RETRACTED: MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Abstract

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, fibrosis, 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 demonstrated 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, inflammation, 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.

Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities

“…Many biological processes, including inflammation, fibrosis, and cancer, are controlled by miR-21 [209]. MicroRNA-21 (miR-21) is an oncogenic miRNA that is typically elevated in hepatocellular carcinoma (HCC) [210][211][212][213]. It promotes the release of inflammatory substances such as interleukin 6 (IL-6) [214], signal transducer, and activator of transcription 3 (STAT3)-dependent mechanism [215].…”

Current Options and Future Directions for NAFLD and NASH Treatment

“…There are some essential molecules and their associated signaling pathways involved in the progression of NAFLD by mediating the lipid and sugar metabolism, cell apoptosis, liver inflammation and fibrosis, and so on. For example, the well-known transforming growth factor-beta 1 ( TGF-β1 ) signaling pathway plays critical roles in liver cell apoptosis [ 15 ], inflammation [ 16 ], NAFLD, and NAFLD-related HCC progression [ 17 , 18 ]. The signaling pathways involved by important molecules are potential targets for developing NAFLD and NASH diagnosis and treatment.…”

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

“…miR-21 induces NASH via the STAT3 signaling pathway and induces liver fibrosis via HSC activation and collagen deposition via the TGF-β/Smad3/Smad7 signaling pathway [ 97 ]. Overexpression of hepatic miR-27 promotes the expression of hepatic insulin receptors, while inhibition decreases insulin sensitivity, suggesting that miR-27 may contribute to the early development of hepatic insulin resistance [ 103 ].…”