Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

Massi, Daniela; Tarantini, Francesca; Franchi, Alessandro; Paglierani, Milena; Serio, Claudia Di; Pellerito, Silvia; Leoncini, Giuseppe; Cirino, Giuseppe; Geppetti, Pierangelo; Santucci, Marco

doi:10.1038/modpathol.3800526

Cited by 94 publications

(65 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have previously investigated the Notch pathway in a series of benign and malignant cutaneous melanocytic lesions and demonstrated that Notch activation represents an early event in melanocytic tumor growth and upregulation of Notch signaling may sustain tumor progression in melanoma. 26 In contrast, we recently reported in nonmelanoma skin cancer a divergent expression of Notch-1, depending on anatomical site and tumor histotype. 27 Whereas in UV-related squamous cell photocarcinogenesis Notch-1 downregulation occurred, mirroring a tumor-suppressor function of the receptor, in sun-protected squamous cell carcinomas Notch-1 was upregulated.…”

Section: Notch-1 Expression In Merkel Cell Carcinoma J Panelos Et Almentioning

confidence: 93%

Expression of Notch-1 and alteration of the E-cadherin/β-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma)

et al. 2009

Self Cite

View full text Add to dashboard Cite

Increasing evidence indicates that Notch signaling contributes to physiological processes, including development and differentiation, as well as tumorigenesis, either as a tumor promoter or suppressor, depending on cellular context, expression levels and cross talk with other signaling systems. Recent studies reported absent or minimal Notch-1 expression in neuroendocrine tumors of the lung and gastrointestinal tract, suggesting a tumor-suppressor function of Notch-1. Merkel cell carcinoma is a rare and highly aggressive primary cutaneous neuroendocrine carcinoma. Because no information is available on Notch-1 expression in this tumor, we have investigated a series of 31 Merkel cell carcinoma for Notch-1 immunoreactivity.Immunoreactivities for E-cadherin and b-catenin were also analyzed. All but 1 Merkel cell carcinoma (30 of 31) retained cytoplasmic and membrane Notch-1 expression in more than 50% of cells. b-Catenin displayed a prevalent membrane-associated staining in 30 of 31 cases, and 22 cases showed more than 50% of immunoreactive cells whereas nuclear b-catenin was seen only in 2 of 31 cases. E-cadherin membranous expression was remarkably low, as only 1 of 26 cases was found positive in more than 50% of cells. In contrast with neuroendocrine tumors in other tissues, evident Notch-1 expression was found in Merkel cell carcinoma. This finding does not support a tumor-suppressor function of Notch-1 in Merkel cell carcinoma. Downregulation of E-cadherin and diffuse membranous b-catenin expression suggest a dysregulation of the E-cadherin/ b-catenin complex in Merkel cell carcinoma. This may contribute to local invasion and distant metastasis.

show abstract

Section: Notch-1 Expression In Merkel Cell Carcinoma J Panelos Et Almentioning

confidence: 93%

Expression of Notch-1 and alteration of the E-cadherin/β-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma)

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among them, we found JAG-1 and CDK6 which are supposed to play important roles in melanoma and which were extensively investigated in the past. [48][49][50][35][36][37]64 Strikingly, the Notch-ligand JAG-1, which was reported to be upregulated in melanoma, 50,64 was found downregulated after binding of RBP2-H1/JARID1B to its promoter region. JAG-1 is discussed to play a role in many central melanoma processes, such as melanocytic differentiation, stem cell renewal and, together with p21, cyclinD1, cyclinE and cdk4,6,2, cell cycle control.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we suggest that, at least in case of these 23 genes, RBP2-H1 might exert transcriptional control by direct interaction with respective regulatory chromosomal elements. Within this intersectional group of genes, the melanoma-relevant genes JAG-1 [48][49][50] and CDK6 [35][36][37][38] were included as well as 1 new candidate melanoma gene, DYRK1A, which was reported to be downregulated in highly metastatic melanoma cells. [63][64][65] RBP2-H1/JARID1B re-expression re-constitutes anti-tumorigenic mechanisms in melanoma cells…”

Section: Rbp2-h1/jarid1b Binds To a Multitude Of Human Chromosomal Rementioning

confidence: 99%

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

Roesch

Mueller²,

Stempfl

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

The RBP2-H1/JARID1B nuclear protein belongs to the ARID family of DNA-binding proteins and is a potential tumor suppressor that is lost during melanoma development. As we have recently shown, one physiological function of RBP2-H1/JARID1B is to exert cell cycle control via maintenance of active retinoblastoma protein. We now add new evidence that RBP2-H1/JARID1B can also directly regulate gene transcription in a reporter assay system, either alone or as part of a multimolecular complex together with the developmental transcription factors FOXG1b and PAX9. In melanoma cells, chromatin immunoprecipitation combined with promoter chip analysis (ChIP-on-chip) suggests a direct binding of re-expressed RBP2-H1/JARID1B to a multitude of human regulatory chromosomal elements (promoters, enhancers and introns). Among those, a set of 23 genes, including the melanoma relevant genes CDK6 and JAG-1 could be confirmed by cDNA microarray analyses to be differentially expressed after RBP2-H1/JARID1B re-expression. In contrast, in nonmelanoma HEK 293 cells, RBP2-H1/JARID1B overexpression only evokes a minor transcriptional response in cDNA microarray analyses. Because the transcriptional regulation in melanoma cells is accompanied by an inhibition of proliferation, an increase in caspase activity and a partial cell cycle arrest in G1/0, our data support an anti-tumorigenic role of RBP2-H1/JARID1B in melanocytic cells. ' 2007 Wiley-Liss, Inc.Key words: melanoma; transcription; gene expression; retinoblastoma protein binding protein; apoptosisIn 1999, our group detected a gene transcript suppressed by UV-B in normal human melanocytes (Acc. No. AF087481, 1 ). Based on its homology to the previously described RBP2, 2 this new gene was termed retinoblastoma binding protein 2-homolog 1 (RBP2-H1). Subsequent expression studies revealed a frequent loss of RBP2-H1 in the majority of advanced and metastatic melanomas in vivo and in many melanoma cell lines, whereas benign melanocytic tumors, normal tissues and other cancer types mostly retain RBP2-H1. 1,3 Recently, we showed that RBP2-H1 has a tumor suppressive activity partly due to binding and stabilization of hypophosphorylated retinoblastoma protein (pRb) leading to maintenance of pRb-mediated cell cycle control. 4 As a result of truncation studies, we located the pRb-binding activity of RBP2-H1 to its C-term, containing a homolog region of the non-T/E1A-pRb binding domain known from other retinoblastoma binding proteins like RBP2. 5 Moreover, RBP2-H1 and its splicing variants PLU-1 and RBBP2H1a contain further well-conserved domains known to be involved in direct gene regulation and chromatin homeostasis, e.g. 3 PHD motifs and the ARID (AT-rich interacting) DNA-binding domain. [6][7][8][9] Although the 3 splicing variants show a cDNA sequence homology of more than 98%, RBP2-H1 differs from PLU-1 and RBBP2H1a by an additional exon encoding a region with strong homology to chromosomal ALU repeats. Thus, previously reported differences in tissue expression (PLU-1 shows a restricted expre...

show abstract

“…Additionally, recurrent amplification was found on 1p12, the smallest amplicon including only NOTCH2 (Figure 2e). Intriguingly, a recent study has shown that Notch2 protein is significantly up regulated in dysplastic nevi and melanomas but not in common melanocytic nevi (Massi et al, 2006). Notch proteins are transmembrane receptors that are activated by specific ligands and increase signaling via the MAPK and PI3K pathways in melanoma cells (Liu et al, 2006).…”

Section: G Jönsson Et Almentioning

confidence: 99%

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

et al. 2007

View full text Add to dashboard Cite

Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.

show abstract

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

Cited by 94 publications

References 35 publications

Expression of Notch-1 and alteration of the E-cadherin/β-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma)

Expression of Notch-1 and alteration of the E-cadherin/β-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma)

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

Contact Info

Product

Resources

About