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Year : 2014  |  Volume : 10  |  Issue : 7  |  Page : 83-88

Wnt5a/Ca 2+ /calcineurin/nuclear factor of activated T signaling pathway as a potential marker of pediatric melanoma

Department of Dermatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China

Date of Web Publication29-Nov-2014

Correspondence Address:
Qiufang Qian
Department of Dermatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.145788

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 > Abstract 

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 2022 May 19];10, Suppl S3:83-8. Available from: https://www.cancerjournal.net/text.asp?2014/10/7/83/145788

 > Introduction Top

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. [1] The incidence of melanoma in children is also increasing. [1],[2] 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. [3],[4] In addition, melanoma in children differs from that in adults in terms of demographics, presentation, and survival. [5] The prognosis for adult patients with melanoma is age related, and several studies have demonstrated that melanoma survival is significantly high in young adults. [6],[7],[8] Age-related disparities have been noted but are less defined in the pediatric population with melanoma. [4]

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. [9] 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. [10] 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. [11] 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. [12] 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. [13] 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. [14] 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. [15] Rubinfeld et al. [16] discovered that the compound formed by LEF and β-catenin is highly expressed in melanocytes. Murakami et al. [17] 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. [18],[19] 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. [15] Morphological changes and cell apoptosis also occur. [15],[20] The high expression of cyclooxygenase 2 (COX-2) in melanoma tissues and cell lines is related to β-catenin expression. [21] Treatment with the COX-2 inhibitors celecoxib and indomethacin represses melanoma growth induces melanocyte apoptosis and triggers G1-S cycle arrest. [22]

The Wnt/JNK pathway of vertebrates can regulate and control the stretch during gastrulation. [23],[24] 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. [25],[26],[27],[28],[29] 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. [30] 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. [31],[32],[33],[34],[35] 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. [36],[37]

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 Top

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. [38],[39] The nonclassical Wnt/Ca 2+ pathway may be activated by Wnt4 and Wnt5a, [40],[41],[42] and their combination with the Frizzled protein receptor activates the G protein and generates messenger DAG and IP3 through phospholipase C. [43] Consequently, DAG activates protein kinase C (PKC), and IP3 promotes the release of Ca 2+[44] in the endoplasmic reticulum. An increase in the intracellular level of Ca 2+ also activates PKC and protein kinase II. [45],[46],[47] PKC regulates cell adhesion and migration by interacting with cytoskeletal proteins. [48],[49]

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. [50] 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 Top

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. [51] Recent studies have shown that NFAT is closely related to the occurrence and development of human tumors. [52] Abnormally activated NFAT has been detected in several tumor cells and tumor micro-environments, such as in breast cancer, [53] colon cancer, [54],[55] pancreatic cancer, [56] hematological malignancy, [57] and melanoma. [58] NFAT has five types: NFAT1 (NFATc2), NFAT2 (NFATc1), NFAT3 (NFATc4), NFAT4 (NFATc3), and NFAT5 (TonEBP). [59] Ca 2 + regulates NFAT1, NFAT2, NFAT3, and NFAT4. [52],[60] NFAT5 lacks the relevant binding site to interact with calcineurin and Ca 2+ . [61] 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, [62] 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. [63],[64] 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. [65] 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. [66],[67] The relationship between the functions of NFAT isoforms and tumors should be further studied. Flockhart et al. [68] 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. [69] 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. [58],[70]

 > Relationship between Wnt5a/Ca 2+ /Calcineurin/nuclear factor of activated T signaling pathway and tumor progression Top

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. [71] 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. [72] Moreover, Wnt5a is highly expressed in aggressive and highly malignant melanoma cells, as well as in forefront melanoma cells that develop toward the matrix. [73] Other studies found that Wnt5a is poorly expressed in superficial melanoma but not in metastatic melanoma. [74]

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. [75] The high expression of Wnt5a is closely related to the lung metastasis of sarcoma cells [76] and to the invasion and metastasis of breast cancer. [77],[78] However, the high expression of Wnt5a in thyroid cancer FTC-133 cell lines may decrease the proliferation, migration, and invasion of tumor cells. [79] The migration of tumor cells is inhibited in SW480 cells treated with recombinant/purified Wnt5a. [80] Wnt5a is also not expressed or poorly expressed in hematological tumors, such as B-cell lymphoma and myeloid leukemia. [81] Da Forno et al. [73] 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. [82],[83] 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. [84] 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. [52],[85] The calcineurin/NFAT signaling pathway in tumor biology is responsible for three phenomena: [59] (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. [86],[87]

 > Conclusion Top

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.

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