简介：AbstractInterleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.

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简介：AbstractMelanoma originates from epidermal melanocytes and is the most malignant form of skin cancer, with an increasing incidence worldwide. In addition to the known pathological mutations in melanoma, the remodeling of epigenetic modification has recently been documented to orchestrate the malignant behaviors of tumor cells and anti-tumor immunity, emerging as an irreversible tumorigenic event that is more preventable and treatable with medications. As a hallmark characteristic of cancer, the disorder of cellular metabolism is also greatly implicated in tumor carcinogenesis and development. Accumulating evidence has revealed the close linkage between metabolism and epigenetics in multiple biological activities. In the pathogenesis of melanoma, the findings of other groups and our laboratory highlight the pivotal role of autophagy, mitochondrial function, and the oncometabolite acetyl-CoA, as well as their epigenetic modification. Targeted metabolism-associated epigenetic modulation might be a novel approach for melanoma therapy in the future.

简介：AbstractObjective:Capsaicin (CPS) is a major component of the red pepper, and its anti-tumor property has been confirmed. However, the underlying mechanism of this anti-tumor effect has not been fully clarified, so we conducted this study to evaluate the role of mitochondrial fission and subsequent mitochondrial dysfunction in CPS-induced apoptosis of melanoma cells.Methods:Two melanoma cell lines and melanocytes were treated with CPS alone or in combination with ruthenium red (a transient receptor potential vanilloid 1 [TRPV] antagonist), Z-VAD-FMK (a pan-caspase inhibitor), or N-acetyl-L-cysteine (an antioxidant). Cell vitality was tested using a cell counting kit-8 assay. The expression levels of related proteins were examined by Western blotting. Apoptosis, intracellular reactive oxygen species, mitochondrial membrane potential, adenosine triphosphate levels, and mitochondrial dynamics were analyzed by flow cytometry, luminometry, and confocal laser microscopy, respectively, and compared between groups.Results:CPS treatment significantly inhibited the vitality of melanoma cells (For A2058 cells: 0 vs. 120 μmol/L: [100.00% ± 0%] vs. [51.02% ± 6.40%], P < 0.05; For WM35 cells: 0 vs. 120 μmol/L: [100.00% ± 0%] vs. [51.80% ± 3.45%], P < 0.05) but exerted less impact on normal melanocytes. CPS promoted melanoma cell apoptosis through TRPV channels and the caspase cascade. CPS treatment then led to TRPV channel-dependent mitochondrial dysfunction with an increase in reactive oxygen species generation (For A2058 cells: CPS vs. CPS+RR: [2.34 ± 0.30] vs. [1.34 ± 0.12], P < 0.05; For WM35 cells: CPS vs. CPS+RR: [2.25 ± 0.25] vs. [1.65 ± 0.13], P < 0.05), dissipation of the mitochondrial membrane potential (Control vs. CPS: [1.00 ± 0] vs. [0.61 ± 0.08], P < 0.05), and adenosine triphosphate reduction (P < 0.05). In addition, reactive oxygen species generation contributed to CPS-induced melanoma cell apoptosis. Mitochondrial fission was subsequently proved to connect CPS treatment to mitochondrial dysfunction, which was also TRPV channel-dependent, thereby inducing melanoma cell apoptosis.Conclusion:Our study highlights the role of mitochondrial fission and its related mitochondrial dysfunction in mediating the pro-apoptotic effect of CPS in melanoma. These findings deepen our understanding of the mechanisms underlying the anti-tumor activity of CPS and indicate the clinical relevancy of extending the use of this agent for cancer therapy.

简介：Melanomaisthedeadliestformofskincancerandhasanincidencethatisrisingfasterthananyothersolidtumor.Metastaticmelanomatreatmenthasconsiderablyprogressedinthepastfiveyearswiththeintroductionoftargetedtherapy(BRAFandMEKinhibitors)andimmunecheckpointblockade(anti-CTLA4,anti-PD-1,andanti-PD-L1).However,eachtreatmentmodalityhaslimitations.Treatmentwithtargetedtherapyhasbeenassociatedwithahighresponserate,butwithshort-termresponses.Conversely,treatmentwithimmunecheckpointblockadehasalowerresponserate,butwithlongtermresponses.Targetedtherapyaffectsantitumorimmunity,andsynergymayexistwhentargetedtherapyiscombinedwithimmunotherapy.Thisarticlepresentsabriefreviewoftherationaleandevidenceforthepotentialsynergybetweentargetedtherapyandimmunecheckpointblockade.Challengesanddirectionsforfuturestudiesarealsoproposed.

简介：Objective:ThepresentstudyaimedtoinvestigatecircularRNA(circRNA)expressioninuvealmelanoma(UM).Methods:First,weusedmicroarraytocomparetheexpressionprofilesofcircRNAinfiveUMsamplesandfivenormaluveatissues.Next,bioinformaticsanalyses,includinggeneontology(GO)analysisandpathwayanalysis,wereappliedtostudythesedifferentiallyexpressedcircRNAstopredictpathogenicpathwaysthatmaybeinvolved.Quantitativereal-timepolymerasechainreaction(qRT-PCR)in20UMsamplesand20normaluveasampleswasusedtoconfirmthecircRNAexpressionprofilesobtainedfromthemicroarraydata.Finally,weanalyzedtheinteractionbetweenvalidatedcircRNAsandtheirpotentialcancer-associatedmiRNAtargets.Results:Intotal,50,579circRNAs[foldchange(FC)≥2.0;P<0.05],including20,654up-regulatedand29,925down-regulatedcircRNAs,wereidentifiedasdifferentiallyexpressedbetweenUMtissuesandnormaluveatissues.WeusedqRT-PCRtoverifysevendysregulatedcircRNAsindicatedbythemicroarraydata,includinghsacirc0119873,hsacirc0128533,hsacirc0047924,hsacirc0103232,hsa-circRNA10628-6,hsacirc0032148andhsacirc0133460,whichmaybepromisingcandidatestostudyfuturemolecularmechanisms.Conclusions:Thisstudyexplored,forthefirsttime,theabnormalexpressionofcircRNAsinUManddescribedtheexpressionprofileofcircRNAs,providinganewpotentialtargetforthemechanismofUMandfuturetreatmentofUM.

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简介：RecentstudiessuggestthatMHCclassⅡgenetransfercouldstimulateprotectiveantitumorimmunity.WhetherxenogeneicMHCⅡtransfectedtumorcellshavetheseeffectisunknown.Inthisstudy,HLA-DR3αandβchaincDNAwereclonedbyRT-PCRfromhumanBlymphomaRajicelllineandconfirmedbyDNAsequencing.TherecombinantexpressingvectorswereconstructedbyinsertingtheαandβchaincDNAintoPCEP4/pLXSNvectorsrespectively.AftertransfectingbylipofectamineandselectingwithG418andHyg,theHLA-DR3transfectedmousemelanomaB16recombinantcloneswereobtained.Approximately59%ofthe

简介：Recombinantvacciniavirushasmanyadvantagesovermorerestrictedvectorslikeretrovirusandadenovirus.Theprovensafetyofvacciniavirus,whichisrestrictedtolocalandtransitoryinfection,favorsclinicalapplicationofvacciniavirustodelivercytokineslocally.

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简介：为uveal黑瘤发现新biomarkers(嗯)由在病人分析浆液peptidomeprofile.METHODSProteomic系列与嗯在操作被分析前后并且与那些相比健康控制。磁性的亲密关系祷告被用来捕获浆液肽和帮助矩阵的激光解吸附作用/电离time-of-flight(MALDI-TOF)质量分光计被用来编49肽的浆液肽profiles.RESULTSA面板差别被表示在之间嗯病人和控制，哪个33肽具有在耐心的组的更高的紧张，16肽具有在控制的更高的紧张组。基于这些潜在的标记的联合使用，有1467和9289.0Da的吝啬的分子的群众的肽提供高敏感(83.3%)，特性(100%)和精确性率(93.0%)一起把黑瘤病人区分开来与健康控制。手术后地6mo指向时间，在外科前表示的许多肽差别的层次显示出病人和控制组之间的没有更多的统计差别。纤维蛋白原链先锋作为潜力被识别嗯markers.CONCLUSIONWe证明了一种方便、快的proteomic技术，亲密关系祷告分离和MALDI-TOF分析与生物信息的软件结合了，便于新奇biomarkers的鉴定为嗯。

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简介：Objective:VitaminDreceptor(VDR)mediatesvitaminDactivity.WeexaminedwhetherVDRexpressioninexcisedmelanomatissuesisassociatedwithVDRgene(VDR)polymorphisms.Methods:WeevaluatedVDRproteinexpression(bymonoclonalantibodyimmunostaining),melanomacharacteristics,andcarriageofVDR-FokI-rs2228570(C>T),VDR-BsmI-rs1544410(G>A),VDR-ApaI-rs7975232(T>G),andVDR-TaqI-rs731236(T>C)polymorphisms(byrestrictionfragmentlengthpolymorphism).Absenceorpresenceofrestrictionsitewasdenotedbyacapitalorlowerletter,respectively:'F'and'f'forFokI,'B'and'b'forBsmI,'A'and'a'forApaI,and'T'and't'forTaqIendonuclease.Seventy-fourItaliancutaneousprimarymelanomas(52.1±12.7yearsold)werestudied;51.4%werestageⅠ,21.6%stageⅡ,13.5%stageⅢ,and13.5%stageⅣmelanomas.VDRexpressionwascategorizedasfollows:100%positivevs.<100%;overthemedian20%(highVDRexpression)vs.≤20%(lowVDRexpression);absencevs.presenceofVDR-expressingcells.Results:StageImelanomas,Breslowthicknessof<1.00mm,levelIIClarkinvasion,Aaheterozygousgenotype,andAaTTcombinedgenotypeweremorefrequentinmelanomaswithhighvs.lowVDRexpression.CombinedgenotypesBbAA,bbAa,AATt,BbAATt,andbbAaTTweremorefrequentin100%vs.<100%VDR-expressingcells.CombinedgenotypeAATTwasmorefrequentinmelanomaslackingVDRexpression(oddsratio=14.5;P=0.025).VDRexpressionwasnotassociatedwithmetastasis,ulceration,mitosis>1,regression,tumor-infiltratinglymphocytes,tumoralinfiltrationofvasculartissues,additionalskinandnon-skincancers,andmelanomafamiliarity.Conclusions:WehighlightedthatVDRpolymorphismscanaffectVDRexpressioninexcisedmelanomacells.LowVDRexpressioninAATTcarriersisanewfindingthatmeritsfurtherstudy.VDRexpressionpossiblyposesimplicationsforvitaminDsupplementationagainstmelanoma.VDRexpressionandVDRgenotypemaybecomeprecisemedicinaltoolsformelanomainthefuture.

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简介：Directgenetransferintosomatictissueinvivoisadevelopingtechnologywithpotentialapplicationforcancergenetherapy.Retrovirusvector,whichwasaneffectivevehicle,stillhassomedisadvantagesingeneratinghightiterrecombinantvectorsandmanipulatingtomediateinvirogenetransfer.Inthispaper,recombinantvacciniavirusvectorencodinghuman

简介：Objective:Fusogenicendogenousretroviralsyncytinplaysanimportantroleintheformationofsyncytiotrophoblastsinhumanplacenta.Apartfromitsexpressioninplacenta,brainandtestis,syncytinhasalsobeenfoundinmanycancers.Althoughsyncytinhasbeenproposedtoserveasapositiveprognosticmarkerinsomecancers,theunderlyingmechanismisunclear.Theaimofthisstudyistoevaluatetheeffectsofsyncytinexpressionontheinvasivephenotypeofmelanomacells.Methods:Theeukaryoticexpressionplasmidforsyncytin-EGFPwasconstructedandtransfectedintoB16F10melanomacells.TheeffectofsyncytinontheinvasionpotentialoftumorcellswasevaluatedinB16F10sublinecellsthatstablyexpressedsyncytin-EGFPfusionproteinorEGFPalone.Results:TheB16F10sublinesthatstablyexpressedsyncytin-EGFPorEGFPalonewereestablishedrespectivelyandconfirmedbyimmunofluorescentandimmunoblottingassay.SyncytinexpressioninB16F10cellswasassociatedwithdecreasedcellproliferation,migrationandinvasion.Multinucleatedgiantcellsthatcontainedasmanyasfivenucleiwereinducedinsyncytin-expressingcells.Inaddition,syncytinexpressiondidnotalterthesensitivityofB16F10cellstotrichosanthin,atoxinthatdamagessyncytiotrophoblastsmoreefficientlythanothertissues.Conclusions:Theseresultssuggestthatsyncytinexpressioninsomecancersmayconfinetheirinvasionpotentialandthusserveasapositiveprognosticfactor.更多还原

简介：AbstractObjective:SOX4, a transcription factor, has been found to contribute to tumorigenesis in several cancers. This study was performed to determine whether SOX4 mediates BRAF inhibitor resistance in melanoma.Methods:Melanoma cell lines with acquired resistance to BRAF inhibitor (SK-MEL-5R, SK-MEL-28R, and A375R) were generated by adding escalating concentrations of PLX4032 into parental SK-MEL-5, SK-MEL-28, and A375 cells for >6 months. The expression of SOX4 and insulin-like growth factor 1 receptor (IGF-1R) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The downstream signaling of IGF-1R was detected by Western blotting. SOX4 and IGF-1R overexpression or knockdown was conducted by lentivirus transfection. Cell viability and apoptosis were demonstrated by MTT and flow cytometry, respectively. The binding ability of SOX4 to IGF-1R promoter was determined by chromatin immunoprecipitation quantitative PCR assay.Results:SOX4 was upregulated in BRAF inhibitor-resistant melanoma cells as compared with parental cells (SK-MEL-5 group, 1.02 vs. 6.33; SK-MEL-28 group, 1.03 vs. 3.22; A375 group, 1.00 vs. 1.86; t=°7.069, 29.26, and 5.291, respectively; all P < 0.01), and PLX4032 treatment could not alter the expression of SOX4 in resistant cells. SOX4 overexpression attenuated the response of parental cells to PLX4032 (for cell viability, SK-MEL-5 group: 77.76% vs. 104.28%, F= 91.50; SK-MEL-28 group: 60.59% vs. 93.13%, F= 171.8; A375 group: 62.50% vs. 80.87%, F= 47.15. For apoptosis rates, SK-MEL-5 group: 34.90% vs. 14.31%, F= 4.781; SK-MEL-28 group, 40.8% vs. 29.4%, F= 13.32, P= 0.063; A375 group: 40.20% vs. 17.09%, F= 11.39; all P < 0.05, otherwise indicated). While SOX4 knockdown enhanced the response of resistant cells to PLX4032 (for cell viability, SK-MEL-5R group: 93.75% vs. 69.53%, F= 94.45, SK-MEL-28R group: 95.60% vs. 66.79%, F= 30.41, A375R group: 95.51% vs. 59.98%, F= 111.6; for apoptosis rates, SK-MEL-5R group: 16.2% vs. 44.4%, F= 25.67, SK-MEL-28R group: 26.59% vs. 44.20%, F= 158.0, A375R group: 5.98% vs. 31.51 %, F= 14.35, and all P < 0.01). Chromatin immunoprecipitation quantitative PCR assay demonstrated that SOX4 binded to the promoter of IGF-1R (1.04 vs. 1.94 [-1044 to -920 bp] and 0.110 vs. 0.139 [GAPDH], F= 534.5, P < 0.01). In addition, SOX4 overexpression increased IGF-1R and its downstream phosphorylated ERK, phosphorylated AKT, and phosphorylated STAT3 expression, while SOX4 knockdown exerted the opposite effects. Moreover, IGF-1R knockdown overcame SOX4 overexpression-induced PLX4032 resistance (cell viability: 35.85% vs. 52.79% vs. 37.84% [A375 group, negative control group vs. SOX4 overexpressing group vs. SOX4 overexpressing + sh-IGF-1R group]; apoptosis rates: 25.30% vs. 9.56% vs. 22.26 [A375 group, negative control group vs. SOX4 overexpressing group vs. SOX4 overexpressing+ sh-IGF-1R group]; F= 13.01 and 41.87, respectively; all P < 0.01), while IGF-1R overexpression abrogated SOX4 knockdown-induced response enhancement to PLX4032 for comparison of negative control group, sh-SOX4 group and sh-SOX4 + IGF-1R overexpressing group (cell viability: 96.62% vs. 86.86% vs. 97.26% (A375R), 98.15% vs. 81.63% vs. 98.49% [SK-MEL-5R]; apoptosis rates: 13.81% vs. 32.00% vs. 12.16 [A375R], 29.70% vs. 41.40% vs. 26.10% [SK-MEL-5R]; F= 13.56, 12.86, 38.81, and 39.85, respectively; all P < 0.01).Conclusion:SOX4 mediates BRAF inhibitor resistance in melanoma through regulation of IGF-1R signaling. SOX4 might serve as a potential target for the treatment of BRAF inhibitor-resistant melanoma.

简介：AbstractBackground:Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. It has been demonstrated that microRNA-145 (miR-145) is correlated with the progression of various cancers by regulating the expression of multiple target genes, especially a number of genes that regulate angiogenesis and proliferation. However, the underlying mechanisms of miR-145 in tumor angiogenesis of UM are still not well illustrated. Thus, we aimed to explore the potential target genes or pathways regulated by miR-145 in UM and the effect of miR-145 on invasion and angiogenesis.Methods:Totally, 24 choroid samples were collected in our study, including 12 UM samples and 12 normal uveal tissues. The expression of neuroblastoma RAS viral oncogene homolog (N-RAS), phosphorylated protein kinase B (p-AKT), and vascular endothelial growth factor (VEGF) in UM tissues and normal uveal tissues was analyzed using Western blotting analysis. Lentivirus expression system was used to construct MUM-2B and OCM-1 cell lines with stable overexpression of miR-145. Transwell and endothelial cell tube formation assay were used to measure the effects of miR-145 on the invasion and angiogenesis of UM in vitro. The downstream target genes of miR-145 were predicted by bioinformatics and confirmed using a luciferase assay. BALB/c nude mice models were established to investigate the mechanisms of miR-145 on tumor growth and angiogenesis in vivo. Group data comparisons were performed using analysis of Student’s t test. A two-tailed P < 0.05 was considered as statistically significant.Results:The results of Western blotting analysis indicated that the expressions of N-RAS (1.10 ± 0.35 vs. 0.41 ± 0.36, t = 3.997, P = 0.012), p-AKT (1.16 ± 0.22 vs. 0.57 ± 0.03, t = 7.05, P = 0.001), and VEGF (0.97 ± 0.32 vs. 0.45 ± 0.21, t = 3.314, P = 0.008) in UM tumor tissues were significantly higher than those in normal uveal tissue. Luciferase assay demonstrated N-RAS and VEGF as downstream targets of miR-145. Moreover, tube formation assay revealed that miR-145-transfected human microvascular endothelial cell line formed shorter tube length (36.10 ± 1.51 mm vs. 42.91 ± 0.94 mm, t = 6.603, P = 0.003) and less branch points (350.00 ± 19.97 vs. 406.67 ± 17.62, t = 3.685, P = 0.021) as compared with controls. In addition, the numbers of invaded MUM-2B and OCM-1 cells with miR-145 overexpression were significantly lower than the controls (35.7 ± 3.3 vs. 279.1 ± 4.9, t = 273.75, P < 0.001 and 69.5 ± 4.4 vs. 95.6 ± 4.7, t = 21.27, P < 0.001, respectively). In vivo, xenografts expressing miR-145 had smaller sizes (miR-145 vs. miR-scr, 717.41 ± 502.62 mm3vs. 1694.80 ± 904.33 mm3, t = 2.314, P = 0.045) and lower weights (miR-145 vs. miR-scr, 0.74 ± 0.46 g vs. 1.65 ± 0.85 g, t = 2.295, P = 0.045).Conclusion:Our results indicated that miR-145 is an important tumor suppressor and the inhibitory strategies against N-RAS/VEGF signaling pathway might be potential therapeutic applications for UM in the future.

简介：Thenon-classicalHLAclassIantigenHLA-GisanimmunemodulatorwhichinhibitsthefunctionsofTcells,NKcells,andtheDendriticcells(DC).Asaresult,HLA-Gexpressioninmalignantcellsmayprovidethemwithamechanismtoescapetheimmunesurveillance.Inmelanoma,HLA-Gantigenexpressionhasbeenfoundin30%ofsurgicallyremovedlesionsbutinlessthan1%ofestablishedcelllines.OnepossiblemechanismunderlyingthedifferentialHLAGexpressioninvivoandinvitroisthattheHLA-Ggeneisepigeneticallyrepressedinmelanomacellsinvitro.Totestthishypothesis,wetreatedtheHLA-GnegativemelanomacelllineOCM-1AwiththeDNAmethyltransferaseinhibitor5-aza-2'-deoxycytidine(5-AC)andanalyzedwhetherHLA-Gexpressioncanberestored.OurdatastronglysuggestthatHLA-GissilencedasaresultofCpGhypermethylationwithina5'regulatoryregionencompassing220bpupstreamofthestartcodon.Aftertreatment,HLA-GmRNAexpressionwasdramaticallyincreased.WesternblotandflowcytometryshowedthatHLA-Gproteinwasinduced.Interestingly,HLA-Gcellsurfaceexpressiononthe5-ACtreatedOCM-1AcellsismuchlessthanthatontheHLA-GpositiveJEG-3cellswhileasimilaramountoftotalHLA-Gwasobserved.Possiblemechanismsforthedifferencewereanalyzedinthestudysuchascellcold-treatment,peptideloadingandantigenprocessingmachinerycomponents(APM)aswellasβ2microglobulin(β2-m)expression.DatarevealedthattheAPMcomponentcalreticulinmightbeinvolvedinthelowerHLA-GsurfaceexpressiononOCM-1Acells.Takentogether,ourresultsindicatedthatDNAmethylationisanimportantepigeneticmechanismbywhichHLA-Gantigenexpressionismodulatedinmelanomacellsinvitro.Furthermore,tothefirsttime,wehypothesizedthatthedeficiencyofcalreticulinmightbeinvolvedinthelowHLA-Gsurfaceexpressiononthe5-ACtreatedOCM-lAcells.