LncRNA TP73-AS1/miR-539/MMP-8 axis modulates M2 macrophage polarization in hepatocellular carcinoma via TGF-β1 signaling
| Autor: | Cheng-Jin Liao, Sha-Ling Li, Xue-Gong Fan, Min Qi, Ze-Bing Huang, Yan Huang, Xingwang Hu, Jun Chen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Carcinoma Hepatocellular Macrophage polarization Flow cytometry Transforming Growth Factor beta1 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Western blot Cell Movement Cell Line Tumor medicine Animals Humans Cell Proliferation Mice Inbred BALB C Gene knockdown medicine.diagnostic_test Chemistry Liver Neoplasms Tumor Protein p73 Cell Biology Transfection Macrophage Activation M2 Macrophage Gene Expression Regulation Neoplastic MicroRNAs Matrix Metalloproteinase 8 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Female CD163 |
| Zdroj: | Cellular Signalling. 75:109738 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2020.109738 |
| Popis: | Purpose Our study aimed to study the role of lncRNA TP73-AS1/miR-539/MMP-8 axis in modulating M2 macrophage polarization in hepatocellular carcinoma (HCC). Methods The gene expression levels of TP73-AS1, miR-539 and MMP-8 were modified by transfection with the overexpression or knockdown vectors. The patient survival rate was analyzed using Kaplan-Meier method. The levels of TP73-AS1, miR-539, MMP-8 and M1/2 macrophage polarization markers were analyzed by qRT-PCR, western blot, and flow cytometry. The release of TGF-β1 in the supernatant was determined by ELISA assay. The interaction between TP73-AS1, miR-539 and MMP-8 was analyzed by bioinformatics analysis and dual-luciferase reporter assays. Mouse xenograft model was further established to examine the therapeutic effects of the TP73-AS1 knockdown and miR-539 overexpression in vivo. Results We found TP73-AS1 and MMP-8 upregulation, and miR-539 downregulation in HCC tissues and cell lines. Lower TP73-AS1 and MMP-8 expressions and higher miR-539 expression were associated with higher survival rate of patients. M2-macrophage markers CD206, Arg-1 and CD163 were significantly upregulated in the tumor tissues. TP73-AS1 negatively and directly regulated miR-539 and knockdown of TP73-AS1 inhibited MMP-8 expression and M2 macrophage polarization. Also, overexpression of miR-539 suppressed M2 macrophage polarization by negatively regulating MMP-8. Furthermore, knockdown of MMP-8 also restrained M2 macrophage polarization via inhibiting TGF-β1 signaling. We also found knockdown of TP73-AS1 or overexpression of miR-539 inhibited HCC tumor growth and M2 macrophage infiltration in vivo. Conclusion Our study demonstrated lncRNA TP73-AS1 negatively regulated miR-539 to promote MMP-8 expression, which activated TGF-β1 signaling to induce M2 macrophage polarization in HCC. |
| Databáze: | OpenAIRE |
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