2022, Volume 16, Issue 9
Engineering >> 2022, Volume 16, Issue 9 doi: 10.1016/j.eng.2021.07.020
MiR-516a-3p is a Novel Mediator of Hepatocellular Carcinoma Oncogenic Activity and Cellular Metabolism
a Department of Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
b 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
c Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
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Abstract
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.
Keywords
Hepatocellular carcinoma ; miRNA cluster ; Exosome ; Multi-omics
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