Abstract
The capability of microRNAs (miRNAs) to regulate gene expression across species has opened new avenues for miRNA-based therapeutics. Here, we investigated the potential of PC-5p-1090 (miR-PC-1090), a miRNA found in deer antlers, to control the malignant phenotypes of hepatocellular carcinoma (HCC) cells. Using Cell Counting Kit-8 and transwell assays, we found that heterologous expression of miR-PC-1090 inhibited HCC cell proliferation, migration, and invasion. Bioinformatics analysis indicated that predicted miR-PC-1090 targets, including MARCKS, SMARCAD1, and SOX9, were significantly elevated in HCC tissues, and their high expressions were associated with poor overall survival of HCC patients. Moreover, mechanistic investigations revealed that miR-PC-1090 promoted the degradation of MARCKS and SMARCAD1 mRNAs and hindered the translation of SOX9 mRNA by recognizing their 3′ untranslated regions. Subsequent loss-of-function and rescue experiments confirmed the involvement of MARCKS, SMARCAD1, and SOX9 in miR-PC-1090-suppressed HCC cell proliferation, migration, and invasion. Notably, MARCKS knockdown induced the downregulation of phosphorylated MARCKS and a corresponding upregulation of phosphorylated AKT in HCC. Conversely, miR-PC-1090 repressed MARCKS phosphorylation and effectively circumvented the activation of the PI3K/AKT pathway. Furthermore, miR-PC-1090 regulates the Wnt/β-catenin pathway through SMARCAD1- and SOX9-mediated reduction of β-catenin expression. Overall, our results illustrate the tumor-suppressive activity and molecular mechanism of antler-derived miR-PC-1090 in HCC cells, indicating its potential as a multiple-target agent for HCC treatment.
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Acknowledgements
The results published here are partly based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
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This work was supported by the National Natural Science Foundation of China (Grant No. 31671283 to DZ) and the Fundamental Research Funds for the Central Universities (Grant No. 2572019AA11 to JW).
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DZ, XDL, JW, and YXC conceived and designed the project. JW and FY performed experiments. MDZ constructed the plasmids. HX conducted the luciferase reporter assay of SOX9 3′ UTR. JW and FY conducted data and visualization analysis. JW and FY wrote and revised the manuscript.
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Wu, J., Yang, F., Zhao, M. et al. Antler-derived microRNA PC-5p-1090 inhibits HCC cell proliferation, migration, and invasion by targeting MARCKS, SMARCAD1, and SOX9. Funct Integr Genomics 23, 156 (2023). https://doi.org/10.1007/s10142-023-01089-x
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DOI: https://doi.org/10.1007/s10142-023-01089-x