miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis

Xiutao Fu; Jingbo Qie; Qingchun Fu; Jiafeng Chen; Yinpeng Jin; Zhenbin Ding

doi:10.3389/fonc.2020.00107

miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis

Front Oncol. 2020 Feb 13:10:107. doi: 10.3389/fonc.2020.00107. eCollection 2020.

Authors

Xiutao Fu¹, Jingbo Qie², Qingchun Fu³, Jiafeng Chen¹, Yinpeng Jin³, Zhenbin Ding¹

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
² Minhang Hospital and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
³ Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Abstract

Combined inhibition of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β) displayed additive anti-tumor response in a subgroup of cancer patients, highlighting the importance of understanding the multifaceted roles of TGF-β in immunity and fibrosis. In the present research, we show that TGF-β signaling pathway, controlled by miR-20a-5p and transforming growth factor-β receptor 2 (TGFBR2), alters the inflammation and fibrosis processes in liver. We performed integrated analysis of differently expressed miRNA (DEM) associated with liver fibrosis and screened miR-20a-5p out as a key regulator in inflammation-driven liver fibrosis. We subsequently conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the genes targeted by miR-20a-5p. And the result showed that 12 target genes were significantly enriched in TGF-β signaling pathway. Further study showed that miR-20a-5p was down-regulated and involved in inflammation during liver fibrosis in human and mouse samples, indicating that miR-20a-5p and inflammation are functionally linked during liver fibrosis progression. To uncover the underlying pro-inflammatory mechanism of miR-20a-5p in liver fibrosis, we selected and verified TGFBR2, which is a key functional receptor in TGF-β signaling pathway, as a direct target gene of miR-20a-5p. The downregulation of miR-20a-5p in liver fibrosis resulted in TGFBR2-activated TGF-β signaling pathway, followed by the activation of macrophage and extracellular matrix (ECM) production by hepatic stellate cell (HSC). Our results identify the miR-20a-5p/TGFBR2 axis as a key regulator of TGF-β signaling, and highlight the critical role of miR-20a-5p in the development of liver fibrosis.

Keywords: TGF-β signaling pathway; TGFBR2; inflammation; liver fibrosis; miR-20a-5p.