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.

The 2010 Revisions to the McDonald Criteria have established that dissemination in time (DIT) of multiple sclerosis (MS) can be demonstrated by simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions on a single magnetic resonance imaging (MRI). However, gadolinium-based contrast agents (GBCAs) have contraindications. Diffusion-weighted imaging (DWI) can detect diffusion alterations in active inflammatory lesions. The purpose of this study was to investigate if DWI can be an alternative to contrast-enhanced T1-weighted imaging (CE T1WI) for demonstrating DIT in MS. We selected patients with clinically definite MS and evaluated their baseline brain MRI. Asymptomatic lesions were identified as either hyperintense or nonhyperintense on DWI and enhancing or nonenhancing on CE T1WI. Fisher’s exact test was performed to determine whether the hyperintensity on DWI was related to the enhancement on CE T1WI (P < 0.05). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the DWI to predict lesion enhancement were calculated. Twenty-two patients with 384 demyelinating lesions that were hyperintense on T2-weighted imaging and more than 3 mm in size were recruited. The diffusion hyperintensity and lesion enhancement were significantly correlated (P <0.001). The sensitivity, specificity, PPV, NPV and accuracy were 100%, 67.9%, 32.3%, 100% and 72.1%, respectively. A hyperintense DWI finding does not necessarily overlap with contrast enhancement. There are many false positives, possibly representing other stages of lesion development. Although DWI may not replace CE T1WI imaging to demonstrate DIT due to the low PPV, it may serve as a screening MRI sequence where the use of GBCAs is a concern.

The authors wish to make the following corrections to this paper

The Cancers Editorial Office retracts the article, “MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling”