DEK expression in melanocytic lesions (original) (raw)
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Melanoma Proliferation and Chemoresistance Controlled by the DEK Oncogene
Cancer Research, 2009
Gain of chromosome 6p is a consistent feature of advanced melanomas. However, the identity of putative oncogene(s) associated with this amplification has remained elusive. The chromatin remodeling factor DEK is an attractive candidate as it maps to 6p (i.e. within common melanomaamplified loci). Moreover, DEK expression is increased in metastatic melanomas, although the functional relevance of this induction remains unclear. Importantly, in other tumor types, DEK can display various tumorigenic effects, in part through its ability to promote proliferation and inhibit p53-dependent apoptosis. Here, we report a generalized upregulation of DEK protein in cells from aggressive melanomas. In addition, we provide genetic and mechanistic evidence to support a key role of DEK in the maintenance of malignant phenotypes of melanoma cells. Specifically, we show that long-term DEK downregulation by independent shRNAs resulted in premature senescence of a variety of melanoma cell lines. Short-term abrogation of DEK expression was also functionally relevant, as it attenuated the traditional resistance of melanomas to DNA damaging agents. Unexpectedly, DEK shRNA had no impact on p53 levels or p53-dependent apoptosis. Instead, we identified a new role for DEK in the transcriptional activation of the antiapoptotic MCL-1. Other MCL-1 related factors such as BCL-2 or BCL-x L were unaffected by changes in the endogenous levels of DEK, indicating a selective impact of this gene on the apoptotic machinery of melanoma * Requests for reprints: María S. Soengas, Centro Nacional de Investigaciones Oncológicas, CNIO, Melchor Fernández Almagro 3. Madrid 28049, Spain. Phone: 34-91-732 8000-Ext 3680. msoengas@cnio.es
Expression of Melan-A and Ki-67 in Desmoplastic Melanoma and Desmoplastic Nevi
The American Journal of Dermatopathology, 2004
Background: Desmoplastic melanoma (DMM) is an uncommon melanoma variant with a distinct morphology, including a prominent spindle cell component with fibrosis, as well as a distinct immunohistochemical profile. Histologically, the spindle cell component of DMM can be confused with sclerotic/desmoplastic nevi, nonpigmented blue nevi, scar, and neural tumors. The histological distinction between sclerotic/desmoplastic/blue nevi and DMM using standard light microscopic techniques can be exceedingly subtle. Therefore, we investigated whether immunohistochemical staining for Melan-A and Ki-67 expression can be used to discriminate these lesions, distinguishing between epithelioid and spindle cell compartments of the lesions. Design: Fifty cases of DMM and 13 cases of sclerotic/desmoplastic/blue nevi were identified. Standard immunohistochemical techniques were used with antibodies towards HMB-45, Melan-A (A103), and Ki-67; 43 of 50 DMM cases were available for staining with Melan-A, 42 of 50 for HMB-45, and 31 of 50 cases were stained with Ki-67. All 13 nevi were stained for Melan-A and 8 for Ki-67. Immunoreactivity to Ki-67 antibody was scored as 0 to 5%, 6 to 10%, 11 to 30%, or greater than 30% positive tumor cells. Results: Only 3 of 43 and 3 of 42 of spindle cell compartments of DMMs were positive for Melan-A and HMB-45, respectively. Focal staining of epithelioid cells in the junctional component or superficial dermis was observed in 33% (14/43). In contrast, 100% of the 13 nevi were strongly positive for Melan-A (P , 0.001). Seventeen melanomas (55%) were 0 to 5% positive for Ki-67, five (16%) fell into the 6 to 10% category, three (10%) were between 11 and 30%, and six (19%) were at least focally greater than 30% positive. All 8 nevi (100%) had less than 5% positive cells for Ki-67 (P = 0.02), with only 2 cases having more than 2% positive cells. Conclusion: The sclerotic/desmoplastic and hypopigmented blue nevi were uniformly positive for Melan-A, while the vast majority of DMM were negative in their spindle cell compartments. Melan-A is very useful in distinguishing between DMM and sclerotic nevi. Ki-67 appears to be an inconsistent marker for DMM. However, a high labeling index (over 5%) may be used as a clue in diagnosing DMM.
Altered molecular pathways in melanocytic lesions
International Journal of Cancer, 2009
To identify gene expression changes in melanocytic lesions, biopsies from 18 common nevi (CMN), 11 dysplastic nevi (DN), 8 radial and 15 vertical growth phase melanomas (RGPM, VGPM), and 5 melanoma metastases (MTS) were analyzed using whole genome microarrays. The comparison between CMN and RGPM showed an enrichment of Gene Ontology terms related to inter and intracellular junctions, whereas the transition from RGPM to VGPM underlined the alteration of apoptosis. Upregulation of genes involved in dsDNA break repair and downregulation of cellular adhesion genes were observed in MTS with respect to VGPM. DN exhibited rather heterogeneous molecular profiles, with some proliferation genes expressed at higher levels than in CMN, altered regulation of transcription compared to RGPM and a subset of processes, such as mismatch repair, equally expressed as in VGPM. Furthermore, the expression profile of genes involved into cellular detoxification and antigen presentation split them into two classes, with different proliferation potential. Finally, molecular profiling of individual lesions identified altered biological processes, such as regulation of apoptosis, regulation of transcription and T-cell activation, not associated with specific histological classes but rather with subgroups of samples without apparent relationship. This holds true for dysplastic nevi in particular. Our data indicate that generally the intersection between stage specific and sample specific molecular alterations may lead to a more precise determination of the individual progression risk of melanocytic lesions.
Higher Expression of the Heterogeneous Nuclear Ribonucleoprotein K in Melanoma
Annals of Surgical Oncology, 2010
Background. The heterogeneous nuclear ribonucleoprotein (hnRNP) K is an essential RNA and DNA binding protein involved in gene expression and signal transduction. The role of hnRNP K in cancer is relatively understudied. However, several cellular functions strongly indicate that hnRNP K is involved in tumorigenesis. Oncogenes c-Src, c-myc, and eIF4E are regulated by hnRNP K. We have shown an increased cytoplasmic hnRNP K in pancreatic cancer. In the present study, we investigated the altered expression of hnRNP K protein and its correlation with p-ERK in melanoma using human melanoma cell lines and tissue microarray. Materials and Methods. The protein levels of hnRNP K and p-ERK in 8 human melanoma cell lines and a melanoma progression tissue microarray containing 80 melanoma, 23 dysplastic nevi, and 14 benign nevi specimens were analyzed using Western blot and immunohistochemistry analysis. hnRNP K was knocked down by siRNA, and its effect on melanoma cells was assessed. Results. We showed a higher hnRNP K protein level in both melanoma cell lines and melanoma tissue specimens, which correlated with a higher c-myc expression. An increase in the cytoplasmic hnRNP K and eIF4E protein levels in melanoma cells is also seen. p-ERK level was also higher in dysplastic nevi and melanoma tissues, but did not correlate with hnRNP K protein level. We then demonstrated that knocking down of hnRNP K by siRNA inhibited melanoma cell growth and colony formation, as well as c-myc expression.
Cancer Biology & Therapy, 2004
Microarray profiling is a powerful approach to establish gene expression patterns for different histopathological stages of a malignancy, and at the same time, to identify individual genes that may have important functions in the early and/or advanced stages of a neoplasm. To identify genes that hitherto have not been shown to be expressed or play a role in advanced-stage melanomas, we conducted microarray analyses with RNAs from primary melanoma and melanoma-positive lymph node specimens. Using RT-PCR, quantitative, real-time RT-PCR, and fluorochrome oligonucleotide-based optical imaging, we established the level and pattern of expression of five of the identified known genes [Suppression of Tumorigenicity 13 (ST13), Cystatin 8 (CST-8), Dyskeratosis Congentia 1 (DKC1), Neuroendocrine Secretory Protein 55 (NESP55), Niemann-Pick Disease, type C2 (NP-C2)], and a gene with unknown function (16.7 kD Hypothetical Protein) in benign and atypical nevocytic lesions, advanced-stage melanomas, and melanoma-positive lymph nodes. © 2 0 0 4 L a n d e s B i o s c i e n c e. N o t f o r d i s t r i b u t i o n .
Modern Pathology, 2009
Melanoma may be difficult to identify histologically and relatively high rates of misdiagnosis leads to many malpractice claims. Currently separation of melanomas from nevi is based primarily on light microscopic interpretation of hematoxylin and eosin stained sections with limited assistance from immunohistology. To increase the accuracy of discrimination of benign and malignant melanocytic lesions we identified DNA microarray-derived gene expression profiles of different melanocytic lesions and evaluated the performance of these gene signatures as molecular diagnostic tools in the molecular classification and separation of melanomas and nevi. Melanocyte-derived cells were isolated by laser capture microdissection from 165 formalin-fixed and paraffin-embedded melanocytic nevi and melanoma tissue sections. RNA was isolated, amplified, labeled, and hybridized to a custom DNA microarray. In all 120 samples were used to identify differentially expressed genes and generate a gene expression classifier capable of distinguishing between melanomas and nevi. These classifiers were tested by the leave-one-out method and in a blinded study. RT-PCR verified the results. Unsupervised hierarchical clustering identified two distinct lesional groups that closely correlated with the histopathologically identified melanomas and nevi. Analysis of gene expression levels identified 36 significant differentially expressed genes. In comparison with nevi, melanomas expressed higher levels of genes promoting signal transduction, transcription, and cell growth. In contrast, expression of L1CAM (homolog) was reduced in melanomas relative to nevi. Genes differentially expressed in melanomas and nevi, on the basis of molecular signal, sub classified a group of unknown melanocytic lesions as melanomas or nevi and had high concordance rates with histopathology. Gene signatures established using DNA microarray gene expression profiling can distinguish melanomas from nevi, indicating the feasibility of using molecular classification as a supplement to standard histology. Our successful use of a standard formalin-fixed and paraffin-embedded tissue further supports the practicability of combining molecular diagnostic testing with histopathology in evaluation of difficult melanocytic lesions.
Expression signatures of early-stage and advanced medaka melanomas
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2017
Melanoma is one of the most aggressive tumors with a very low survival rate once metastasized. The incidence of newly detected cases increases every year suggesting the necessity of development and application of innovative treatment strategies. Human melanoma develops from melanocytes localized in the epidermis of the skin to malignant tumors because of deregulated effectors influencing several molecular pathways. Despite many advances in describing the molecular changes accompanying melanoma formation, many critical and clinically relevant molecular features of the transformed pigment cells and the underlying mechanisms are largely unknown. To contribute to a better understanding of the molecular processes of melanoma formation, we use a transgenic medaka melanoma model that is well suited for the investigation of melanoma tumor development because fish and human melanocytes are both localized in the epidermis. The purpose of our study was to gain insights into melanoma developmen...
Clinics in laboratory medicine, 2011
Melanoma is the most serious type of skin cancer. Unfortunately, treatment has progressed little and advanced melanoma has appalling survival rates. A goal of molecular analysis is to fully describe the alterations that underpin melanoma's clinical phenotype so that diagnosis can be more accurate, outcome can be predicted with greater confidence, and treatment that is tailored to the patient can be given. This article describes the handful of "signature" changes that are known to occur, describes how some recent studies have shed light on changes beyond this signature, and finally discusses the impact of molecular pathology for practicing histopathologists.