Identification of Core Genes and Pathways in Melanoma Metastasis via Bioinformatics Analysis

Metastasis is the leading cause of melanoma-related mortality. Current therapies are rarely curative for metastatic melanoma, revealing the urgent need to identify more effective preventive and therapeutic targets. This study aimed to screen the core genes and molecular mechanisms related to melanoma metastasis. A gene expression profile, GSE8401, including 31 primary melanoma and 52 metastatic melanoma clinical samples, was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between melanoma metastases and primary melanoma were screened using GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses of DEGs were performed using the Database for Annotation Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape with Molecular Complex Detection (MCODE) plug-in tools were utilized to detect the protein–protein interaction (PPI) network among DEGs. The top 10 genes with the highest degrees of the PPI network were defined as hub genes. In the results, 425 DEGs, including 60 upregulated genes and 365 downregulated genes, were identified. The upregulated genes were enriched in ECM–receptor interactions and the regulation of actin cytoskeleton, while 365 downregulated genes were enriched in amoebiasis, melanogenesis, and ECM–receptor interactions. The defined hub genes included CDK1, COL17A1, EGFR, DSG1, KRT14, FLG, CDH1, DSP, IVL, and KRT5. In addition, the mRNA and protein levels of the hub genes during melanoma metastasis were verified in the TCGA database and paired post- and premetastatic melanoma cells, respectively. Finally, KRT5-specific siRNAs were utilized to reduce the KRT5 expression in melanoma A375 cells. An MTT assay and a colony formation assay showed that KRT5 knockdown significantly promoted the proliferation of A375 cells. A Transwell assay further suggested that KRT5 knockdown significantly increased the cell migration and cell invasion of A375 cells. This bioinformatics study provided a deeper understanding of the molecular mechanisms of melanoma metastasis. The in vitro experiments showed that KRT5 played the inhibitory effects on melanoma metastasis. Therefore, KRT5 may serve important roles in melanoma metastasis.

Postoperative assessment of malignant melanoma aggressiveness for further treatment personalization

The aim of the study was to develop, implement and evaluate a method for predicting the aggressiveness of primary melanoma after surgical removal.It was established that the method for predicting tumor aggressiveness allows to determine the degree of aggressiveness, life expectancy, and to identify patients with poor prognosis in order to individualize treatment. The survival rate of patients was found to depend on the degree of aggressiveness of the tumor. A group of patients with stages 0-IIa (16,4 %) and tumor aggressiveness Grade II was identified as having a potentially high risk of progression, which can help individualize treatment for this category of patients. Using the method for predicting disease progression may potentially expand the scope of indications for further personalized treatment.

Melanoma Management during the COVID-19 Pandemic Emergency: A Literature Review and Single-Center Experience

Background: The current COVID-19 pandemic has influenced the modus operandi of all fields of medicine, significantly impacting patients with oncological diseases and multiple comorbidities. Thus, in recent months, the establishment of melanoma management during the emergency has become a major area of interest. In addition to original articles, case reports and specific guidelines for the period have been developed. Purpose: This article aims to evaluate whether melanoma management has been changed by the outbreak of COVID-19, and if so, what the consequences are. We summarized the main issues concerning the screening of suspicious lesions, the diagnosis of primary melanoma, and the management of early-stage and advanced melanomas during the pandemic. Additionally, we report on the experience of our dermatological clinic in northern Italy. Methods: We performed a literature review evaluating articles on melanomas and COVID-19 published in the last two years on PubMed, as well as considering publications by major healthcare organizations. Concerning oncological practice in our center, we collected data on surgical and therapeutic procedures in patients with a melanoma performed during the first months of the pandemic. Conclusions: During the emergency period, the evaluation of suspicious skin lesions was ensured as much as possible. However, the reduced level of access to medical care led to a documented delay in the diagnosis of new melanomas. When detected, the management of early-stage and advanced melanomas was fully guaranteed, whereas the follow-up visits of disease-free patients have been postponed or replaced with a teleconsultation when possible.

An Observational Study on the Molecular Profiling of Primary Melanomas Reveals a Progression Dependence on Mitochondrial Activation

Melanoma in advanced stages is one of the most aggressive tumors and the deadliest of skin cancers. To date, the histopathological staging focuses on tumor thickness, and clinical staging is a major estimate of the clinical behavior of primary melanoma. Here we report on an observational study with in-depth molecular profiling at the protein level including post-translational modifications (PTMs) on eleven primary tumors from melanoma patients. Global proteomics, phosphoproteomics, and acetylomics were performed on each sample. We observed an up-regulation of key mitochondrial functions, including the mitochondrial translation machinery and the down-regulation of structural proteins involved in cell adhesion, the cytoskeleton organization, and epidermis development, which dictates the progression of the disease. Additionally, the PTM level pathways related to RNA processing and transport, as well as chromatin organization, were dysregulated in relation to the progression of melanoma. Most of the pathways dysregulated in this cohort were enriched in genes differentially expressed at the transcript level when similar groups are compared or metastasis to primary melanomas. At the genome level, we found significant differences in the mutation profiles between metastatic and primary melanomas. Our findings also highlighted sex-related differences in the molecular profiles. Remarkably, primary melanomas in women showed higher levels of antigen processing and presentation, and activation of the immune system response. Our results provide novel insights, relevant for developing personalized precision treatments for melanoma patients.

Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression

While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in WM983B metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and prolongs survival of mice. NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration, and increasing NTF2 expression leads to changes in nuclear size, nuclear lamin A levels, and chromatin organization. Thus, ectopic expression of NTF2 in WM983B metastatic melanoma abrogates phenotypes associated with advanced stage cancer both in vitro and in vivo, concomitantly altering nuclear and chromatin structure and generating a gene expression profile with characteristics of primary melanoma. We propose that NTF2 is a melanoma tumor suppressor and could be a novel therapeutic target to improve health outcomes of melanoma patients.

Exploration and Validation of Metastasis-associated Genes for Skin Cutaneous Melanoma

Background: Skin cutaneous melanoma is a malignant and highly metastatic skin tumor, and its morbidity and mortality are still rising worldwide. However, the molecular mechanisms that promote melanoma metastasis are unclear. Methods: Two datasets (GSE15605 and GSE46517) were retrieved to identify the differentially expressed genes (DEGs), including 23 normal skin tissues (N), 77 primary melanoma tissues (T) and 85 metastatic melanoma tissues (M). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed to explore the functions of the DEGs. The protein–protein interaction (PPI) network was constructed using the STRING tool and Cytoscape software. We used the cytoHubba plugin of Cytoscape to identify the most significant hub genes by five topological analyses (Degree, Bottleneck, MCC, MNC, and EPC). Hub gene expression was validated using the UALCAN website. Clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Finally, we explored the association between metastasis-associated genes and immune infiltrates through the Tumor Immune Estimation Resource (TIMER) database and performed drug-gene interaction analysis using the Drug-Gene Interaction database.Results: A total of 294 specific genes were related to melanoma metastasis and were mainly involved in the positive regulation of locomotion, mitotic cell cycle process, and epithelial cell differentiation. Four hub genes (CDK1, FOXM1, KIF11, and RFC4) were identified from the cytoHubba plugin of Cytoscape. CDK1 was significantly upregulated in metastatic melanoma compared with primary melanoma, and high expression of CDK1 was positively correlated with poor prognosis. We found that CDK1 expression correlated positively with the infiltration levels of macrophage cells (Rho = -0.164, P = 2.02e-03) and neutrophil cells (Rho = 0.269, P = 2.72e-07) in SKCM metastasis. In addition, we identified that CDK1 had a close interaction with 10 antitumor drugs. Conclusions: CDK1 was identified as a hub gene involved in the progression of melanoma metastasis and may be regarded as a therapeutic target for melanoma patients to improve prognosis and prevent metastasis in the future.

Primary malignant melanoma of the nipple: a case report

Primary melanoma origi­nating on the female nipple remains an extremely rare variant of malignant melanoma and only a few cases haves been reported in the literature. We describe a case of a patient admitted for a black pigment deposition on the left nipple. Surgical resection of the left nipple and areola with clear margins and an axillary lymph node dissection was performed confirming the diagnosis of non-invasive superficial spreading melanoma.

Excision Margin and Survival in Patients with High-Risk, Primary Cutaneous Melanoma: A Retrospective Study Based on Surveillance Epidemiology and End Result (SEER) Database

<b><i>Objectives:</i></b> The optimal excision margin of primary cutaneous melanoma greater than 2 mm in thickness is still a controversial topic. The aim of the present study was to compare the long-term survival between narrow and wide excision margins in the surgical excision of patients with high-risk primary melanoma. <b><i>Methods:</i></b> We chose the patients with primary melanoma of the skin thicker than 2 mm in The Surveillance, Epidemiology, and End Results database. Patients were divided into a narrow margin group (1–2 cm) and a wide margin group (&#x3e;2 cm) according to the resection margin information. The primary outcome was overall survival and disease-specific survival. <b><i>Results:</i></b> From 2004 to 2015, a total of 2,772 patients diagnosed as having melanoma of the skin were recruited into this study and were assigned to the narrow margin group (<i>n</i> = 1996) and the wide margin group (<i>n</i> = 776). A total of 1,098 patients died during the follow-up, and 681 of these were due to melanoma. There were 779 deaths in the narrow margin group and 319 deaths in the wide margin group (HR: 0.96, 95% CI: 0.84–1.10, <i>p</i> = 0.26). A total of 490 melanoma-specific deaths were reported in the narrow margin group and 191 were reported in the wide margin group (HR: 1.01, 95% CI: 0.85–1.19, <i>p</i> = 0.91). <b><i>Conclusions:</i></b> Wider excision margin greater than 2 cm did not provide any additional therapeutic benefits compared to narrow excision margin between 1 and 2 cm. A 2-cm margin is adequate and safe for high-risk primary melanoma of the skin thicker than 2 mm.