Panicle number per plant,grain number per panicle,and grain weight are three key factors influencing rice grain yield.Gn1a,a major QTL for grain number per panicle,encodes the cytokinin oxidase/dehydrogenase(CKX)OsCKX...Panicle number per plant,grain number per panicle,and grain weight are three key factors influencing rice grain yield.Gn1a,a major QTL for grain number per panicle,encodes the cytokinin oxidase/dehydrogenase(CKX)OsCKX2.While the use of elite Gn1a alleles has been well documented in indica rice cultivars,their potential in japonica rice remains largely unexplored.In this study,we characterized three suppressor mutants of the rice cytokinin receptor mutant pal1/ohk4 and found that all causal genes were novel alleles of Gn1a identified through the MutMap approach.These three suppressor mutants caused single amino acid substitutions in the FAD-binding domain(G556D and G156D)and the cytokinin-binding domain(Y357C),resulting in significantly reduced enzymatic activity of OsCKX2 and elevated cytokinin levels in the panicle.Haplotype analysis of Gn1a using a natural population from the 3K Rice Genomes Project showed that G556D,G156D,and Y357C were novel alleles of Gn1a.G556,G156,and Y357 were highly conserved,whereas four natural variants G54A,A105V,H116R,and N535K identified in different haplotypes of Gn1a showed extremely low conservation.By backcrossing the suppressor mutants with their original wild-type Huaidao 5,an elite japonica rice variety,we developed improved lines carrying only the gn1a mutation.The improved lines showed a significant increase in grain number per panicle,grain weight,panicle number per plant,plant height,and stem thickness,leading to a 25.7%-28.7%increase in grain yield per plot compared with Huaidao 5.This study provides valuable Gn1a alleles for synergistic improvement of the three key yield factors and offers germplasm resources for high-yielding breeding in japonica rice.展开更多
MicreRNAs （miRs） are small single-stranded RNA molecules, which function as key negative regulators of post-transcriptional modulation in almost all biological processes. Abnormal expression of microRNAs has been ob...MicreRNAs （miRs） are small single-stranded RNA molecules, which function as key negative regulators of post-transcriptional modulation in almost all biological processes. Abnormal expression of microRNAs has been ob- sewed in various types of cancer including breast cancer. Great efforts have been made to identify an association between microRNA expression profiles and breast cancer, and to understand the functional role and molecular mechanism of aberrant-expressed microRNAs. As research progressed, ＇oncogenic microRNAs＇ and ＇tumor sup- pressive microRNAs＇ became a focus of interest. The potential of candidate microRNAs from both intercellular （tissue） and extraceUular （serum） sources for clinical diagnosis and prognosis was revealed, and treatments involving microRNA achieved some amazing curative effects in cancer disease models. In this review, advances from the most recent studies of microRNAs in one of the most common cancers, breast cancer, are highlighted, especially the functions of specifically selected microRNAs. We also assess the potential value of these microRNAs as diagnostic and prognostic markers, and discuss the possible development of microRNA-based therapies.展开更多
AIM:To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC). METHODS:Biopsy specimens for histological analysis and mRNA...AIM:To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC). METHODS:Biopsy specimens for histological analysis and mRNA detection were obtained endoscopically from the rectum of 62 patients with UC (36 men; age 13-76 years). The patients were classified endoscopically according to Matts' grade (grade 1 to 4). Expression of SOCS1 and SOCS3 mRNAs was quantified in samples by competitive reverse transcription-polymerase chain reaction (RT-PCR). GAPDH was used as an internal control for efficiency of RT-PCR and amount of RNA. RESULTS:SOCS3 mRNA expression was significantly higher in inflamed mucosa of UC than in inactive mucosa. The level of expression was well correlated with the degree of both endoscopic and histologic inflammation. Interestingly,among the patients in remission,the group with relatively low expression of SOCS3 showed a higher rate of remission maintenance over a 12-mo period. In contrast,SOCS1 mRNA was expressed in both inflamed and non-inflamed colonic mucosa and was not correlated with the activity of colonic mucosa or prognosis. CONCLUSION:These observations suggest that increased expression of mucosal SOCS3,but not of SOCS1,may play a critical role in the development of the colonic inflammation of UC.展开更多
Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer and the third leading cause of cancer-related death in the world and is more common in Asia than in most Western countries. There is an urgent need to i...Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer and the third leading cause of cancer-related death in the world and is more common in Asia than in most Western countries. There is an urgent need to identify potential novel oncogenes and tumor suppressor genes, and biomarkers for STAD. 6652 differentially expressed genes were identified between STAD and normal samples based on the transcriptome data analysis of the TCGA and GEO databases. 13 key modules were identified in STAD by WGCNA analysis. 293 potential STAD associated genes were identified from intersection by Venn Diagram. The 293 intersected genes were enriched in cell cortex and infection by GO and KEGG analysis. 10 hub genes were identified from PPI and Cytoscape analyses of the intersected genes. KLF4/CGN low and SHH/LIF high expression were associated with short overall survival of Asian STAD patients. Bioinformatics analysis revealed potential novel tumor suppressors (KLF4/CGN), oncogenes (SHH/LIF) and biomarkers for diagnosis, therapy and prognosis of STAD, specifically for Asian patients.展开更多
Gerbera Hybrida is one of the important cut flowers across the world.The novel traits are the primarily market requirements and the breeding targets,mainly determined by the degree of genetic variation after hybridiza...Gerbera Hybrida is one of the important cut flowers across the world.The novel traits are the primarily market requirements and the breeding targets,mainly determined by the degree of genetic variation after hybridization.However,meiotic recombination is highly conserved in most eukaryotes which suppressed the crossover formation and limited the genetic diversity.Recently,several meiotic recombination suppressors have been identified and characterized in plants,whereas it remains elusive in G.hybrida.In order to characterize the expression patterns of these suppressors in G.hybrida,20 candidate reference genes were identified from the transcriptome datasets of G.hybrida,and their expression stabilities during plant development were evaluated by geNorm,NormFinder and BestKeeper.Although the most stable reference genes were variable in different softwares,comprehensive ranking revealed that PGK2 was the most stable reference gene and GAPDH was the most unstable one.The expression patterns of FANCM,FIGL1,RECQ4,RM1,and FLIP further validated that PGK2 was suitable for normalization of gene expression.Our study identified a reliable reference gene for gene expression during meiotic recombination,and provided functional insights into meiotic recombination suppressors in G.hybrida.展开更多
RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21–23 nt RNA molecules.During infection,RNAi can act as an innate...RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21–23 nt RNA molecules.During infection,RNAi can act as an innate immune system to defend against viruses.As a counter-defensive strategy,silencing suppressors are encoded by viruses to inhibit various stages of the silencing process.These suppressors are diverse in sequence and structure and act via different mechanisms.In this review,we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses.We also review the modes of action proposed for some silencing suppressors.展开更多
The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3...The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial ...This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial disease resulting from a combination of genetic and epigenetic alterations in cell DNA,influencing proliferation,differentiation,and migration.TP53 gene,which codifies p53 protein,is a known tumor suppressor,and it plays an important role in cell maintenance as DNA repair,cell proliferation control,and apoptosis activation.TP53 expression can be modulated by several miRNAs,as miR-30c,miR-34a,and the miR-200 family,inhibiting p53 production and silencing its tumor suppressor effects.On the other hand,p53 protein can modulate several miRNAs expression,as miR-146a,miR-192,and the miR-200 family,by acting as a transcription factor or by modulating miRNA processing,interfering with BC aggressiveness and progression.Understanding the role of p53 and miRNAs in BC may aid in identifying new biomarkers and developing new targeted therapies for patient treatment.展开更多
Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets...Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.展开更多
Inactivating mutations in tumor suppressor genes(TSGs)are known to drive tumorigenesis by decoupling proliferation and survival from tight regulatory mechanisms.In a recent study published in Science,Martin et al.1 sh...Inactivating mutations in tumor suppressor genes(TSGs)are known to drive tumorigenesis by decoupling proliferation and survival from tight regulatory mechanisms.In a recent study published in Science,Martin et al.1 shed light on an unappreciated role of TSGs in preventing immune evasion by demonstrating enrichment of TSG inactivation in tumor cell transplants in mice when facing an intact adaptive immune system.展开更多
This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion throug...This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion through interactions with myeloid-derived suppressor cells(MDSCs).Using single-cell transcriptomic sequencing,we analyzed the interplay between COL11A1-positive CAFs and MDSCs in the CC microenvironment,focusing on how COL11A1 impacts MDSC differentiation and activation.The results demonstrate that COL11A1 expression in fibroblasts significantly enhances matrix metalloproteinase(MMP)3 and MMP13 expression,leading to paracrine induction of MDSC differentiation and activation,which promotes immune evasion and tumor growth.Additionally,we observed that COL11A1 knockout(COL11A1KO)suppresses tumor growth and hinders immune evasion.These findings underscore the essential role of COL11A1-positive CAFs in establishing an immunosuppressive tumor microenvironment conducive to CC progression.By elucidating the molecular pathway through which COL11A1 influences MDSC activity,this research suggests new therapeutic avenues for targeting the tumor microenvironment in CC,particularly through modulating COL11A1 expression in CAFs.展开更多
Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in man...Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activati...The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activation is sufficient to induce tumor initiation,recurrence,and therapeutic resistance.However,CDK12 may also exert tumor-suppressive functions in a context-dependent manner.Therefore,caution is warranted when targeting CDK12 in future clinical trials.A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology.This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer.Subsequently,we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts.Finally,we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology,offering insights into future directions for innovative cancer treatment strategies.展开更多
Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive ...Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive bladder cancer(MIBC),with radical cystectomy being the treatment for MIBC,which significantly reduces quality of life.MicroRNAs(miRs)act as critical genetic regulators,with both oncogenic and tumor-suppressive roles.MiR-10a is described as a tumor suppressor in various neoplasms,but its role in BC is controversial.This study aims to assess the activity of miR-10a in cellular invasion and proliferation in two distinct BC cell lines.Methods:The study used high-grade T24 and low-grade RT4 bladder cell lines.Cells were transfected with miR-10a mimic or a non-targeting control.Transfection efficiency was validated by qPCR.Cell proliferation was cultured for 10–14 days.Cell migration and invasion were evaluated using Matrigel.All assays were conducted in triplicate.Results:The T24 cells transfected with miR-10a presented decreased cellular proliferation and invasion compared to the Scramble(p=0.0481 and p<0.0001,respectively).In the RT4 cell line,there was only a significant reduction in cellular proliferation after miR-10a transfection(p=0.0029).Conclusions:Our findings suggest that miR-10a has a tumoral suppressor role in BC,demonstrating higher efficacy in high-grade cells.展开更多
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,...BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.展开更多
BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor ...BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.展开更多
Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to ...Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to several pathologies,including cancer.This deregulation contributes to their pro-tumorigenic activity since they participate in the degradation of extracellular matrix components and adhesion molecules,and the activation of growth factors.However,some proteases,such as ADAM metallopeptidase with thrombospondin type 1 motif 8 and kallikrein-related peptidases 5 and 10,have emerged as tumor suppressors due to their antitumoral actions in specific cancer contexts.In this article,we discuss the antitumoral effects of ADAM metallopeptidase with thrombospondin type 1 motif 8,kallikrein-related peptidases 5 and 10 that have been described to date,suggesting their potential use as novel biomarkers and therapeutic targets in cancer.展开更多
Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppress...Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppressor cells,macrophages,T cells,and B cells.Imbalances of these immune cells can promote the proliferation and metastasis of osteosarcoma.Recent studies have indicated a substantial increase in the levels of myeloid-derived suppressor cells,an immune cell associated with immunosuppressive and pro-cancer effects,in the peripheral blood of patients with osteosarcoma.Moreover,the levels of the pro-inflammatory cytokine interleukin 18 are positively correlated with those of myeloid-derived suppressor cells in the peripheral blood of animal models of osteosarcoma.In this review,we explore the function of myeloid-derived suppressor cells in osteosarcoma based on the clinical diagnoses of patients with osteosarcoma and discuss future therapeutic approaches for targeting osteosarcoma.Targeting myeloid-derived suppressor cells represents a promising approach to improving the prognosis and survival rates of patients with osteosarcoma.展开更多
This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression...This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression pattern in OSCC,and the expression levels of PERs in OSCC patients are correlated with a favorable prognosis.PERs impact the occurrence and development of OSCC through multiple pathways.In the regulation of cell proliferation,they can function not only through cell cycle regultion but also via metabolic pathways.For example,PER1 can interact with receptors for activated C kinase 1(RACK1)and phosphatidylinositol 3-kinase(PI3K)through its PAS domain to inhibit glycolysis and thereby reduce cell proliferation.Regarding the regulation of cell death,PERs mediate various types of cell death in OSCC cells,such as p53-dependent apoptosis,protein kinase B(AKT)/mammalian target of rapamycin(mTOR)dependent autophagy,or hypoxia-inducible factor l-alpha(HIF-1a)mediated ferroptosis.In regulating epithelia-mesenchymal transition(EMT),PERs can lead to the downregulation of EMT related genes,such as zinc finger E-box binding homeobox 1/2(ZEBI/2),twist family BHLH transcription factor 1/2(TWIST1/2),and Vimentin,thereby influencing the migration and invasion capabilities of OSCC cells.In tumor angiogenesis,PERs exert regulatory effects on related factors,such as methionyl aminopeptidase 2(MetAP2)and vascular endothelial growth factor(VEGF).In the tumor immune microenvironment,PERs can inhibit the inhibitor of kappa B kinase(IKK)/nuclear factor kappa B(NF-kB)pathway and programmed cell death ligand 1(PD-L1)expression,thereby enhancing the cytotoxic effect of CD8+T cells on OSCC cells.In-depth studies focusing on elucidating the precise regulatory mechanisms of PERs can facilitate the development of therapeutic strategies targeting PERs,including restoration of PERs expression/activity,targeting PERs-regulated pathways,combination therapies,and chronotherapy.These furnish a theoretical foundation for formulating individualized treatment plans to achieve precise treatment for patients with OSCC.展开更多
Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma ...Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.展开更多
基金supported by the Biological Breeding-National Science and Technology Major Project,China(Grant No.2023ZD0406801)the National Natural Science Foundation of China(Grant No.32300278)+2 种基金the Key R&D Plan of Shandong Province,China(Grant No.2024LZGC009)the Innovation Program of Chinese Academy of Agricultural Sciences(Grant No.CAAS-CSCB-202402)the Science and Technology Innovation Project of Shandong Academy of Agricultural Sciences,China(Grant No.CXGC2025B09).
文摘Panicle number per plant,grain number per panicle,and grain weight are three key factors influencing rice grain yield.Gn1a,a major QTL for grain number per panicle,encodes the cytokinin oxidase/dehydrogenase(CKX)OsCKX2.While the use of elite Gn1a alleles has been well documented in indica rice cultivars,their potential in japonica rice remains largely unexplored.In this study,we characterized three suppressor mutants of the rice cytokinin receptor mutant pal1/ohk4 and found that all causal genes were novel alleles of Gn1a identified through the MutMap approach.These three suppressor mutants caused single amino acid substitutions in the FAD-binding domain(G556D and G156D)and the cytokinin-binding domain(Y357C),resulting in significantly reduced enzymatic activity of OsCKX2 and elevated cytokinin levels in the panicle.Haplotype analysis of Gn1a using a natural population from the 3K Rice Genomes Project showed that G556D,G156D,and Y357C were novel alleles of Gn1a.G556,G156,and Y357 were highly conserved,whereas four natural variants G54A,A105V,H116R,and N535K identified in different haplotypes of Gn1a showed extremely low conservation.By backcrossing the suppressor mutants with their original wild-type Huaidao 5,an elite japonica rice variety,we developed improved lines carrying only the gn1a mutation.The improved lines showed a significant increase in grain number per panicle,grain weight,panicle number per plant,plant height,and stem thickness,leading to a 25.7%-28.7%increase in grain yield per plot compared with Huaidao 5.This study provides valuable Gn1a alleles for synergistic improvement of the three key yield factors and offers germplasm resources for high-yielding breeding in japonica rice.
基金supported by the National Basic Research Program(973)of China(No.2013CB967202)the National Natural Science Foundation of China(No.81472654)
文摘MicreRNAs （miRs） are small single-stranded RNA molecules, which function as key negative regulators of post-transcriptional modulation in almost all biological processes. Abnormal expression of microRNAs has been ob- sewed in various types of cancer including breast cancer. Great efforts have been made to identify an association between microRNA expression profiles and breast cancer, and to understand the functional role and molecular mechanism of aberrant-expressed microRNAs. As research progressed, ＇oncogenic microRNAs＇ and ＇tumor sup- pressive microRNAs＇ became a focus of interest. The potential of candidate microRNAs from both intercellular （tissue） and extraceUular （serum） sources for clinical diagnosis and prognosis was revealed, and treatments involving microRNA achieved some amazing curative effects in cancer disease models. In this review, advances from the most recent studies of microRNAs in one of the most common cancers, breast cancer, are highlighted, especially the functions of specifically selected microRNAs. We also assess the potential value of these microRNAs as diagnostic and prognostic markers, and discuss the possible development of microRNA-based therapies.
文摘AIM:To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC). METHODS:Biopsy specimens for histological analysis and mRNA detection were obtained endoscopically from the rectum of 62 patients with UC (36 men; age 13-76 years). The patients were classified endoscopically according to Matts' grade (grade 1 to 4). Expression of SOCS1 and SOCS3 mRNAs was quantified in samples by competitive reverse transcription-polymerase chain reaction (RT-PCR). GAPDH was used as an internal control for efficiency of RT-PCR and amount of RNA. RESULTS:SOCS3 mRNA expression was significantly higher in inflamed mucosa of UC than in inactive mucosa. The level of expression was well correlated with the degree of both endoscopic and histologic inflammation. Interestingly,among the patients in remission,the group with relatively low expression of SOCS3 showed a higher rate of remission maintenance over a 12-mo period. In contrast,SOCS1 mRNA was expressed in both inflamed and non-inflamed colonic mucosa and was not correlated with the activity of colonic mucosa or prognosis. CONCLUSION:These observations suggest that increased expression of mucosal SOCS3,but not of SOCS1,may play a critical role in the development of the colonic inflammation of UC.
文摘Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer and the third leading cause of cancer-related death in the world and is more common in Asia than in most Western countries. There is an urgent need to identify potential novel oncogenes and tumor suppressor genes, and biomarkers for STAD. 6652 differentially expressed genes were identified between STAD and normal samples based on the transcriptome data analysis of the TCGA and GEO databases. 13 key modules were identified in STAD by WGCNA analysis. 293 potential STAD associated genes were identified from intersection by Venn Diagram. The 293 intersected genes were enriched in cell cortex and infection by GO and KEGG analysis. 10 hub genes were identified from PPI and Cytoscape analyses of the intersected genes. KLF4/CGN low and SHH/LIF high expression were associated with short overall survival of Asian STAD patients. Bioinformatics analysis revealed potential novel tumor suppressors (KLF4/CGN), oncogenes (SHH/LIF) and biomarkers for diagnosis, therapy and prognosis of STAD, specifically for Asian patients.
基金funded by Yunnan Fundamental Research Projects(Grant No.2019FD030)Major Science and Technology Project of Yunnan Provincial Department of Science and Technology(Grant Nos.2019ZG006,202102AE090052)Ten-thousand Talents Program of Yunnan Province–Yunling Scholar of Industrial Technology Leading Talent Project(Grant No.Yun Fagai Renshi[2018]No.212)。
文摘Gerbera Hybrida is one of the important cut flowers across the world.The novel traits are the primarily market requirements and the breeding targets,mainly determined by the degree of genetic variation after hybridization.However,meiotic recombination is highly conserved in most eukaryotes which suppressed the crossover formation and limited the genetic diversity.Recently,several meiotic recombination suppressors have been identified and characterized in plants,whereas it remains elusive in G.hybrida.In order to characterize the expression patterns of these suppressors in G.hybrida,20 candidate reference genes were identified from the transcriptome datasets of G.hybrida,and their expression stabilities during plant development were evaluated by geNorm,NormFinder and BestKeeper.Although the most stable reference genes were variable in different softwares,comprehensive ranking revealed that PGK2 was the most stable reference gene and GAPDH was the most unstable one.The expression patterns of FANCM,FIGL1,RECQ4,RM1,and FLIP further validated that PGK2 was suitable for normalization of gene expression.Our study identified a reliable reference gene for gene expression during meiotic recombination,and provided functional insights into meiotic recombination suppressors in G.hybrida.
基金the National Basic Research Program(973 Project)(Grant No.2011CB504805)the National Natural Science Foundation of China(Grant No.30900759/C0709)the Postdoctoral Foundation of China.
文摘RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21–23 nt RNA molecules.During infection,RNAi can act as an innate immune system to defend against viruses.As a counter-defensive strategy,silencing suppressors are encoded by viruses to inhibit various stages of the silencing process.These suppressors are diverse in sequence and structure and act via different mechanisms.In this review,we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses.We also review the modes of action proposed for some silencing suppressors.
文摘The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
文摘This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial disease resulting from a combination of genetic and epigenetic alterations in cell DNA,influencing proliferation,differentiation,and migration.TP53 gene,which codifies p53 protein,is a known tumor suppressor,and it plays an important role in cell maintenance as DNA repair,cell proliferation control,and apoptosis activation.TP53 expression can be modulated by several miRNAs,as miR-30c,miR-34a,and the miR-200 family,inhibiting p53 production and silencing its tumor suppressor effects.On the other hand,p53 protein can modulate several miRNAs expression,as miR-146a,miR-192,and the miR-200 family,by acting as a transcription factor or by modulating miRNA processing,interfering with BC aggressiveness and progression.Understanding the role of p53 and miRNAs in BC may aid in identifying new biomarkers and developing new targeted therapies for patient treatment.
基金funded by the Medical University of Lublin,Poland,grant number DS 458.
文摘Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.
文摘Inactivating mutations in tumor suppressor genes(TSGs)are known to drive tumorigenesis by decoupling proliferation and survival from tight regulatory mechanisms.In a recent study published in Science,Martin et al.1 shed light on an unappreciated role of TSGs in preventing immune evasion by demonstrating enrichment of TSG inactivation in tumor cell transplants in mice when facing an intact adaptive immune system.
文摘This study aimed to elucidate the role of collagen type XI alpha 1(COL11A1)-positive cancer-associated fibroblasts(CAFs)in modifying the tumor microenvironment of colon cancer(CC)and facilitating immune evasion through interactions with myeloid-derived suppressor cells(MDSCs).Using single-cell transcriptomic sequencing,we analyzed the interplay between COL11A1-positive CAFs and MDSCs in the CC microenvironment,focusing on how COL11A1 impacts MDSC differentiation and activation.The results demonstrate that COL11A1 expression in fibroblasts significantly enhances matrix metalloproteinase(MMP)3 and MMP13 expression,leading to paracrine induction of MDSC differentiation and activation,which promotes immune evasion and tumor growth.Additionally,we observed that COL11A1 knockout(COL11A1KO)suppresses tumor growth and hinders immune evasion.These findings underscore the essential role of COL11A1-positive CAFs in establishing an immunosuppressive tumor microenvironment conducive to CC progression.By elucidating the molecular pathway through which COL11A1 influences MDSC activity,this research suggests new therapeutic avenues for targeting the tumor microenvironment in CC,particularly through modulating COL11A1 expression in CAFs.
文摘Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82260718,82460716 and 82111530101)Natural Science Foundation of Jiangxi Province,China(Grant Nos.:20224BAB216121,20232BAB216137 and 20242BAB25579)+1 种基金Jiangxi Provincial Thousand Talents Training Program for High Level Entrepreneurial and Innovative Talents,China(Program No.:jxsq2019201106)Ganzhou“Taking the Lead”Youth Project of Technology Innovation Empowerment(Project No.:JBGS20230001).
文摘The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 overexpression or activation is sufficient to induce tumor initiation,recurrence,and therapeutic resistance.However,CDK12 may also exert tumor-suppressive functions in a context-dependent manner.Therefore,caution is warranted when targeting CDK12 in future clinical trials.A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology.This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer.Subsequently,we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts.Finally,we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology,offering insights into future directions for innovative cancer treatment strategies.
基金supported by grants from the São Paulo Research Foundation(FAPESP)to ThaináRodrigues(2021/04603-8).
文摘Objectives:Bladder Cancer(BC)is one of the most commonly diagnosed malignancies worldwide,with high rates of mortality and morbidity.It can be classified as non-muscle invasive bladder cancer(NMIBC)or muscle-invasive bladder cancer(MIBC),with radical cystectomy being the treatment for MIBC,which significantly reduces quality of life.MicroRNAs(miRs)act as critical genetic regulators,with both oncogenic and tumor-suppressive roles.MiR-10a is described as a tumor suppressor in various neoplasms,but its role in BC is controversial.This study aims to assess the activity of miR-10a in cellular invasion and proliferation in two distinct BC cell lines.Methods:The study used high-grade T24 and low-grade RT4 bladder cell lines.Cells were transfected with miR-10a mimic or a non-targeting control.Transfection efficiency was validated by qPCR.Cell proliferation was cultured for 10–14 days.Cell migration and invasion were evaluated using Matrigel.All assays were conducted in triplicate.Results:The T24 cells transfected with miR-10a presented decreased cellular proliferation and invasion compared to the Scramble(p=0.0481 and p<0.0001,respectively).In the RT4 cell line,there was only a significant reduction in cellular proliferation after miR-10a transfection(p=0.0029).Conclusions:Our findings suggest that miR-10a has a tumoral suppressor role in BC,demonstrating higher efficacy in high-grade cells.
文摘BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.
基金Supported by Wu Jieping Medical Foundation,No.320.6750.2021-06-30Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110120National Natural Science Foundation of China,No.82002974。
文摘BACKGROUND Liver hepatocellular carcinoma(LIHC)is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment(TME)and immune evasion.Regulatory T cells(Tregs)play a critical role in tumor progression.Suppressor of cytokine signaling 2(SOCS2),a key immune regulator,may modulate Treg activity and impact LIHC growth and metastasis.AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis,Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data,and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration.Key prognostic genes were identified using Weighted Gene Coexpression Network Analysis and machine learning.In vitro,co-culture experiments,migration assays,apoptosis detection,and enzyme-linked immunosorbent assay were conducted.In vivo,tumor growth,metastasis,and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining,Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling,and immunohistochemistry analyses.RESULTS SOCS2 overexpression inhibited Treg cell activity,reducing LIHC cell migration and invasion while increasing apoptosis.In vivo,SOCS2 suppressed tumor growth and metastasis,confirming its therapeutic potential.CONCLUSION SOCS2 modulates CD4+T function in the TME,contributing to LIHC progression.Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.
基金Supported by Colegio de Ciencia y Tecnologia de la Universidad Autónoma de la Ciudad de México,No.UACM-CCyT-2025-CON-11.
文摘Proteases are essential for homeostasis,and their primary function is proteolytic in extracellular and intracellular compartments.The deregulation of expression,abundance,and activity of proteases has been related to several pathologies,including cancer.This deregulation contributes to their pro-tumorigenic activity since they participate in the degradation of extracellular matrix components and adhesion molecules,and the activation of growth factors.However,some proteases,such as ADAM metallopeptidase with thrombospondin type 1 motif 8 and kallikrein-related peptidases 5 and 10,have emerged as tumor suppressors due to their antitumoral actions in specific cancer contexts.In this article,we discuss the antitumoral effects of ADAM metallopeptidase with thrombospondin type 1 motif 8,kallikrein-related peptidases 5 and 10 that have been described to date,suggesting their potential use as novel biomarkers and therapeutic targets in cancer.
基金supported by the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2021R1A2C3003414,2021R1A6A1A03038890,2022R1I1A1A01053839,RS-2023-00246963)the Korea government(MSIT)(RS-2024-00344635)the Korea Basic Science Institute(National Research Facilities and Equipment Center,No.2021R1A6C101A564).
文摘Osteosarcoma is a bone malignancy characterized by strong invasiveness and rapid disease progression.The tumor microenvironment of osteosarcoma contains various types of immune cells,including myeloid-derived suppressor cells,macrophages,T cells,and B cells.Imbalances of these immune cells can promote the proliferation and metastasis of osteosarcoma.Recent studies have indicated a substantial increase in the levels of myeloid-derived suppressor cells,an immune cell associated with immunosuppressive and pro-cancer effects,in the peripheral blood of patients with osteosarcoma.Moreover,the levels of the pro-inflammatory cytokine interleukin 18 are positively correlated with those of myeloid-derived suppressor cells in the peripheral blood of animal models of osteosarcoma.In this review,we explore the function of myeloid-derived suppressor cells in osteosarcoma based on the clinical diagnoses of patients with osteosarcoma and discuss future therapeutic approaches for targeting osteosarcoma.Targeting myeloid-derived suppressor cells represents a promising approach to improving the prognosis and survival rates of patients with osteosarcoma.
基金supported by the following funding:National Natural Science Foundations of China(82002888,82272899 and 82370974)Sichuan Science and Technology Program(2022YFS0207 and 2023YFS0127)+1 种基金Scientific Research Foundation,WestChinaHospital of Stomatology SichuanUniversity(RCDWJS2021-8)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-004).
文摘This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression pattern in OSCC,and the expression levels of PERs in OSCC patients are correlated with a favorable prognosis.PERs impact the occurrence and development of OSCC through multiple pathways.In the regulation of cell proliferation,they can function not only through cell cycle regultion but also via metabolic pathways.For example,PER1 can interact with receptors for activated C kinase 1(RACK1)and phosphatidylinositol 3-kinase(PI3K)through its PAS domain to inhibit glycolysis and thereby reduce cell proliferation.Regarding the regulation of cell death,PERs mediate various types of cell death in OSCC cells,such as p53-dependent apoptosis,protein kinase B(AKT)/mammalian target of rapamycin(mTOR)dependent autophagy,or hypoxia-inducible factor l-alpha(HIF-1a)mediated ferroptosis.In regulating epithelia-mesenchymal transition(EMT),PERs can lead to the downregulation of EMT related genes,such as zinc finger E-box binding homeobox 1/2(ZEBI/2),twist family BHLH transcription factor 1/2(TWIST1/2),and Vimentin,thereby influencing the migration and invasion capabilities of OSCC cells.In tumor angiogenesis,PERs exert regulatory effects on related factors,such as methionyl aminopeptidase 2(MetAP2)and vascular endothelial growth factor(VEGF).In the tumor immune microenvironment,PERs can inhibit the inhibitor of kappa B kinase(IKK)/nuclear factor kappa B(NF-kB)pathway and programmed cell death ligand 1(PD-L1)expression,thereby enhancing the cytotoxic effect of CD8+T cells on OSCC cells.In-depth studies focusing on elucidating the precise regulatory mechanisms of PERs can facilitate the development of therapeutic strategies targeting PERs,including restoration of PERs expression/activity,targeting PERs-regulated pathways,combination therapies,and chronotherapy.These furnish a theoretical foundation for formulating individualized treatment plans to achieve precise treatment for patients with OSCC.
基金Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C803).
文摘Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.
