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Review
. 2020 Jul 23;9(8):1767.
doi: 10.3390/cells9081767.

MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury

Jovana Markovic  1   2 , Amar Deep Sharma  1   2 , Asha Balakrishnan  1   3
Affiliations
Review

MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury

Jovana Markovic et al. Cells. .

Abstract

The last decade has witnessed significant advancements in our understanding of how small noncoding RNAs, such as microRNAs (miRNAs), regulate disease progression. One such miRNA, miR-221, has been shown to play a key role in the progression of liver fibrosis, a common feature of most liver diseases. Many reports have demonstrated the upregulation of miR-221 in liver fibrosis caused by multiple etiologies such as viral infections and nonalcoholic steatohepatitis. Inhibition of miR-221 via different strategies has shown promising results in terms of the suppression of fibrogenic gene signatures in vitro, as well as in vivo, in independent mouse models of liver fibrosis. In addition, miR-221 has also been suggested as a noninvasive serum biomarker for liver fibrosis and cirrhosis. In this review, we discuss the biology of miR-221, its significance and use as a biomarker during progression of liver fibrosis, and finally, potential and robust approaches that can be utilized to suppress liver fibrosis via inhibition of miR-221.

Keywords: HCC; NASH; liver fibrosis; miR-221; noninvasive biomarker.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The sequences of miR-221 and miR-221*. Mature sequence of miR-221-5p is in blue, while miR-221-3p is shown in red. The seed sequence of the miRNA is highlighted.
Figure 2
Figure 2
Biogenesis of miR-221 is shown on the right side of the figure. The pri-miR-221/222 cluster is first generated and then processed into pre-miR-221 and pre-miR-222 in the nuclei. Upon translocation of pre-miR-221 from the nuclei to the cytoplasm, Dicer mediates another processing to generate miRNA duplex. One of the strands may be incorporated into RISC complex to regulate gene expression at the posttranscriptional level. On the left side of the schematic, multiple approaches of in vivo miR-221 inhibition are shown. MiR-221 can be inhibited via sponges, antimiR containing nanoparticles, TuDs, miR-zips and LNAs. Each method has been shown to be effective in miR-221 in vivo inhibition. Due to miR-221 inhibition, amelioration of liver fibrosis and attenuation of HCC development was observed.
Figure 3
Figure 3
The main etiologies of liver fibrosis are chronic viral hepatitis infection, NASH and cholestatic diseases. If left untreated, extensive liver fibrosis often leads to the development of HCC. At present, the most commonly used method to diagnose liver disease is biopsy, which is invasive and often time-consuming. More importantly, the biopsy is often performed at later stages, by which time the only effective treatment option is transplantation. MiR-221 has been shown as a miRNA that can serve as a serum biomarker for diagnosis, to distinguish different diseases and as a marker of recovery. (A) HCV is one of the most prevalent causes of liver fibrosis. Multiple studies have shown miR-221 upregulation in the sera of patients with HCV. Furthermore, in HCV, miR-221 expression is under the control of NF-Kb, and it targets SOCS1 and SOCS3. (B) HCC is the fourth leading cause of cancer-related deaths worldwide. High levels of miR-221 have been detected in HCC tissues and in the sera of patients with HCC. Based on the serum levels, miR-221 can be used together with AFP as a biomarker of HCC development, severity and outcome. Patients with high miR-221 had more advanced HCC and lower survival rates than those with low miR-221 serum levels. (C) In contrast, in AOC, the upregulation of miR-221 in patient’s sera is considered a sign of recovery. In AOC, hepatocyte proliferation and liver regeneration occur due to high HGF signaling. HGF is the key ligand for the receptor tyrosine kinase, c-Met, which, in turn, enhances miR-221 transcription. High levels of miR-221 in the liver repress SOCS1 levels. Since SOCS1 is an inhibitor of HGF signaling, its repression by miR-221 leads to enhanced HGF signaling and active liver regeneration and recovery.
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