/Ca 2+ /calcineurin/nuclear factor of activated T signaling pathway as a potential marker of pediatric melanoma
Yun Yang, Qiufang Qian
Department of Dermatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
|Date of Web Publication||29-Nov-2014|
Department of Dermatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai
Source of Support: None, Conflict of Interest: None
Melanoma is rare in children, but its incidence appears to be increasing. Melanoma accounts for the highest mortality among all skin cancer types. This disease is characterized by high-grade malignancy, easy metastasis, poor prognosis, and high death rate. Melanoma in children may be biologically different from that in adults. Therefore, novel biomarkers need to be developed to understand the mechanism by which melanoma cells migrate and infiltrate. Such biomarkers will also be useful for the molecular recognition and targeted therapy of melanoma. Ca 2+ regulates the migration, proliferation, infiltration, and metastasis of cancer cells. Consequently, many studies investigated the relationship of the Wnt/Ca 2+ signaling pathway to tumor occurrence and development. This review summarizes and discusses the function of the Wnt5a/Ca 2+ /calcineurin/nuclear factor of the activated T signaling pathway in melanoma and evaluates its potential to be a biomarker of pediatric melanoma.
Keywords: Ca 2+ , molecular marker, pediatric melanoma, tumor development, Wnt
|How to cite this article:|
Yang Y, Qian Q. Wnt5a/Ca 2+ /calcineurin/nuclear factor of activated T signaling pathway as a potential marker of pediatric melanoma. J Can Res Ther 2014;10, Suppl S3:83-8
|How to cite this URL:|
Yang Y, Qian Q. Wnt5a/Ca 2+ /calcineurin/nuclear factor of activated T signaling pathway as a potential marker of pediatric melanoma. J Can Res Ther [serial online] 2014 [cited 2019 Dec 6];10:83-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/83/145788
| > Introduction|| |
Skin tumor generally consists of melanoma and nonmelanoma skin tumor, with the latter having a higher incidence, but relatively lower fatality rate than the former. Although cases among children and adolescents represent <1% of the total reported incidence, melanoma is the second most common adult-type cancer in this age group after thyroid cancer.  The incidence of melanoma in children is also increasing. , Melanoma in young people is related to both age and gender. Although this disease rarely affects prepubertal children, melanoma has sharply increased in incidence among children aged 12 years and is more pronounced in girls than in boys. , In addition, melanoma in children differs from that in adults in terms of demographics, presentation, and survival.  The prognosis for adult patients with melanoma is age related, and several studies have demonstrated that melanoma survival is significantly high in young adults. ,, Age-related disparities have been noted but are less defined in the pediatric population with melanoma. 
Diagnosis of melanoma in children is difficult because of its clinical and pathologic characteristics. Several melanocytic lesions in children have an atypical appearance and may resemble a pyogenic granuloma or other benign skin lesions.  The biopsy of pediatric melanoma may not appear clinically similar to that of adult melanoma, and melanoma can be missed or delayed because this rare disease is sometimes not considered in young children. One persistent difficulty in the study of melanoma among young people is distinguishing benign from malignant melanocytic lesions. Patients with melanoma discovered in the early stage may have a poor prognosis because of metastasis. Melanoma treatment is complicated, and currently available treatment methods are limited. Despite the remarkable research progress on melanoma pathogenesis and signaling pathway, the mechanism by which melanoma cells invade and metastasize remains unknown. Several signaling pathways are closely related to the occurrence and development of melanoma and even to the migration and infiltration of tumor cells. For instance, the Wnt signaling pathway might be involved in the invasion and metastasis of melanoma and might be a promising molecular biomarker of pediatric melanoma.
The Wnt signaling pathway is named after its activated Wnt protein and includes two signaling pathways: Classic and nonclassic. The former includes the Wnt/β-catenin signaling pathway, and the latter includes the Wnt/JNK and Wnt/Ca 2+ signaling pathways. The Wnt signaling pathway, which regulates cell growth, proliferation, apoptosis, embryonic development, and tumorigenesis, is mediated by the Wnt gene coding product.  The Wnt protein family consists of two types: Wnt1 and Wnt5a. The former type includes Wnt1 and Wnt3a, which activate the Wnt/β-catenin signaling pathway. The latter includes Wnt4 and Wnt5a, which allow ion release in cells and activate the Wnt/Ca 2+ signaling pathway.
The Wnt/β-catenin signaling pathway is closely related to the development and transformation of melanocytes and to the occurrence of melanoma.  β-catenin can be expressed by normal melanocytes at each development stage, and its abnormal expression and nuclear expression can be observed in melanoma. Excessive β-catenin promotes the proliferation and migration of melanocytes.  The nuclear and/or cytoplasm accumulation of β-catenin is caused by a mutation at the GSK3 β phosphorylation site of CTNNB1, the gene that encodes β-catenin.  This phenomenon may result in the constitutive activation of the T cell factor/lymph enhancement factor (LEF) target gene. These changes significantly contribute to the occurrence of many tumors, such as colon tumor and melanoma. However, mutations in the exon 3 of CTNNB1 do not lead to the cytoplasm and nuclear accumulation of β-catenin, and β-catenin distribution changes because of the translated modification event.  The high expression of adenomatoid polyp coli or axin causes β-catenin to migrate to the cytoplasm and be degraded; thus, the excessive methylation of the gene promoter of the highly expressed adenomatoid polyp has been detected in melanocytes. LEF-1 also functions in melanoma.  Rubinfeld et al.  discovered that the compound formed by LEF and β-catenin is highly expressed in melanocytes. Murakami et al.  demonstrated that β-catenin accumulation in the nucleus is related to LEF expression and that mutant LEF may suppress melanocyte migration. The transfection of the LEF expression vector upregulates the expression of β-catenin and enhances the migration of melanocytes. However, the transfection of LEF that mutated on the binding site of β-catenin downregulates the expression of β-catenin and reduces the migration of cancer cells.
Although the expression of adenomatous polyosis coli protein declines, β-catenin and LEFs are highly expressed, which influence the metastasis and stage of melanoma. , LEF inhibition by transfecting melanoma cells with the siRNA expression vector of LEF can prevent the proliferation of the transfected melanoma and arrest the cell cycle of the transfected cells at the G1 stage.  Morphological changes and cell apoptosis also occur. , The high expression of cyclooxygenase 2 (COX-2) in melanoma tissues and cell lines is related to β-catenin expression.  Treatment with the COX-2 inhibitors celecoxib and indomethacin represses melanoma growth induces melanocyte apoptosis and triggers G1-S cycle arrest. 
The Wnt/JNK pathway of vertebrates can regulate and control the stretch during gastrulation. , Frizzled protein receptor can combine with Wnt7a to activate the Wnt/JNK pathway. Its downstream target genes include the disheveled protein, prickle, and so on. ,,,, In these molecules, only the disheveled protein is related to the Wnt/β-catenin signaling pathway because the DEP structural domain of the disheveled protein is required by the Wnt/JNK and Wnt/Ca 2+ signaling pathways.  The combination of the Frizzled protein and Wnt7a may activate the DEP domain of the disheveled protein, the guanosine triphosphatases Rho and Rac, and the transcription factors Elk-1 and Ets-2. ,,,, The downstream molecule may contain cytoskeletal proteins (e.g. vinculin, actin, vimentin, and keratin) and matrix metalloproteinase in the cytoplasm. The activated Wnt/JNK pathway regulates the expression of intranuclear genes, but also influences the functions and structures of cytoplasm substrate molecules. ,
Therefore, the occurrence of melanoma, including pediatric melanoma, is related to the classical Wnt/β-catenin signaling pathway, but is not directly related to the infiltration and development of tumors. Moreover, the invasion and metastasis of melanoma may be closely related to the Wnt/Ca 2+ pathway. Considering that the clinical and histopathologic features of childhood melanoma are poorly characterized, this review discusses the significance of the Wnt5a/Ca 2+ /calcineurin/nuclear factor of activated T (NFAT) pathway in pediatric melanoma and evaluates its potential to be a biomarker of pediatric melanoma.
| > Wnt/Ca 2+ signaling pathway and invasion and metastasis in melanoma|| |
Invasion and metastasis are important features of melanoma development and causes of death among melanoma patients. The migration and motility of tumor cells determine the invasion and metastasis of tumor, which are closely related to cytoskeletal proteins and integrin; the Wnt/Ca 2+ signaling pathway controls and regulates tumor development by influencing the expression and biological functions of these proteins. , The nonclassical Wnt/Ca 2+ pathway may be activated by Wnt4 and Wnt5a, ,, and their combination with the Frizzled protein receptor activates the G protein and generates messenger DAG and IP3 through phospholipase C.  Consequently, DAG activates protein kinase C (PKC), and IP3 promotes the release of Ca 2+ in the endoplasmic reticulum. An increase in the intracellular level of Ca 2+ also activates PKC and protein kinase II. ,, PKC regulates cell adhesion and migration by interacting with cytoskeletal proteins. ,
Ca 2+ , a crucial factor in the Wnt/Ca 2+ pathway, is evidently upregulated in melanoma cells at different growth stages. Carbachol manifests no clear effect on Ca 2+ concentration in normal melanocytes but remarkably increases Ca 2+ concentration in melanoma cells, particularly in A2058 cells (lymph metastasis). Moreover, PKC activation by the agonist may repress carbachol-induced Ca 2+ response, suggesting that the variations in Ca 2+ concentration are related to the development, invasion, and metastasis of melanoma.  Furthermore, the Wnt/Ca 2+ pathway may be involved in the invasion and metastasis of melanoma.
| > Function of Calcineurin/nuclear factor of activated T signaling in tumorigenesis and development|| |
Nuclear factor of activated T is widely expressed in mammalian cells. It is closely related to cell growth and development, complicated cell interactions, and several signaling pathways. NFAT regulates cell stability and carcinogenic potential.  Recent studies have shown that NFAT is closely related to the occurrence and development of human tumors.  Abnormally activated NFAT has been detected in several tumor cells and tumor micro-environments, such as in breast cancer,  colon cancer, , pancreatic cancer,  hematological malignancy,  and melanoma.  NFAT has five types: NFAT1 (NFATc2), NFAT2 (NFATc1), NFAT3 (NFATc4), NFAT4 (NFATc3), and NFAT5 (TonEBP).  Ca 2 + regulates NFAT1, NFAT2, NFAT3, and NFAT4. , NFAT5 lacks the relevant binding site to interact with calcineurin and Ca 2+ .  An increase in Ca 2+ level may activate calcineurin, which dephosphorylates NFAT. This phenomenon leads to NFAT nuclear translocation and binding to the specific DNA binding site,  thereby regulating the transcription and expression of downstream target genes, such as COX-2 and vascular endothelial growth factor-A (VEGF-A), which may influence tumor development. , Clone formation and cell transformation in fibroblasts are induced by activated NFAT2; calcineurin and NFAT2 may induce Myc transcription to enhance the proliferation and nonadherence-dependent growth of pancreatic cancer cells.
The dephosphorylation of NFAT1 and NFAT2 can be observed in invasive T-cell lymphoma and diffuse B-cell lymphoma. NFAT activation depends on calcineurin in lymphocytic leukemia and diffuse B-cell lymphoma. Treatment with calcineurin inhibitors phosphorylates NFAT, which may inhibit the proliferation of tumor cells and induce apoptosis.  The expression and nuclear localization of NFAT2 can also be detected in T-cell lymphoma and non-Hodgkin B cell. However, the ectopic expression of NFAT1 in Burkitt's lymphoma may accelerate apoptosis. Compared with that in wild-type mice, T-cell lymphoma in lymphomagenic retrovirus-infected NFAT4-deficient mice occurs more frequently and faster; this result suggests that NFAT isoforms in some cells can suppress tumor. , The relationship between the functions of NFAT isoforms and tumors should be further studied. Flockhart et al.  discovered that NFAT2 and NFAT4 are expressed in melanoma cell lines. NFAT, as the upstream regulatory gene of COX-2, regulates and controls protein expression and promoter activity. Juhαsz et al.  reported that the activity of calcineurin in melanoma can be inhibited by the immune-suppressor cyclosporine A. This phenomenon reduces cell metabolism activity and proliferation rate, alters cellular morphology and intracellular actin structure, and eventually increases death rate. These data suggest that the calcineurin influences the biological functions of melanoma. The low expression of NFAT1 and NFAT2 in immortalized melanoma and their high expression in metastatic melanoma suggest that the NFAT signaling pathway is significant in tumorigenesis. ,
| > Relationship between Wnt5a/Ca 2+ /Calcineurin/nuclear factor of activated T signaling pathway and tumor progression|| |
Wnt5a, a promoter of the Wnt/Ca 2+ pathway, is highly expressed during the migration of neural crest cells to the skin in embryonic development. This event may alter cellular morphology. However, Wnt5a is evidently downregulated after melanocyte formation. The PKC inhibitor may influence the aggressive ability of melanoma; thus, the PKC pathway has been associated with melanoma invasion.  Wnt5a influences the invasion and metastasis of melanoma. Thus, Wnt5a is highly expressed in melanoma with strengthened invasion, and Wnt5a silencing can reduce the invasion of melanocytes.  Moreover, Wnt5a is highly expressed in aggressive and highly malignant melanoma cells, as well as in forefront melanoma cells that develop toward the matrix.  Other studies found that Wnt5a is poorly expressed in superficial melanoma but not in metastatic melanoma. 
Tumor invasion is closely related to the activation of the Wnt/Ca 2+ signaling pathway, and the activation of a signaling pathway may increase the intracellular level of Ca 2+ . Thus, protein kinase II and PKC can be activated to regulate the migration and adhesive capacities of cells. Wnt5a is highly expressed in advanced and poor prognostic gastric carcinoma cells, and Wnt5a knockdown may suppress the migration and metastasis of gastric carcinoma cells.  The high expression of Wnt5a is closely related to the lung metastasis of sarcoma cells  and to the invasion and metastasis of breast cancer. , However, the high expression of Wnt5a in thyroid cancer FTC-133 cell lines may decrease the proliferation, migration, and invasion of tumor cells.  The migration of tumor cells is inhibited in SW480 cells treated with recombinant/purified Wnt5a.  Wnt5a is also not expressed or poorly expressed in hematological tumors, such as B-cell lymphoma and myeloid leukemia.  Da Forno et al.  reported that the expression level of Wnt5a is higher in metastatic melanoma than in normal melanoma cells. These results suggest that the high expression of Wnt5a may strengthen the invasion of melanoma, resulting in poor prognosis. However, whether or not Wnt5a inhibits or promotes cancer development and its correlation with the biological state and growth regulation of cells warrant further investigations.
The expression levels of Wnt5a and Wnt11 are low in normal melanocytes but high in melanoma cells. , The NFAT1 and NFAT5 in tissues and cells promote the invasion of colon cancer and breast cancer, enhance the angiogenesis and hyperplasia by increasing the transcription of COX-2 gene, and inhibit apoptosis.  Calcineurin and NFAT2 are not expressed or lowly expressed in prostatitis and normal prostate tissues but highly expressed in prostate cancer cells and tissue specimens. NFAT2 silencing by calcineurin inhibitors or RNA interference significantly reduces the growth and proliferation of prostatic cancer cells. , The calcineurin/NFAT signaling pathway in tumor biology is responsible for three phenomena:  (a) Activation of VEGF and angiogenesis; (b) upregulation of c-Myc levels and promotion of tumor proliferation; and (c) activation of COX-2 and enhancement of cell invasion and migration. Moreover, the invasion and metastasis of melanoma depend on the migration activity and motility of melanoma, which are closely related to cytoskeletal proteins. ,
| > Conclusion|| |
The significant differences between children and adolescents suggest the existence of age-based inherent differences in the biology of melanoma. Therefore, novel biomarkers that will assist in the diagnosis and prognosis of melanoma need to be developed. The Wnt5a/Ca 2+ /caldneurin/NFAT signaling pathway serves significant functions in melanoma occurrence and development. The grade malignancy and metastasis potential of melanoma possibly contribute to pediatric melanoma. However, little is known about pediatric melanoma. Therefore, future studies must focus on elucidating the specific function of the Wnt5a/Ca 2+ /caldneurin/NFAT signaling pathway in pediatric melanoma to reveal the occurrence mechanism, clinical diagnosis, and targeted therapy of this disease.
| > References|| |
Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: Risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol 2005;23:4735-41.
Slade AD, Austin MT. Childhood melanoma: An increasingly important health problem in the USA. Curr Opin Pediatr 2014;26:356-61.
Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen SK, Byrnes GB, et al.
Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: Data linkage study of 11 million Australians. BMJ 2013;346:f2360.
Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics 2013;131:846-54.
Lange JR, Palis BE, Chang DC, Soong SJ, Balch CM. Melanoma in children and teenagers: An analysis of patients from the National Cancer Data Base. J Clin Oncol 2007;25:1363-8.
Francken AB, Accortt NA, Shaw HM, Wiener M, Soong SJ, Hoekstra HJ, et al.
Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma. Ann Surg Oncol 2008;15:1476-84.
Lasithiotakis K, Leiter U, Meier F, Eigentler T, Metzler G, Moehrle M, et al.
Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer 2008;112:1795-804.
Zhang L, Ma W, Li Y. Huge primary malignant melanoma of the esophagus: A case report and literature review. Thorac Cancer 2013;4:479-483.
Khorsand K, Sidbury R. Recent advances in paediatric dermatology. Arch Dis Child 2014;99:944-8.
Gordon MD, Nusse R. Wnt signaling: Multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006;281:22429-33.
Larue L, Delmas V. The WNT/Beta-catenin pathway in melanoma. Front Biosci 2006;11:733-42.
Larue L, Kumasaka M, Goding CR. Beta-catenin in the melanocyte lineage. Pigment Cell Res 2003;16:312-7.
Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, et al.
Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer 2002;100:549-56.
Zhong D.-s, Sun L.-l. and Dong L.-x. (2013), Molecular mechanisms of LKB1 induced cell cycle arrest. Thoracic Cancer, 4: 229-33.
Yin HH, Liao WJ, Gao Y, Gao TW. [Expression of lymphatic enhancer factor-1 in malignant melanoma tissue and its significance]. Zhonghua Yi Xue Za Zhi 2005;85:1573-5.
Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997;275:1790-2.
Murakami T, Toda S, Fujimoto M, Ohtsuki M, Byers HR, Etoh T, et al.
Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: Role of LEF-1 in melanoma with increased metastatic potential. Biochem Biophys Res Commun 2001;288:8-15.
Filali M, Cheng N, Abbott D, Leontiev V, Engelhardt JF. Wnt-3A/beta-catenin signaling induces transcription from the LEF-1 promoter. J Biol Chem 2002;277:33398-410.
Henderson BR, Galea M, Schuechner S, Leung L. Lymphoid enhancer factor-1 blocks adenomatous polyposis coli-mediated nuclear export and degradation of beta-catenin. Regulation by histone deacetylase 1. J Biol Chem 2002;277:24258-64.
Eichhoff OM, Weeraratna A, Zipser MC, Denat L, Widmer DS, Xu M, et al.
Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching. Pigment Cell Melanoma Res 2011;24:631-42.
Serini S, Fasano E, Piccioni E, Monego G, Cittadini AR, Celleno L, et al.
DHA induces apoptosis and differentiation in human melanoma cells in vitro
: Involvement of HuR-mediated COX-2 mRNA stabilization and ß-catenin nuclear translocation. Carcinogenesis 2012;33:164-73.
Seo KW, Coh YR, Rebhun RB, Ahn JO, Han SM, Lee HW, et al.
Antitumor effects of celecoxib in COX-2 expressing and non-expressing canine melanoma cell lines. Res Vet Sci 2014;96:482-6.
Moriguchi T, Kawachi K, Kamakura S, Masuyama N, Yamanaka H, Matsumoto K, et al.
Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates. J Biol Chem 1999;274:30957-62.
Yamanaka H, Moriguchi T, Masuyama N, Kusakabe M, Hanafusa H, Takada R, et al.
JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep 2002;3:69-75.
Park M, Moon RT. The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nat Cell Biol 2002;4:20-5.
Feiguin F, Hannus M, Mlodzik M, Eaton S. The ankyrin repeat protein Diego mediates Frizzled-dependent planar polarization. Dev Cell 2001;1:93-101.
Mouri K, Horiuchi SY, Uemura T. Cohesin controls planar cell polarity by regulating the level of the seven-pass transmembrane cadherin Flamingo. Genes Cells 2012;17:509-24.
Matsubara D, Horiuchi SY, Shimono K, Usui T, Uemura T. The seven-pass transmembrane cadherin Flamingo controls dendritic self-avoidance via its binding to a LIM domain protein, Espinas, in Drosophila sensory neurons. Genes Dev 2011;25:1982-96.
Usui T, Shima Y, Shimada Y, Hirano S, Burgess RW, Schwarz TL, et al.
Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 1999;98:585-95.
Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N. Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev 1998;12:2610-22.
Strutt DI, Weber U, Mlodzik M. The role of RhoA in tissue polarity and Frizzled signalling. Nature 1997;387:292-5.
Strutt D. Planar polarity: Getting ready to ROCK. Curr Biol 2001;11:R506-9.
Boutros M, Paricio N, Strutt DI, Mlodzik M. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 1998;94:109-18.
Strutt H, Strutt D. Nonautonomous planar polarity patterning in Drosophila: Dishevelled-independent functions of frizzled. Dev Cell 2002;3:851-63.
Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 2005;8:34-42.
Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781-810.
Habas R, Dawid IB. Dishevelled and Wnt signaling: Is the nucleus the final frontier? J Biol 2005;4:2.
Lai SL, Chien AJ, Moon RT. Wnt/Fz signaling and the cytoskeleton: Potential roles in tumorigenesis. Cell Res 2009;19:532-45.
Kikuchi A, Yamamoto H. Tumor formation due to abnormalities in the beta-catenin-independent pathway of Wnt signaling. Cancer Sci 2008;99:202-8.
Du SJ, Purcell SM, Christian JL, McGrew LL, Moon RT. Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos. Mol Cell Biol 1995;15:2625-34.
Dissanayake SK, Wade M, Johnson CE, O'Connell MP, Leotlela PD, French AD, et al.
The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 2007;282:17259-71.
Ekström EJ, Bergenfelz C, von Bülow V, Serifler F, Carlemalm E, Jönsson G, et al.
WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Mol Cancer 2014;13:88.
Slusarski DC, Corces VG, Moon RT. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 1997;390:410-3.
Jafri MS, Keizer J. On the roles of Ca 2+
diffusion, Ca 2+
buffers, and the endoplasmic reticulum in IP3-induced Ca 2+
waves. Biophys J 1995;69:2139-53.
Kühl M, Sheldahl LC, Malbon CC, Moon RT. Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem 2000;275:12701-11.
Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT. The Wnt/Ca 2+
pathway: A new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000;16:279-83.
Purohit A, Rokita AG, Guan X, Chen B, Koval OM, Voigt N, et al.
Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation 2013;128:1748-57.
Sheldahl LC, Park M, Malbon CC, Moon RT. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol 1999;9:695-8.
Jönsson M, Smith K, Harris AL. Regulation of Wnt5a expression in human mammary cells by protein kinase C activity and the cytoskeleton. Br J Cancer 1998;78:430-8.
Wang H, Yu YQ, Liao WJ, Wang ZR, Lv YJ, Zhang YG, et al.
Negative regulation of endogenous protein kinase Calpha on the dynamic change of carbachol-induced intracellular calcium response in different melanoma cells. J Cell Physiol 2009;221:276-82.
Qin JJ, Nag S, Wang W, Zhou J, Zhang WD, Wang H, et al.
NFAT as cancer target: Mission possible? Biochim Biophys Acta 2014;1846:297-311.
Müller MR, Rao A. NFAT, immunity and cancer: A transcription factor comes of age. Nat Rev Immunol 2010;10:645-56.
Zheng J, Fang F, Zeng X, Medler TR, Fiorillo AA, Clevenger CV. Negative cross talk between NFAT1 and Stat5 signaling in breast cancer. Mol Endocrinol 2011;25:2054-64.
Daniel C, Gerlach K, Väth M, Neurath MF, Weigmann B. Nuclear factor of activated T cells - a transcription factor family as critical regulator in lung and colon cancer. Int J Cancer 2014;134:1767-75.
Gerlach K, Daniel C, Lehr HA, Nikolaev A, Gerlach T, Atreya R, et al.
Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis. Cancer Res 2012;72:4340-50.
König A, Fernandez-Zapico ME, Ellenrieder V. Primers on molecular pathways - The NFAT transcription pathway in pancreatic cancer. Pancreatology 2010;10:416-22.
Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O'Hare T, et al.
/NFAT signaling maintains survival of Ph+leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 2010;18:74-87.
Perotti V, Baldassari P, Bersani I, Molla A, Vegetti C, Tassi E, et al.
NFATc2 is a potential therapeutic target in human melanoma. J Invest Dermatol 2012;132:2652-60.
Buchholz M, Ellenrieder V. An emerging role for Ca 2+
/calcineurin/NFAT signaling in cancerogenesis. Cell Cycle 2007;6:16-9.
Macian F. NFAT proteins: Key regulators of T-cell development and function. Nat Rev Immunol 2005;5:472-84.
Neuhofer W. Role of NFAT5 in inflammatory disorders associated with osmotic stress. Curr Genomics 2010;11:584-90.
Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 2003;17:2205-32.
Suehiro J, Kanki Y, Makihara C, Schadler K, Miura M, Manabe Y, et al
. Genome-wide approaches reveal functional vascular endothelial growth factor (VEGF)-inducible nuclear factor of activated T cells (NFAT) c1 binding to angiogenesis-related genes in the endothelium. J Biol Chem 2014;289:29044-59.
Mena MP, Papiewska-Pajak I, Przygodzka P, Kozaczuk A, Boncela J, Cierniewski CS. NFAT2 regulates COX-2 expression and modulates the integrin repertoire in endothelial cells at the crossroads of angiogenesis and inflammation. Exp Cell Res 2014;324:124-36.
Medyouf H, Ghysdael J. The calcineurin/NFAT signaling pathway: A novel therapeutic target in leukemia and solid tumors. Cell Cycle 2008;7:297-303.
Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol 2008;28:7168-81.
Glud SZ, Sørensen AB, Andrulis M, Wang B, Kondo E, Jessen R, et al.
A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 2005;106:3546-52.
Flockhart RJ, Armstrong JL, Reynolds NJ, Lovat PE. NFAT signalling is a novel target of oncogenic BRAF in metastatic melanoma. Br J Cancer 2009;101:1448-55.
Juhász T, Matta C, Veress G, Nagy G, Szíjgyártó Z, Molnár Z, et al.
Inhibition of calcineurin by cyclosporine A exerts multiple effects on human melanoma cell lines HT168 and WM35. Int J Oncol 2009;34:995-1003.
Lee YS, Kim DW, Kim S, Choi HI, Lee Y, Kim CD, et al.
Downregulation of NFAT2 promotes melanogenesis in B16 melanoma cells. Anat Cell Biol 2010;43:303-9.
Bachmann IM, Straume O, Puntervoll HE, Kalvenes MB, Akslen LA. Importance of P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res 2005;11:8606-14.
Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, et al.
Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002;1:279-88.
Da Forno PD, Pringle JH, Hutchinson P, Osborn J, Huang Q, Potter L, et al.
WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res 2008;14:5825-32.
Medrano EE. Wnt5a and PKC, a deadly partnership involved in melanoma invasion. Pigment Cell Res 2007;20:258-9.
Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, et al.
Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 2006;66:10439-48.
Mazieres J, He B, You L, Xu Z, Jablons DM. Wnt signaling in lung cancer. Cancer Lett 2005;222:1-10.
Fernandez-Cobo M, Zammarchi F, Mandeli J, Holland JF, Pogo BG. Expression of Wnt5A and Wnt10B in non-immortalized breast cancer cells. Oncol Rep 2007;17:903-7.
Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S, et al.
Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci U S A 2006;103:5454-9.
Kremenevskaja N, von Wasielewski R, Rao AS, Schöfl C, Andersson T, Brabant G. Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene 2005;24:2144-54.
Dejmek J, Dejmek A, Säfholm A, Sjölander A, Andersson T. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res 2005;65:9142-6.
Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A, et al.
Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 2003;4:349-60.
Fan Y, Yao Y, Li L, Wu Z, Xu F, Hou M, Wu H, Shen Y, Wan H and Zhou Q. (2013), nm23-H1 gene driven by hTERT promoter induces inhibition of invasive phenotype and metastasis of lung cancer xenograft in mice. Thoracic Cancer, 4: 41-52.
Katoh M. WNT/PCP signaling pathway and human cancer (review). Oncol Rep 2005;14:1583-8.
Yiu GK, Toker A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 2006;281:12210-7.
Lehen'kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways. Oncogene 2007;26:7380-5.
Helige C, Hofmann-Wellenhof R, Fink-Puches R, Smolle J. Mofarotene-induced inhibition of melanoma cell motility by increasing vinculin-containing focal contacts. Melanoma Res 2004;14:547-54.
Rodríguez MI, Peralta-Leal A, O'Valle F, Rodriguez-Vargas JM, Gonzalez-Flores A, Majuelos-Melguizo J, et al.
PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genet 2013;9:e1003531.