Microrna‐21 plays multiple oncometabolic roles in the process of nafld‐related hepatocellular carcinoma via pi3k/akt, tgf‐β, and stat3 signaling

Chi Yu Lai, Kun Yun Yeh, Chiu Ya Lin, Yang Wen Hsieh, Hsin Hung Lai, Jim Ray Chen, Chia Chun Hsu, Guor Mour Her*

*此作品的通信作者

研究成果: Article同行評審

21 引文 斯高帕斯(Scopus)

摘要

MicroRNA‐21 (miR‐21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)‐inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR‐21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibro-sis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR‐21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)‐related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR‐21 regulatory proteins (i.e., PTEN, SMAD7, p‐AKT, p‐SMAD3, and p‐STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demon-strated that miR‐21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR‐21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF‐β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, in-flammation, fibrosis and activation of the PI3K/AKT, TGF‐β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR‐21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

原文English
文章編號940
頁(從 - 到)1-31
頁數31
期刊Cancers
13
發行號5
DOIs
出版狀態Published - 1 3月 2021

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