Hepatocellular carcinoma(HCC)remains one of the most lethal malignancies.We previously demon-strated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prog-nosis in patients with HCC.In the current study,we aim to explore the role of miR-516a-3p-an identical mature microRNA(miRNA)co-spliced by four oncogenic pre-miRNAs of C19MC(i.e.,mir-516a-1,mir-516a-2,mir-516b-1,and mir-516b-2)—in HCC.In our cohort of HCC patients,miR-516a-3p was highly expressed in HCC tissues in comparison with adjacent non-tumor tissues.High expression of tumor miR-516a-3p significantly correlated with advanced tumor stages,distinguished high HCC recurrence and mortality,and independently predicted poor prognosis.We further found that miR-516a-3p enhanced the proliferation,migration,and invasiveness of HCC cells in vitro and promoted tumor growth and metastasis in vivo.Among cancer cells,miR-516a-3p could be delivered via exosomes or extracellular vesicles and increased the oncogenic activity of recipient cells.Moreover,we performed comprehensive transcriptomics,proteomics,and metabolomics analysis on the potential mechanism underlying miR-516a-3p-promoted oncogenicity.MixOmic DIABLO analysis showed a close correlation and strong cluster consistency between the proteomics and metabolomics datasets.We further confirmed six proteins(i.e.,LMBR1,CHST9,RBM3,SLC7A6,PTGFRN,and NOL12)as the direct targets of miR-516a-3p and as central players in miR-516a-3p-mediated metabolism regulation.The integrated multi-omics and co-enriched pathway analysis showed that miR-516a-3p regulates the metabolic pathways of HCC cells,particularly purine and pyrimidine metabolism.In conclusion,our findings suggest that miR-516a-3p promotes malignant behaviors in HCC cells by regulating cellular metabolism and affecting neighboring cells via the exosome delivery system.Thus,we suggest miR-516a-3p as a novel molecular target for HCC therapy.

Tao Rui;Xueyou Zhang;Shi Feng;Haitao Huang;Shaowei Zhan;Haiyang Xie;Lin Zhou;Shusen Zheng;Qi Ling

Department of Surgery,Affiliated Hangzhou First People's Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China;Department of Surgery,Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China;Key Laboratory of Organ Transplantation,Research Center for Diagnosis and Treatment of Hepatobiliary Diseases,Zhejiang Province,Hangzhou 310003,China

工程（英文）

[1]Tao Rui;Xueyou Zhang;Shi Feng;Haitao Huang;Shaowei Zhan;Haiyang Xie;Lin Zhou;Shusen Zheng;Qi Ling-.MiR-516a-3p is a Novel Mediator of Hepatocellular Carcinoma Oncogenic Activity and Cellular Metabolism)[J].工程（英文）,2022(09):162-175

516a,Oncogenic,C19MC,516b,oncogenicity,MixOmic,LMBR1,CHST9,SLC7A6,PTGFRN,NOL12

MiR,3p,Novel,Mediator,Hepatocellular,Carcinoma,Activity,Cellular,Metabolism,carcinoma,HCC,remains,one,most,lethal,malignancies,We,previously,demon,strated,that,chromosome,microRNA,cluster,was,associated,tumor,burden,patients,In,current,study,aim,explore,role,identical,mature,spliced,by,four,miRNAs,mir,cohort,highly,expressed,tissues,comparison,adjacent,High,expression,significantly,correlated,advanced,stages,distinguished,recurrence,mortality,independently,predicted,poor,prognosis,further,found,enhanced,proliferation,migration,invasiveness,cells,vitro,promoted,growth,metastasis,vivo,Among,cancer,could,delivered,via,exosomes,extracellular,vesicles,increased,activity,recipient,Moreover,performed,comprehensive,transcriptomics,proteomics,metabolomics,analysis,potential,mechanism,underlying,DIABLO,showed,close,correlation,strong,consistency,between,datasets,confirmed,six,proteins,RBM3,direct,targets,central,players,mediated,metabolism,regulation,integrated,multi,enriched,regulates,metabolic,pathways,particularly,purine,pyrimidine,conclusion,findings,suggest,promotes,malignant,behaviors,regulating,affecting,neighboring,delivery,system,Thus,novel,molecular,therapy

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