Biological characteristics and clinical management of uveal and conjunctival melanoma

Uveal and conjunctival melanomas are relatively rare tumors;nonetheless,they pose a significant risk of mortality for a large number of affected individuals.The pathogenesis of melanoma at different sites is very similar,however,the prognosis for patients with ocular melanoma remains unfavourable,primarily due to its distinctive genetic profile and tumor microenvironment.Regardless of considerable advances in understanding the genetic characteristics and biological behaviour,the treatment of uveal and conjunctival melanoma remains a formidable challenge.To enhance the prospect of success,collaborative efforts involving medical professionals and researchers in thefields of ocular biology and oncology are essential.Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors.Despite advancements in the development of effective melanoma therapeutic strategies,all current treatments for uveal melanoma(UM)and conjunctival melanoma(CoM)remain unsatisfactory,resulting in a poor long-term prognosis.Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors.A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy,with various potential therapeutic targets currently under consideration.Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents,with the hope of improving the prognosis for patients with metastatic disease.

Circ_0053943 complexed with IGF2BP3 drives uveal melanoma progression via regulating N6-methyladenosine modification of Epidermal growth factor receptor

Numerous studies have characterized the critical role of circular RNAs(circRNAs)as regulatory factors in the progression of multiple cancers.However,the biological functions of circRNAs and their underlying molecular mechanisms in the progression of uveal melanoma(UM)remain enigmatic.In this study,we identified a novel circRNA,circ_0053943,through re-analysis of UM microarray data and quantitative RT-PCR.Circ_0053943 was found to be upregulated in UM and to promote the proliferation and metastatic ability of UM cells in both in vitro and in vivo settings.Mechanistically,circ_0053943 was observed to bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3),thereby enhancing the function of IGF2BP3 by stabilizing its target mRNA.RNA sequencing assays identified epidermal growth factor receptor(EGFR)as a target gene of circ_0053943 and IGF2BP3 at the transcriptional level.Rescue assays demonstrated that circ_0053943 exerts its biological function by stabilizing EGFR mRNA and regulating the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway.Collectively,circ_0053943 may promote UM progression by stabilizing EGFR mRNA and activating the MAPK/ERK signaling pathway through the formation of a circ_0053943/IGF2BP3/EGFR RNA-protein ternary complex,thus providing a potential biomarker and therapeutic target for UM.

Uveal melanoma:Recent advances in immunotherapy

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.

Novel circular RNA expression profile of uveal melanoma revealed by microarray

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 hsacirc0119873,hsacirc0128533,hsacirc0047924,hsacirc0103232,hsa-circRNA10628-6,hsacirc0032148 and hsacirc0133460,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.

Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells

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.

Role of microRNA-21 in uveal melanoma cell invasion and metastasis by regulating p53 and its downstream protein

AIM： To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microRNA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 and its downstream targets which been found significant expression in our previous study.METHODS： Quantitative real-time polymerase chain reaction （qRT-PCR） was used to detect microRNA-21 expression in normal uveal tissue and uveal melanoma cell lines. Lenti-virus expression system was used to construct OCM-1, MuM-2B and M619 cell line with stable overexpression and inhibition of microRNA-21. In vitro cell function tests such as cell proliferation, cell apoptosis, cell circle and abilities of migration and invasion were examined by MTT, BrdU 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 qRT-PCR in mRNA level and western blotting analysis in protein level. Finally, the effect of microRNA-21 in a xenograft tumor model was assessed in four-week-old BALB/c nude mice. RESULTS： Compared to normal uveal melanoma, expressions of microRNA-21 were significantly higher in uveal melanoma cell lines. Overexpression of microRNA-21 promoted proliferation, migration, and invasion of OCM-1, M619 and MuM-2B cells, while inhibition of microRNA-21 reveal opposite effects. Wild type p53 was identified as a target gene of microRNA-21-3p, and proved by dual luciferase reporter assay. Up-regulated microRNA-21 inhibited the expression of wild type p53 gene, and the increased expression of LASP1 in mRNA level and protein level, while down-regulated microRNA-21 presented opposite way. However, GST-pi showed the potential pattern as expected, but relative mRNA level showed no statistically significant difference in OCM-1 cells. Furthermore, the mRNA expression of GST-pi was decreased in microRNA-21 overexpressing MuM-2B, and increased in M619 cells with inhibition of microRNA-21. In vivo, inhibition of microRNA-21 reduced tumor growth with statistically significant difference.CONCLUSION： These findings provide novel insight into molecular etiology of microRNA-21 in uveal melanoma cell lines, and suggest that microRNA-21 might be a potential candidate for the diagnosis and prognostic factor of human uveal melanoma in future.

miRNA-145/miRNA-205 inhibits proliferation and invasion of uveal melanoma cells by targeting NPR1/CDC42

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.

Treatment of liver metastases from uveal melanoma: a retrospective single-center analysis

BACKGROUND:Metastatic liver melanoma is a rare event in the Chinese population with extremely poor prognosis.Any treatment that controls a metastatic hepatic lesion potentially prolongs survival.This study aimed to evaluate the survival of patients with isolated liver metastases from uveal melanoma treated with partial hepatectomy or non-surgical management and to find the best therapeutic modality for these patients.METHODS:From January 1996 to September 2008,eight patients with liver metastases secondary to uveal melanoma were admitted to our hospital.Five patients underwent partial hepatectomy and 3 received other treatments(TACE,RFA,PEI).Their medical records were reviewed and overall survival was analyzed.RESULTS:The patients comprised 3 men and 5 women,with a median age of 44 years.Six patients presented with liver metastases at the time the primary tumor was diagnosed.The interval from the diagnosis of uveal melanoma to liver metastasis in the remaining 2 patients was 9.5 and 32.5 months,respectively.The median survival after the treatment of liver metastasis was 11.5 and 7.5 months in the surgical and nonsurgical groups,respectively.There was no procedure-related mortality in the whole study cohort.CONCLUSIONS:Partial hepatectomy or other therapies were safe and feasible for isolated liver metastases from uveal mela-noma.Aggressive treatment with multidisciplinary modalities may result in prolonged survival.

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD^(+)synthesis by reprogramming H3K79 methylation in uveal melanoma

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.

LncRNA SNHG15 predicts poor prognosis in uveal melanoma and its potential pathways

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.

Identification and validation of tumor microenvironment-related lnc RNA prognostic signature for uveal melanoma

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.

Immune oppression array elucidating immune escape and survival mechanisms in uveal melanoma

AIM： To examine the genetic profile of primary uveal melanoma （UM） as compared to UM in immune escape.METHODS： Dendritic cells （DC） loaded with lysates of UM cells of high metastatic potential were used to stimulate CTLs（CTLs）. When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction （qRT-PCR）, and analyzed the correlation of these expressions and patients’ survival.RESULTS： Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2. The expression of these genes in the relapsed UM was significantly greater than those in primary UM. UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression.CONCLUSION： Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells.

Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K

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.

Elevated VEGF-A & PLGF concentration in aqueous humor of patients with uveal melanoma following Iodine-125 plaque radiotherapy

AIM: To measure the concentration of vascular endothelial growth factor-A(VEGF-A), and placental growth factor(PLGF) in aqueous humor of uveal melanoma patients before and after Iodine-125 plaque therapy(IPT), determine the postoperative fluctuation and evaluate associated factors in vivo.METHODS: Participants were 18 Chinese patients with uveal melanoma who were elected to IPT. Undiluted aqueous humor samples were collected at Iodine plaque implant and removal time, then stored immediately at-80℃ until assayed. The concentration of VEGF-A, PLGF and other 7 cytokines comprising interleukin-2(IL-2), IL-8, IL-10, interferon(IFN)-γ, programmed death(PD)-1, transforming growth factor(TGF)-β1 and insulin-like growth factor(IGF)-1 in aqueous humor was measured using Raybiotech immunoassay kit, a high throughput strategy. The VEGF-A and PLGF levels were compared across preoperation and postoperation subgroups, as well as those of other 7 interleukins. Correlation and grouped analyses were conducted to determine the independent effects of clinical parameters and other cytokines on VEGF-A and PLGF concentration or fluctuation. This study set a self-control design.RESULTS: VEGF-A(P=0.038) and PLGF(P=0.026) were the only two increased cytokines after IPT. Preoperative and postoperative level of VEGF-A and PLGF(r=0.575, P=0.013;r=0.987, P<0.001) correlated with each other significantly. Level of VEGF-A(r=0.626, P=0.005;r=0.588, P=0.01) and PLGF(r=0.616, P=0.007;r=0.588, P=0.01) had positive correlation with tumor thickness consistently. Elevated VEGF-A or PLGF level were strong predictive factors of each other(P=0.007, OR=60.0). The elevated VEGF-A group showed a higher postoperative level of IFN-γ(P=0.005), IL-2(P<0.001) and IL-10(P=0.004) in aqueous humor. When the elevated PLGF group got similar results that a higher postoperative level of IFN-γ(P=0.007), IL-2(P<0.001) and IL-10(P=0.013) in aqueous humor. CONCLUSION: This study reveals that VEGF-A and PLGF in aqueous humor significantly increased with tumor thickness and radiation process in uveal melanoma patients. VEGF-A and PLGF may be crucial in uveal melanoma genesis and radiotherapy reactions. Immune mediators comprised IFN-γ, IL-2 and IL-10 could play roles in the link between inflammation and angiogenesis in uveal melanoma when exposed to radiotherapy.

Identification of differentially expressed metastatic genes and their signatures to predict the overall survival of uveal melanoma patients by bioinformatics analysis

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.

Regional chemotherapy for uveal melanoma liver metastases

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.

Research trends of uveal melanoma: a bibliometric study and visualization analysis

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.

Calpastatin participates in the regulation of cell migration in BAP1-deficient uveal melanoma cells

AIM: To detect how BRCA-associated protein 1(BAP1) regulates cell migration in uveal melanoma(UM) cells. METHODS: Wound healing and transwell assays were performed to detect UM cell migration abilities. Protein chip, immunoprecipitations and surface plasmon resonance analyses were applied to identify BAP1 protein partners. Western blot and calpain activity assays were used to test the expression and function of calpastatin(CAST). RESULTS: CAST protein was confirmed as a new BAP1 protein partner, and loss of BAP1 reduced the expression and function of CAST in UM cells. The overexpression of CAST rescued the cell migration phenotype caused by BAP1 loss.CONCLUSION: BAP1 interacts with CAST in UM cells, and CAST and its subsequent calpain pathway may mediate BAP1-related cell migration regulation.

Identification of an immune-related signature for the prognosis of uveal melanoma

AIM:To construct an immune-related prognostic signature(IPS)that can distinguish and predict prognosis in uveal melanoma(UM).METHODS:The transcriptomic data and clinicopathological information of 80 UM patients were extracted from the TCGA database.These patients were randomly assigned to a training and a testing set.RESULTS:Lasso Cox analysis was performed for the prognostic immune-related genes to develop an IPS for UM in the training set.The signature was validated in both the testing set and entire cohort.We confirmed the prognostic value of our IPS in distinct subgroups and found its association with the T stage and basal diameter of the tumor.Tumor Immune Estimation Resource database analysis revealed that the IPS was negatively correlated with the infiltration of neutrophils and dendritic cells,but positively correlated with the infiltration level of CD8+T cells.In addition,we demonstrated that immune checkpoints containing PD-1,CTLA-4,IDO,and TIGIT were moderately associated with the IPS.CONCLUSION:This is the first study to develop and validate an immune-related signature with the ability of predicting prognosis for UM patients.Further studies are needed to validate its prediction accuracy.

Nanomedicine in the application of uveal melanoma

Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.