Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and ...Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.展开更多
Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding o...Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.展开更多
Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effect...Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effects.Regional chemotherapy for UM liver metastases includes hepatic ar ter y infusion(HAI),transarterial chemoembolization(TACE),and isolated hepatic perfusion(IHP).In this review,we aim to examine the efficacy of regional chemotherapy and compare HAI,TACE,and IHP in terms of overall survival(OS).The three approaches showed no obvious difference in OS results.展开更多
Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and in...Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and integrin-binding protein 1 (CIB1) is emerging as an important factor in tumor progression. Purpose: To determine the contribution of CIB1 in the diagnosis of UVM. Method: Immunohistochemical staining is used to detect the CIB1 expression level, while Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN online tools were used to analyze patient survival and CIB1 correlation genes in UVM. Integrative analysis using STRING and GeneMANIA predicted the correlated genes with CIB1 in UVM. Results: CIB1 expression level in UVM was significantly enhanced when compared with that in paracancerous tissues. A higher CIB1 expression level resulted in a significantly worse disease-free survival as well as overall survival. Moreover, the survival probability of patients was associated with body weight and gender of the patients with UVM. The correlated genes with CIB1 in UVM, and the similarity of the genes in UVM expression and survival heatmap were verified. Furthermore, Gene ontology enrichment analysis revealed that CIB1 and its correlated genes are significantly enriched in ITGA2B-ITGB3-CIB1 complex, regulation of intracellular protein transport and regulation of ion transport. Conclusions: Our novel findings suggested that CIB1 might be a potential diagnostic predictor for UVM, and might contribute to the potential strategy for UVM treatment by targeting CIB1.展开更多
AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 a...AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 and its downstream targets.METHODS: Quantitative reverse transcription polymerase chain reaction(qR T-PCR) was used to detect microR NA-21 expression in normal uveal tissue and uveal melanoma cell lines. Lenti-virus expression system was used to construct OCM-1, MuM-2 B and M619 cell line with stable overexpression and inhibition of microR NA-21. In vitro cell function tests such as cell proliferation, cell apoptosis, cell circle and abilities of migration and invasion were examined by MTT, Brd U assay, flow cytometry, transwell assay and Matrigel invasion assay respectively. The target gene was predicted by bioinformatics and confirmed by using a dual luciferase reporter assay. The expression of p53 and its suspected downstream targets LIM and SH3 protein 1(LASP1) and glutathione S transferase pi(GST-Pi) were determined by qR T-PCR in mR NA level and Western blotting analysis in protein level. Finally, the effect of microR NA-21 in a xenograft tumor model was assessed in four-week-old BALB/c nude mice. RESULTS: Compared to normal uveal melanoma, expressions of micro RNA-21 were significantly higher in uveal melanoma cell lines. Overexpression of microR NA-21 promoted proliferation, migration, and invasion of OCM-1, M619 and MuM-2 B cells, while inhibition of microR NA-21 reveal opposite effects. Wild type p53 was identified as a target gene of micro RNA-21-3 p, and proved by dual luciferase reporter assay. Up-regulated micro RNA-21 inhibited the expression of wild type p53 gene, and the increased expression of LASP1 in mR NA level and protein level, while down-regulated microR NA-21 presented opposite way. However, GST-pi showed the potential pattern as expected, but relative mR NA level showed no statistically significant difference in OCM-1 cells. Furthermore, the mR NA expression of GST-pi was decreased in microR NA-21 overexpressing Mu M-2 B, and increased in M619 cells with inhibition of microR NA-21. In vivo, inhibition of microR NA-21 reduced tumor growth with statistically significant difference.CONCLUSION: These findings provide novel insight into molecular etiology of microR NA-21 in uveal melanoma cell lines, and suggest that microR NA-21 might be a potential candidate for the diagnosis and prognostic factor of human uveal melanoma.展开更多
AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM pat...AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM patients were determined by real-time polymerase chain reaction(RT-PCR).The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205.Several epithelial-to-mesenchymal transition(EMT)-related proteins were screened by Western blotting.UM clinical samples from The Cancer Genome Atlas(TCGA)were applied to search for potential protein interaction.Pearson’s correlation analysis was applied to estimate co-expression between genes.Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205.RESULTS:The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples.Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miR NA-205 overexpression.The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42(CDC42).After database searching and sequence alignment,we identified that Neuropilin 1(NRP1)had binding sites for both miRNA-145 and miRNA-205.CONCLUSION:The miRNA-145 and miRNA-205 can reduce the proliferation,migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.展开更多
AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHOD...AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODS:UM expression profile data were downloaded from the Cancer Genome Atlas(TCGA)and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration.The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis(ss GSEA)method,and the immune cell infiltration of a single specimen was evaluated.Finally,the specimens were divided into high and low infiltration groups.The differential expression between the two groups was analyzed using the R package‘edge R’.Univariate,multivariate and Least Absolute Shrinkage and Selection Operator(LASSO)Cox regression analyses were performed to explore the prognostic value of TMErelated lncRNAs.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional analyses were also performed.The Connectivity Map(CMap)data set was used to screen molecular drugs that may treat UM.RESULTS:A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups.Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis.Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements.Among 269 differentially expressed lncRNAs,69 were up-regulated and 200 were down-regulated.Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age,TNM stage,tumor base diameter,and low and high risk indices had significant prognostic value.We screened the potential small-molecule drugs for UM,including W-13,AH-6809 and Imatinib.CONCLUSION:The prognostic markers identified in this study are reliable biomarkers of UM.This study expands our current understanding of the role of TME-related lncRNAs in UM genesis,which may lay the foundations for future treatment of this disease.展开更多
AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patie...AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas(TCGA)database and further analyzed.The SPSS 24.0 statistical software package was used for statistical analyses.To investigate the potential function of SNHG15 in UM,we conducted in-depth research on Gene Set Enrichment Analysis(GSEA).RESULTS:The univariate analysis revealed that the age,tumor diameter,pathological type,extrascleral extension,cancer status,and high expression of SNHG15 were statistical risk factors for death from all causes.The multivariate analysis suggested that the mR NA expression level of SNHG15 was an independent risk factor for death from all causes,as was age and pathological type.KaplanMeier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis.In addition,SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage,metastasis and living status.Besides,the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status,pathologic stage,metastasis,and living status.Moreover,the GSEA indicated the potential pathways regulated by SNHG15 in UM.CONCLUSION:Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis.Besides,GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.展开更多
Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been r...Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been reported.Methods:Uveal melanoma-related articles and reviews published between 2005 and 2019 were retrieved in the Web of Science Core Collection on March 15,2020.Three bibliometric tools(HistCite,VOSviewer,and CiteSpace)were employed to conduct the current study.Results:A total of 3,404 publications related to uveal melanoma were identified,involving 3015 articles(88.57%)and 389 reviews(11.43%)with 65,429 co-cited references in 9 languages,which were published by 2,875 institutions in 66 countries/regions.The United States contributed to most publications(n=1427,41.92%),and the Thomas Jefferson University was involved in most of the studies(n=160,5.56%).Investigative Ophthalmology&Visual Science published the majority of the papers(n=175,5.14%),whereas Ophthalmology received the most co-citations(n=7050).Shields CL owned the most publications and co-citations(n=122 and 2151,respectively).Gene and molecular biology aspects,prevalence,the main prognosis factor,and treatment were the intellectual foundations of uveal melanoma research.In the field of uveal melanoma,emerging hotspots of uveal melanoma include epidemiologic characteristics,prognosis factors,mechanisms of uveal melanoma development,the use of novel predictive tools,and clinical applications of novel targeted drugs.Conclusion:This first bibliometric study focused on the integral tendency of the past 15 years,identified landmark items,and revealed current research hotspots in the field of uveal melanoma,which will provide references for clinicians and researchers,as well as an example of visualization analysis to explore research hotspots in other fields.展开更多
AIM:To present the multi-omics landscape of cutaneous melanoma(CM)and uveal melanoma(UM)from The Cancer Genome Atlas(TCGA).METHODS:The differentially expressed genes(DEGs)between CM and UM were found and integrated in...AIM:To present the multi-omics landscape of cutaneous melanoma(CM)and uveal melanoma(UM)from The Cancer Genome Atlas(TCGA).METHODS:The differentially expressed genes(DEGs)between CM and UM were found and integrated into a gene ontology enrichment analysis.Besides,the differentially expressed miRNAs were also identified.We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation.The differentially expressed transcription factors(TFs)were identified.RESULTS:Though CM had more mutational burden than UM,they shared several similarities such as the same rankings in diverse variant types.Except GNAQ and GNA11,the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM.On the transcriptomic level,4610 DEGs were found and integrated into a gene ontology enrichment analysis.We also identified 485 differentially expressed miRNAs.The methylation analysis showed that UM had a significantly higher methylation level than CM.The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo-and hypermethylation presented no obvious difference within these DEGs.Finally,116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM.CONCLUSION:This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels.Of notice,the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas,the different metastatic routes of CM and UM and the liver tropism of metastatic UM.展开更多
AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three d...AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines(OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib(EGF-R), everolimus(mTOR), selumetinib(MAPK), trametinib(MAPK) or the alkylphosphocholine erufosine(PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) dye reduction assay after 24 h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC_(50) was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, trametinib, and erufosine significantly decreased cell viability of all OMM cell lines(P<0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation(P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations(P<0.05). Besides an increase of necrotic cells after erufosine treatment(P<0.001), no changes in the number of dead cells for the other substances were observed.CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/m TOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.展开更多
AIM:To identify metastatic genes and mi RNAs and to investigate the metastatic mechanism of uveal melanoma(UVM).METHODS:GSE27831,GSE39717,and GSE73652 gene expression profiles were downloaded from the Gene Expression ...AIM:To identify metastatic genes and mi RNAs and to investigate the metastatic mechanism of uveal melanoma(UVM).METHODS:GSE27831,GSE39717,and GSE73652 gene expression profiles were downloaded from the Gene Expression Omnibus(GEO)database,and the limma R package was used to identify differentially expressed genes(DEGs).Gene Ontology(GO)term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed using the DAVID online tool.A comprehensive list of interacting DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software.The Cytoscape MCODE plug-in was used to identify clustered sub-networks and modules of hub genes from the proteinprotein interaction network.GEPIA online software was used for survival analysis of UVM patients(n=80)from the The Cancer Genome Atlas(TCGA)cohort.Oncomi R online software was used to find that the mi RNAs were associated with UVM prognosis from the TCGA cohort.Target Scan Human 7.2 software was then used to identify the mi RNAs targeting the genes.RESULTS:There were 1600 up-regulated genes and 1399 down-regulated genes.The up-regulated genes were mainly involved in protein translation in the cytosol,whereas the down-regulated genes were correlated with extracellular matrix organization and cell adhesion in the extracellular space.Among the 2999 DEGs,five genes,Znf391,Mrps11,Htra3,Sulf2,and Smarcd3 were potential predictors of UVM prognosis.Otherwise,three mi RNAs,hsa-mi R-509-3-5 p,hsa-mi R-513 a-5 p,and hsa-mi R-1269 a were associated with UVM prognosis.CONCLUSION:After analyzing the metastasis-related enriched terms and signaling pathways,the up-regulated DEGs are mainly involved in protein synthesis and cell proliferation by ribosome and mitogen-activated protein kinase(MAPK)pathways.However,the down-regulated DEGs are mainly involved in processes that reduced cell-cell adhesion and promoted cell migration in the extracellular matrix through PI3 K-Akt signaling pathway,focal adhesion,and extracellular matrix-receptor interactions.Bioinformatics and interaction analysis may provide new insights on the events leading up to the development and progression of UVM.展开更多
BACKGROUND Uveal melanoma is the most common primary intraocular malignant tumor affecting the eyes in adults.Nearly half of all primary uveal melanoma tumors metastasize;yet,there are currently no effective treatment...BACKGROUND Uveal melanoma is the most common primary intraocular malignant tumor affecting the eyes in adults.Nearly half of all primary uveal melanoma tumors metastasize;yet,there are currently no effective treatments for metastatic uveal melanoma.At the time of diagnosis,less than 4%of patients with uveal melanoma have detectable metastatic disease.Uveal melanoma disseminates hematogenously,with the most common site of metastasis being liver(93%),followed by lung(24%)and bone(16%).CASE SUMMARY A 57-year-old woman was diagnosed with a dysplastic nevus on her eyelid,which was histologically confirmed as malignant melanoma after resection.The patient had no evidence of metastasis to other organs and received both radiation therapy and chemotherapy.After systemic treatment,a metastatic left neck lymph node was found and another round of chemotherapy was performed after resection.Positron emission tomography-Computed Tomography tracking after completion of chemotherapy revealed two metastatic liver nodules.The patient underwent partial liver resection and showed no signs of recurrence at 1 year after surgery.CONCLUSION Surgery is an effective treatment for metastatic uveal melanoma.In patients with liver metastatic lesions,hepatectomy improves outcome.展开更多
Animal models are crucial for the study of tumorigenesis and therapies in oncology research.Though rare,uveal melanoma(UM)is the most common intraocular tumor and remains one of the most lethal cancers.Given the limit...Animal models are crucial for the study of tumorigenesis and therapies in oncology research.Though rare,uveal melanoma(UM)is the most common intraocular tumor and remains one of the most lethal cancers.Given the limitations of studying human UM cells in vitro,animal models have emerged as excellent platforms to investigate disease onset,progression,and metastasis.Since Greene’s initial studies on hamster UM,researchers have dramatically improved the array of animal models.Animals with spontaneous tumors have largely been replaced by engrafted and genetically engineered models.Inoculation techniques continue to be refined and expanded.Newer methods for directed mutagenesis have formed transgenic models to reliably study primary tumorigenesis.Human UM cell lines have been used to generate rapidly growing xenografts.Most recently,patient-derived xenografts have emerged as models that closely mimic the behavior of human UM.Separate animal models to study metastatic UM have also been established.Despite the advancements,the prognosis has only recently improved for UM patients,especially in patients with metastases.There is a need to identify and evaluate new preclinical models.To accomplish this goal,it is important to understand the origin,methods,advantages,and disadvantages of current animal models.In this review,the authors present current and historic animal models for the experimental study of UM.The strengths and shortcomings of each model are discussed and potential future directions are explored.展开更多
Background:Sharing biological material and clinical data from patients with uveal melanoma.Methods:Uveal melanoma is the most common intraocular malignancy in the adult population.Because uveal melanoma is primarily a...Background:Sharing biological material and clinical data from patients with uveal melanoma.Methods:Uveal melanoma is the most common intraocular malignancy in the adult population.Because uveal melanoma is primarily a sporadic cancer and familial cases are rare,it is difficult to prevent or detect it.Despite effective treatment of ocular tumors,more than 50%of patients develop incurable liver metastases mainly in the 5-10 years following the detection of the primary tumor.This cancer is relatively rare and the obtained biopsies are very small.About 20 samples are taken each year in Quebec.This provincial infrastructure is made of biological material from donors with uveal melanoma and a large clinical database.Collected tumor biopsies are used for culturing cell lines and the creation of a DNA/RNA library used for genomic and genetic studies.Results:This infrastructure plays an important role in the achievement of various research programs for a better understanding of genetic and environmental factors involved in the development of melanoma and the spread of metastasis.It allows collaboration with other researchers at a provincial,national and international level in order to make progress in basic and clinical research on uveal melanoma.Conclusions:The biological material and clinical data of this infrastructure are available upon request to VHRN members whose research project was approved by the ethics committee of the institution.展开更多
Background:Uveal melanoma(UM)is the most common primary eye tumor in adults,and the most frequent site of malignant transformation of the melanocytes after the skin.It spreads to the liver in half of the cases,and the...Background:Uveal melanoma(UM)is the most common primary eye tumor in adults,and the most frequent site of malignant transformation of the melanocytes after the skin.It spreads to the liver in half of the cases,and the death rate following the report of metastasis is 92%at 2 years.Hepatic tropism of UM cannot simply be explained by the blood circulatory system organization,and illustrates the“seed and soil”hypothesis that describes an interaction between tumor cells(seed)and a specific microenvironment(soil).We decided to focus our study on the synergic interaction between UM cells and hepatic stellate cells(HSC),whose role has been previously described in the metastatic progression of colon and pancreatic cancers.Furthermore,HSC have been found surrounding UM liver metastasis,and the UM secretome contains activating cytokines of hepatic stromal cells.Our hypothesis is that HSC provide a specific microenvironment in the liver enhancing the growth of UM cells and increasing their therapeutic resistance.Using an in vitro 3D model and an original xenograft mouse model,we aim to decipher the mechanisms of UM metastatic progression,in order to elaborate new therapeutic strategies.Methods:First,using an agar coating,spheroids were generated with UM cells and were allowed to grow for 72 h.These tumor spheroids were then embedded in Matrigel and the HSC conditioned medium was used to evaluate the impact of the HSC secretome on UM invasion.Next,an original in vivo xenograft mouse model was generated,in which metastatic UM cells were injected alone or with human HSC in the spleen of immunodeficient mice.This model allows us to evaluate in 3-6 weeks the metastatic potential of each cell population,and thus to determine the cooperation between HSC and UM cells in the liver.Results:The HSC conditioned medium increased the invasion of UM spheroids compared to non-conditioned medium in our in vitro model.In addition,UM cells inoculated in the mouse spleen alone or with human HSC were able to metastasize to the liver,and the host HSC were also recruited by UM metastases.Conclusions:Our preliminary results strongly suggest that the secretome of HSC provides a permissive microenvironment for UM metastatic progression.We now have to confirm these results by characterizing the secretome of HSC,in order to identify cytokines or growth factors that increase the invasion of the liver by UM.Our models can be used to test the efficacy of new therapeutic strategies targeting the UM microenvironment.展开更多
Background:Uveal melanoma(UM)is a malignant neoplasia that is composed of two main types of cells:spindle and epithelioid.There is a subset of neoplastic small epithelioid cells located predominantly in the infiltrati...Background:Uveal melanoma(UM)is a malignant neoplasia that is composed of two main types of cells:spindle and epithelioid.There is a subset of neoplastic small epithelioid cells located predominantly in the infiltrative tumor margins or surrounding blood vessels.The aim of this study is to characterize and evaluate the correlation between the presence of these small epithelioid cells and clinical outcome.Methods:The clinical-pathological features of 70 UM patients were evaluated.The presence of small epithelioid cells was quantified based on percentage of tumor volume,and they were characterized using melanocytic markers(HMB-45,Melan A and SOX-10),stem cell markers(CD133,CD24 and CD38),and T cell lymphocytes(CD3).Univariate and multivariate analyses were conducted.Clinical follow up was available for all patients.Results:The ratio of small epithelioid cell components of all 70 tumors ranged from 0%to 30%(median,1%).Thirty-nine tumors(55.7%)had areas with small epithelioid cells.Univariate analysis showed that mixed versus spindle cell,higher lymphocytic infiltration,macrophage infiltration,ciliary body involvement,and>5%of small epithelioid cell component had a significant negative impact on metastasis-free survival.Small epithelioid cell component>5%was present in 24 cases(34.3%).Of these,three were classified as spindle and 21 were mixed.Multivariate analysis revealed that a>5%small cell component was the most significant morphological adverse prognostic factor.Moreover,the small epithelioid cells were negative for HMB45,stem cell markers and CD3,and focally and weakly positive for MELAN A and SOX10.Conclusions:A high small epithelioid cell component is a strong negative prognostic indicator in patients with UM.展开更多
Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artific...Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artificial intelligence offers rule-based models that favor the research of human signaling processes.In this paper,we give an overview of the advantages of the formalism of symbolic models in medical biology and cell biology of the uveal melanoma.A language is described that allows us:(1)To define the system states and elements with their alterations;(2)To model the dynamics of the cellular system;and(3)To perform inference-based analysis with the logical tools of the language.展开更多
Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five norm...Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five normal uvea tissues.Next,bioinformatics analyses,including gene ontology(GO) analysis and pathway analysis,were applied to study these differentially expressed circRNAs to predict pathogenic pathways that may be involved.Quantitative real-time polymerase chain reaction(qRT-PCR) in 20 UM samples and 20 normal uvea samples was used to confirm the circRNA expression profiles obtained from the microarray data.Finally,we analyzed the interaction between validated circRNAs and their potential cancer-associated miRNA targets.Results: In total,50,579 circRNAs [fold change(FC) ≥2.0; P<0.05],including 20,654 up-regulated and 29,925 down-regulated circRNAs,were identified as differentially expressed between UM tissues and normal uvea tissues.We used qRT-PCR to verify seven dysregulated circRNAs indicated by the microarray data,including hsa_circ_0119873,hsa_circ_0128533,hsa_circ_0047924,hsa_circ_0103232,hsa-circRNA10628-6,hsa_circ_0032148 and hsa_circ_0133460,which may be promising candidates to study future molecular mechanisms.Conclusions: This study explored,for the first time,the abnormal expression of circRNAs in UM and described the expression profile of circRNAs,providing a new potential target for the mechanism of UM and future treatment of UM.展开更多
AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting ...AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting kit-8(CCK-8) were performed to detect the cell viability. Flow cytometry was used to analyze cell cycle and apoptosis. Quantitative realtime polymerase chain reaction(qRT-PCR) and Western blot assays were performed to measure proliferation-related and apoptosis-related factors.RESULTS: Firstly, PTL decreased the viability of C918 and SP6.5 cells in a dose-dependent manner, and the effect of PTL on C918 cells was stronger than on SP6.5;however, it did not affect normal cells. Secondly, PTL increased the proportion of cell number at cell cycle G1 phase in C918 cells, and decreased the proportion of cell number at S phase, but the proportion did not change at G2 phase. In addition, PTL induced the apoptosis of C918 cells, and decreased the expressions of Cyclin D1, B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large(Bcl-XL). Also, PTL increased Cyclin inhibition protein 1(P21), Bcl-2-associated X protein(Bax), Cysteinyl aspartate specific proteinas-3(Caspase-3) and Caspase-9 expression. However, the expression of Caspase-8 was not changed. CONCLUSION: PTL inhibites proliferation and induces apoptosis in UM cells by arresting G1 phase and regulating mitochondrial pathway, however, it does not affect normal cells.展开更多
文摘Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.
基金supported by grants from Shanghai Key Clinical Specialty,Shanghai Eye Disease Research Center(Grant No.:2022Zz01003 to Xianqun Fan)the National Key Research and Development Plan(Grant No.:2018YFC1106100 to Xianqun Fan)+1 种基金the National Natural Science Foundation of China(Grant Nos.:12275178 to Shengfang Ge and 82103240 to Peiwei Chai)Innovative Research Team of High-level Local Universities in Shanghai(Grant Nos.:SHSMU-ZDCX20210902 to Renbing Jia and SHSMUZDCX20210900 to Xianqun Fan),the Science and Technology Commission of Shanghai(Grant No.:19JC1410200 to Xianqun Fan),and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital,Shanghai Jiao Tong university School of Medicine(Grant No.:JYJC202210 to Ai Zhuang).
文摘Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
基金Supported by National Natural Science Foundation of China(No.82141128)The Capital Health Research and Development of Special(No.2020-1-2052)+4 种基金Beijing Natural Science Foundation(No.7204245)Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z201100005520045,No.Z181100001818003)Scientific Research Common Program of Beijing Municipal Commission of Education(No.KM202010025018)Beijing Municipal Administration of Hospitals’Youth Programme(No.QML20190202)Beijing Dongcheng District Outstanding Talents Cultivating Plan(No.2018)。
文摘Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effects.Regional chemotherapy for UM liver metastases includes hepatic ar ter y infusion(HAI),transarterial chemoembolization(TACE),and isolated hepatic perfusion(IHP).In this review,we aim to examine the efficacy of regional chemotherapy and compare HAI,TACE,and IHP in terms of overall survival(OS).The three approaches showed no obvious difference in OS results.
文摘Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and integrin-binding protein 1 (CIB1) is emerging as an important factor in tumor progression. Purpose: To determine the contribution of CIB1 in the diagnosis of UVM. Method: Immunohistochemical staining is used to detect the CIB1 expression level, while Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN online tools were used to analyze patient survival and CIB1 correlation genes in UVM. Integrative analysis using STRING and GeneMANIA predicted the correlated genes with CIB1 in UVM. Results: CIB1 expression level in UVM was significantly enhanced when compared with that in paracancerous tissues. A higher CIB1 expression level resulted in a significantly worse disease-free survival as well as overall survival. Moreover, the survival probability of patients was associated with body weight and gender of the patients with UVM. The correlated genes with CIB1 in UVM, and the similarity of the genes in UVM expression and survival heatmap were verified. Furthermore, Gene ontology enrichment analysis revealed that CIB1 and its correlated genes are significantly enriched in ITGA2B-ITGB3-CIB1 complex, regulation of intracellular protein transport and regulation of ion transport. Conclusions: Our novel findings suggested that CIB1 might be a potential diagnostic predictor for UVM, and might contribute to the potential strategy for UVM treatment by targeting CIB1.
基金Supported by the National Natural Science Foundation of China (No.81570891 No.81272981)+3 种基金Beijing Natural Science Foundation (No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau (No.2014-2-003)the Capital Health Research and Development of Special (No.2016-1-2051)Hospitals’ Ascent Plan (No.DFL20150201)
文摘AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 and its downstream targets.METHODS: Quantitative reverse transcription polymerase chain reaction(qR T-PCR) was used to detect microR NA-21 expression in normal uveal tissue and uveal melanoma cell lines. Lenti-virus expression system was used to construct OCM-1, MuM-2 B and M619 cell line with stable overexpression and inhibition of microR NA-21. In vitro cell function tests such as cell proliferation, cell apoptosis, cell circle and abilities of migration and invasion were examined by MTT, Brd U assay, flow cytometry, transwell assay and Matrigel invasion assay respectively. The target gene was predicted by bioinformatics and confirmed by using a dual luciferase reporter assay. The expression of p53 and its suspected downstream targets LIM and SH3 protein 1(LASP1) and glutathione S transferase pi(GST-Pi) were determined by qR T-PCR in mR NA level and Western blotting analysis in protein level. Finally, the effect of microR NA-21 in a xenograft tumor model was assessed in four-week-old BALB/c nude mice. RESULTS: Compared to normal uveal melanoma, expressions of micro RNA-21 were significantly higher in uveal melanoma cell lines. Overexpression of microR NA-21 promoted proliferation, migration, and invasion of OCM-1, M619 and MuM-2 B cells, while inhibition of microR NA-21 reveal opposite effects. Wild type p53 was identified as a target gene of micro RNA-21-3 p, and proved by dual luciferase reporter assay. Up-regulated micro RNA-21 inhibited the expression of wild type p53 gene, and the increased expression of LASP1 in mR NA level and protein level, while down-regulated microR NA-21 presented opposite way. However, GST-pi showed the potential pattern as expected, but relative mR NA level showed no statistically significant difference in OCM-1 cells. Furthermore, the mR NA expression of GST-pi was decreased in microR NA-21 overexpressing Mu M-2 B, and increased in M619 cells with inhibition of microR NA-21. In vivo, inhibition of microR NA-21 reduced tumor growth with statistically significant difference.CONCLUSION: These findings provide novel insight into molecular etiology of microR NA-21 in uveal melanoma cell lines, and suggest that microR NA-21 might be a potential candidate for the diagnosis and prognostic factor of human uveal melanoma.
基金Supported by National Natural Science Foundation of China(No.81570891)Beijing Natural Science Foundation(No.7204245+6 种基金No.7151003)Scientific Research Common Program of Beijing Municipal Commission of Education(No.KM202010025018)Beijing Municipal Administration of Hospitals’Youth Programme(No.QMS20190202)Beijing Municipal Administration of Hospitals,Ascent Plan(No.DFL20150201)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(2014-2-003)The Capital Health Research and Development of Special(2016-1-2051)Beijing Dongcheng District Outstanding Talents Cultivating Plan(2018)。
文摘AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM patients were determined by real-time polymerase chain reaction(RT-PCR).The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205.Several epithelial-to-mesenchymal transition(EMT)-related proteins were screened by Western blotting.UM clinical samples from The Cancer Genome Atlas(TCGA)were applied to search for potential protein interaction.Pearson’s correlation analysis was applied to estimate co-expression between genes.Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205.RESULTS:The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples.Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miR NA-205 overexpression.The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42(CDC42).After database searching and sequence alignment,we identified that Neuropilin 1(NRP1)had binding sites for both miRNA-145 and miRNA-205.CONCLUSION:The miRNA-145 and miRNA-205 can reduce the proliferation,migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.
基金Supported by Shanghai Key Laboratory of Fundus Diseases,2017(No.01030)Luzhou Southwest Medical University,Municipal Department Level(No.2017LZXNYD-J01)。
文摘AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODS:UM expression profile data were downloaded from the Cancer Genome Atlas(TCGA)and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration.The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis(ss GSEA)method,and the immune cell infiltration of a single specimen was evaluated.Finally,the specimens were divided into high and low infiltration groups.The differential expression between the two groups was analyzed using the R package‘edge R’.Univariate,multivariate and Least Absolute Shrinkage and Selection Operator(LASSO)Cox regression analyses were performed to explore the prognostic value of TMErelated lncRNAs.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional analyses were also performed.The Connectivity Map(CMap)data set was used to screen molecular drugs that may treat UM.RESULTS:A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups.Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis.Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements.Among 269 differentially expressed lncRNAs,69 were up-regulated and 200 were down-regulated.Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age,TNM stage,tumor base diameter,and low and high risk indices had significant prognostic value.We screened the potential small-molecule drugs for UM,including W-13,AH-6809 and Imatinib.CONCLUSION:The prognostic markers identified in this study are reliable biomarkers of UM.This study expands our current understanding of the role of TME-related lncRNAs in UM genesis,which may lay the foundations for future treatment of this disease.
基金Supported by the National Natural Science Foundation of China(No.81970835,No.81800867)。
文摘AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas(TCGA)database and further analyzed.The SPSS 24.0 statistical software package was used for statistical analyses.To investigate the potential function of SNHG15 in UM,we conducted in-depth research on Gene Set Enrichment Analysis(GSEA).RESULTS:The univariate analysis revealed that the age,tumor diameter,pathological type,extrascleral extension,cancer status,and high expression of SNHG15 were statistical risk factors for death from all causes.The multivariate analysis suggested that the mR NA expression level of SNHG15 was an independent risk factor for death from all causes,as was age and pathological type.KaplanMeier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis.In addition,SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage,metastasis and living status.Besides,the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status,pathologic stage,metastasis,and living status.Moreover,the GSEA indicated the potential pathways regulated by SNHG15 in UM.CONCLUSION:Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis.Besides,GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.
文摘Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been reported.Methods:Uveal melanoma-related articles and reviews published between 2005 and 2019 were retrieved in the Web of Science Core Collection on March 15,2020.Three bibliometric tools(HistCite,VOSviewer,and CiteSpace)were employed to conduct the current study.Results:A total of 3,404 publications related to uveal melanoma were identified,involving 3015 articles(88.57%)and 389 reviews(11.43%)with 65,429 co-cited references in 9 languages,which were published by 2,875 institutions in 66 countries/regions.The United States contributed to most publications(n=1427,41.92%),and the Thomas Jefferson University was involved in most of the studies(n=160,5.56%).Investigative Ophthalmology&Visual Science published the majority of the papers(n=175,5.14%),whereas Ophthalmology received the most co-citations(n=7050).Shields CL owned the most publications and co-citations(n=122 and 2151,respectively).Gene and molecular biology aspects,prevalence,the main prognosis factor,and treatment were the intellectual foundations of uveal melanoma research.In the field of uveal melanoma,emerging hotspots of uveal melanoma include epidemiologic characteristics,prognosis factors,mechanisms of uveal melanoma development,the use of novel predictive tools,and clinical applications of novel targeted drugs.Conclusion:This first bibliometric study focused on the integral tendency of the past 15 years,identified landmark items,and revealed current research hotspots in the field of uveal melanoma,which will provide references for clinicians and researchers,as well as an example of visualization analysis to explore research hotspots in other fields.
基金Supported by the China Scholarship Council(CSC)Program(No.201708080023,No.201708080104)Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of University of Tübingen。
文摘AIM:To present the multi-omics landscape of cutaneous melanoma(CM)and uveal melanoma(UM)from The Cancer Genome Atlas(TCGA).METHODS:The differentially expressed genes(DEGs)between CM and UM were found and integrated into a gene ontology enrichment analysis.Besides,the differentially expressed miRNAs were also identified.We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation.The differentially expressed transcription factors(TFs)were identified.RESULTS:Though CM had more mutational burden than UM,they shared several similarities such as the same rankings in diverse variant types.Except GNAQ and GNA11,the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM.On the transcriptomic level,4610 DEGs were found and integrated into a gene ontology enrichment analysis.We also identified 485 differentially expressed miRNAs.The methylation analysis showed that UM had a significantly higher methylation level than CM.The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo-and hypermethylation presented no obvious difference within these DEGs.Finally,116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM.CONCLUSION:This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels.Of notice,the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas,the different metastatic routes of CM and UM and the liver tropism of metastatic UM.
文摘AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines(OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib(EGF-R), everolimus(mTOR), selumetinib(MAPK), trametinib(MAPK) or the alkylphosphocholine erufosine(PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) dye reduction assay after 24 h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC_(50) was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, trametinib, and erufosine significantly decreased cell viability of all OMM cell lines(P<0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation(P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations(P<0.05). Besides an increase of necrotic cells after erufosine treatment(P<0.001), no changes in the number of dead cells for the other substances were observed.CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/m TOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.
基金Supported by the Natural Science Foundation for Young Scholars of Shanxi(No.201801D221256)the Science Foundation for Young Scholars of Shanxi Eye Hospital(No.Q201803)。
文摘AIM:To identify metastatic genes and mi RNAs and to investigate the metastatic mechanism of uveal melanoma(UVM).METHODS:GSE27831,GSE39717,and GSE73652 gene expression profiles were downloaded from the Gene Expression Omnibus(GEO)database,and the limma R package was used to identify differentially expressed genes(DEGs).Gene Ontology(GO)term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed using the DAVID online tool.A comprehensive list of interacting DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software.The Cytoscape MCODE plug-in was used to identify clustered sub-networks and modules of hub genes from the proteinprotein interaction network.GEPIA online software was used for survival analysis of UVM patients(n=80)from the The Cancer Genome Atlas(TCGA)cohort.Oncomi R online software was used to find that the mi RNAs were associated with UVM prognosis from the TCGA cohort.Target Scan Human 7.2 software was then used to identify the mi RNAs targeting the genes.RESULTS:There were 1600 up-regulated genes and 1399 down-regulated genes.The up-regulated genes were mainly involved in protein translation in the cytosol,whereas the down-regulated genes were correlated with extracellular matrix organization and cell adhesion in the extracellular space.Among the 2999 DEGs,five genes,Znf391,Mrps11,Htra3,Sulf2,and Smarcd3 were potential predictors of UVM prognosis.Otherwise,three mi RNAs,hsa-mi R-509-3-5 p,hsa-mi R-513 a-5 p,and hsa-mi R-1269 a were associated with UVM prognosis.CONCLUSION:After analyzing the metastasis-related enriched terms and signaling pathways,the up-regulated DEGs are mainly involved in protein synthesis and cell proliferation by ribosome and mitogen-activated protein kinase(MAPK)pathways.However,the down-regulated DEGs are mainly involved in processes that reduced cell-cell adhesion and promoted cell migration in the extracellular matrix through PI3 K-Akt signaling pathway,focal adhesion,and extracellular matrix-receptor interactions.Bioinformatics and interaction analysis may provide new insights on the events leading up to the development and progression of UVM.
文摘BACKGROUND Uveal melanoma is the most common primary intraocular malignant tumor affecting the eyes in adults.Nearly half of all primary uveal melanoma tumors metastasize;yet,there are currently no effective treatments for metastatic uveal melanoma.At the time of diagnosis,less than 4%of patients with uveal melanoma have detectable metastatic disease.Uveal melanoma disseminates hematogenously,with the most common site of metastasis being liver(93%),followed by lung(24%)and bone(16%).CASE SUMMARY A 57-year-old woman was diagnosed with a dysplastic nevus on her eyelid,which was histologically confirmed as malignant melanoma after resection.The patient had no evidence of metastasis to other organs and received both radiation therapy and chemotherapy.After systemic treatment,a metastatic left neck lymph node was found and another round of chemotherapy was performed after resection.Positron emission tomography-Computed Tomography tracking after completion of chemotherapy revealed two metastatic liver nodules.The patient underwent partial liver resection and showed no signs of recurrence at 1 year after surgery.CONCLUSION Surgery is an effective treatment for metastatic uveal melanoma.In patients with liver metastatic lesions,hepatectomy improves outcome.
基金supported by National Institutes of Health,National Eye Institute,NIH NEI P3006360 and by an unrestricted departmental grant to the Emory Eye Center from Research to Prevent Blindness(New York,NY).
文摘Animal models are crucial for the study of tumorigenesis and therapies in oncology research.Though rare,uveal melanoma(UM)is the most common intraocular tumor and remains one of the most lethal cancers.Given the limitations of studying human UM cells in vitro,animal models have emerged as excellent platforms to investigate disease onset,progression,and metastasis.Since Greene’s initial studies on hamster UM,researchers have dramatically improved the array of animal models.Animals with spontaneous tumors have largely been replaced by engrafted and genetically engineered models.Inoculation techniques continue to be refined and expanded.Newer methods for directed mutagenesis have formed transgenic models to reliably study primary tumorigenesis.Human UM cell lines have been used to generate rapidly growing xenografts.Most recently,patient-derived xenografts have emerged as models that closely mimic the behavior of human UM.Separate animal models to study metastatic UM have also been established.Despite the advancements,the prognosis has only recently improved for UM patients,especially in patients with metastases.There is a need to identify and evaluate new preclinical models.To accomplish this goal,it is important to understand the origin,methods,advantages,and disadvantages of current animal models.In this review,the authors present current and historic animal models for the experimental study of UM.The strengths and shortcomings of each model are discussed and potential future directions are explored.
文摘Background:Sharing biological material and clinical data from patients with uveal melanoma.Methods:Uveal melanoma is the most common intraocular malignancy in the adult population.Because uveal melanoma is primarily a sporadic cancer and familial cases are rare,it is difficult to prevent or detect it.Despite effective treatment of ocular tumors,more than 50%of patients develop incurable liver metastases mainly in the 5-10 years following the detection of the primary tumor.This cancer is relatively rare and the obtained biopsies are very small.About 20 samples are taken each year in Quebec.This provincial infrastructure is made of biological material from donors with uveal melanoma and a large clinical database.Collected tumor biopsies are used for culturing cell lines and the creation of a DNA/RNA library used for genomic and genetic studies.Results:This infrastructure plays an important role in the achievement of various research programs for a better understanding of genetic and environmental factors involved in the development of melanoma and the spread of metastasis.It allows collaboration with other researchers at a provincial,national and international level in order to make progress in basic and clinical research on uveal melanoma.Conclusions:The biological material and clinical data of this infrastructure are available upon request to VHRN members whose research project was approved by the ethics committee of the institution.
文摘Background:Uveal melanoma(UM)is the most common primary eye tumor in adults,and the most frequent site of malignant transformation of the melanocytes after the skin.It spreads to the liver in half of the cases,and the death rate following the report of metastasis is 92%at 2 years.Hepatic tropism of UM cannot simply be explained by the blood circulatory system organization,and illustrates the“seed and soil”hypothesis that describes an interaction between tumor cells(seed)and a specific microenvironment(soil).We decided to focus our study on the synergic interaction between UM cells and hepatic stellate cells(HSC),whose role has been previously described in the metastatic progression of colon and pancreatic cancers.Furthermore,HSC have been found surrounding UM liver metastasis,and the UM secretome contains activating cytokines of hepatic stromal cells.Our hypothesis is that HSC provide a specific microenvironment in the liver enhancing the growth of UM cells and increasing their therapeutic resistance.Using an in vitro 3D model and an original xenograft mouse model,we aim to decipher the mechanisms of UM metastatic progression,in order to elaborate new therapeutic strategies.Methods:First,using an agar coating,spheroids were generated with UM cells and were allowed to grow for 72 h.These tumor spheroids were then embedded in Matrigel and the HSC conditioned medium was used to evaluate the impact of the HSC secretome on UM invasion.Next,an original in vivo xenograft mouse model was generated,in which metastatic UM cells were injected alone or with human HSC in the spleen of immunodeficient mice.This model allows us to evaluate in 3-6 weeks the metastatic potential of each cell population,and thus to determine the cooperation between HSC and UM cells in the liver.Results:The HSC conditioned medium increased the invasion of UM spheroids compared to non-conditioned medium in our in vitro model.In addition,UM cells inoculated in the mouse spleen alone or with human HSC were able to metastasize to the liver,and the host HSC were also recruited by UM metastases.Conclusions:Our preliminary results strongly suggest that the secretome of HSC provides a permissive microenvironment for UM metastatic progression.We now have to confirm these results by characterizing the secretome of HSC,in order to identify cytokines or growth factors that increase the invasion of the liver by UM.Our models can be used to test the efficacy of new therapeutic strategies targeting the UM microenvironment.
文摘Background:Uveal melanoma(UM)is a malignant neoplasia that is composed of two main types of cells:spindle and epithelioid.There is a subset of neoplastic small epithelioid cells located predominantly in the infiltrative tumor margins or surrounding blood vessels.The aim of this study is to characterize and evaluate the correlation between the presence of these small epithelioid cells and clinical outcome.Methods:The clinical-pathological features of 70 UM patients were evaluated.The presence of small epithelioid cells was quantified based on percentage of tumor volume,and they were characterized using melanocytic markers(HMB-45,Melan A and SOX-10),stem cell markers(CD133,CD24 and CD38),and T cell lymphocytes(CD3).Univariate and multivariate analyses were conducted.Clinical follow up was available for all patients.Results:The ratio of small epithelioid cell components of all 70 tumors ranged from 0%to 30%(median,1%).Thirty-nine tumors(55.7%)had areas with small epithelioid cells.Univariate analysis showed that mixed versus spindle cell,higher lymphocytic infiltration,macrophage infiltration,ciliary body involvement,and>5%of small epithelioid cell component had a significant negative impact on metastasis-free survival.Small epithelioid cell component>5%was present in 24 cases(34.3%).Of these,three were classified as spindle and 21 were mixed.Multivariate analysis revealed that a>5%small cell component was the most significant morphological adverse prognostic factor.Moreover,the small epithelioid cells were negative for HMB45,stem cell markers and CD3,and focally and weakly positive for MELAN A and SOX10.Conclusions:A high small epithelioid cell component is a strong negative prognostic indicator in patients with UM.
文摘Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artificial intelligence offers rule-based models that favor the research of human signaling processes.In this paper,we give an overview of the advantages of the formalism of symbolic models in medical biology and cell biology of the uveal melanoma.A language is described that allows us:(1)To define the system states and elements with their alterations;(2)To model the dynamics of the cellular system;and(3)To perform inference-based analysis with the logical tools of the language.
基金supported by Beijing Municipal Administration of Hospitals’ Ascent Plan(No.DFL20150201)the National Natural Science Foundation of China(No.81570891)+2 种基金Beijing Natural Science Foundation(No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(No.2014-2-003)The Capital Health Research and Development of Special(No.2016-1-2051)
文摘Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five normal uvea tissues.Next,bioinformatics analyses,including gene ontology(GO) analysis and pathway analysis,were applied to study these differentially expressed circRNAs to predict pathogenic pathways that may be involved.Quantitative real-time polymerase chain reaction(qRT-PCR) in 20 UM samples and 20 normal uvea samples was used to confirm the circRNA expression profiles obtained from the microarray data.Finally,we analyzed the interaction between validated circRNAs and their potential cancer-associated miRNA targets.Results: In total,50,579 circRNAs [fold change(FC) ≥2.0; P<0.05],including 20,654 up-regulated and 29,925 down-regulated circRNAs,were identified as differentially expressed between UM tissues and normal uvea tissues.We used qRT-PCR to verify seven dysregulated circRNAs indicated by the microarray data,including hsa_circ_0119873,hsa_circ_0128533,hsa_circ_0047924,hsa_circ_0103232,hsa-circRNA10628-6,hsa_circ_0032148 and hsa_circ_0133460,which may be promising candidates to study future molecular mechanisms.Conclusions: This study explored,for the first time,the abnormal expression of circRNAs in UM and described the expression profile of circRNAs,providing a new potential target for the mechanism of UM and future treatment of UM.
基金Supported by the Health Special Project of Jilin Province Department of Finance (No.3D5177883429)
文摘AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting kit-8(CCK-8) were performed to detect the cell viability. Flow cytometry was used to analyze cell cycle and apoptosis. Quantitative realtime polymerase chain reaction(qRT-PCR) and Western blot assays were performed to measure proliferation-related and apoptosis-related factors.RESULTS: Firstly, PTL decreased the viability of C918 and SP6.5 cells in a dose-dependent manner, and the effect of PTL on C918 cells was stronger than on SP6.5;however, it did not affect normal cells. Secondly, PTL increased the proportion of cell number at cell cycle G1 phase in C918 cells, and decreased the proportion of cell number at S phase, but the proportion did not change at G2 phase. In addition, PTL induced the apoptosis of C918 cells, and decreased the expressions of Cyclin D1, B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large(Bcl-XL). Also, PTL increased Cyclin inhibition protein 1(P21), Bcl-2-associated X protein(Bax), Cysteinyl aspartate specific proteinas-3(Caspase-3) and Caspase-9 expression. However, the expression of Caspase-8 was not changed. CONCLUSION: PTL inhibites proliferation and induces apoptosis in UM cells by arresting G1 phase and regulating mitochondrial pathway, however, it does not affect normal cells.
