Hepatocellular carcinoma(HCC)remains one of the most lethal malignancies.We previously demonstrated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prognosis in patients with HCC.In ...Hepatocellular carcinoma(HCC)remains one of the most lethal malignancies.We previously demonstrated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prognosis 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.展开更多
Liver transplantation(LT)provides a cure for various end-stage liver diseases.The liver graft becomes the recipient’s new metabolic center,and donor genetics plays a potent role in the development of complications in...Liver transplantation(LT)provides a cure for various end-stage liver diseases.The liver graft becomes the recipient’s new metabolic center,and donor genetics plays a potent role in the development of complications in the recipient,such as metabolic disorders1 and even tumor recurrence.2 Notably,both the donor’s3 and recipient’s genetics4 contributes significantly to intrahepatic complications(e.g.,liver fibrosis and de novo steatosis).Therefore,crosstalk between donor and recipient tissue remodels the architecture and homeostasis of the transplanted liver,which is still a great challenge to explore.展开更多
基金supported by the National Natural Science Foundation of China(81771713 and 81721091)the Zhejiang Provincial Natural Science Foundation of China(LR18H030001)。
文摘Hepatocellular carcinoma(HCC)remains one of the most lethal malignancies.We previously demonstrated that the chromosome 19 microRNA cluster(C19MC)was associated with tumor burden and prognosis 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.
基金supported by the National Natural Science Foundation of China(81771713)the Zhejiang Provincial Natural Science Foundation of China(LR18H030001)the Fundamental Research Funds for the Central Universities(2019QNA7030).
文摘Liver transplantation(LT)provides a cure for various end-stage liver diseases.The liver graft becomes the recipient’s new metabolic center,and donor genetics plays a potent role in the development of complications in the recipient,such as metabolic disorders1 and even tumor recurrence.2 Notably,both the donor’s3 and recipient’s genetics4 contributes significantly to intrahepatic complications(e.g.,liver fibrosis and de novo steatosis).Therefore,crosstalk between donor and recipient tissue remodels the architecture and homeostasis of the transplanted liver,which is still a great challenge to explore.
