Overview of miR-221
Numerous studies indicated that miRNAs are especially abundant in the
nervous system, and play a part in maintaining efficient mammalian brain
function. miRNAs have a unique cellular or tissue expression profile in
response to the nervous system (L. Zhao & Wang, 2019a). miRNAs
typically bind to the 3’ untranslated region (UTR) of target mRNAs,
leading to post-transcriptional regulation of gene expression.
Repression of mRNA translation or degradation is the result of this
interaction, which depends on the degree of complementarity between
miRNA and its target mRNA (Di Martino et al., 2022).
miR-221 was first identified in 2002 by Lagos-Quintana and colleagues as
a small non-coding RNA molecule that is highly expressed in human
endothelial cells (Lendeckel). Various cellular mechanisms, such as cell
proliferation, differentiation, and apoptosis, are regulated by miR-221,
which is involved in numerous diseases, including cancer and
cardiovascular disease (Eyermann, Czaplinski, & Colognato, 2012;
Garofalo & Croce, 2011; Im & Kenny, 2012). In human DNA, the miR-221
is a gene cluster located on chromosome Xp11.3, which is transcribed
together with miR-222 as primary miRNA (pri-miR)-221/222. They have the
same seed sequence and are 726 base pairs far apart. The promoter of
pri-miR-221/222 is located in the intergenic region between the CDKN1B
and TMEM87A genes on chromosome Xp11.3 in humans (Fornari et al., 2008;
Visone et al., 2007). The promoter region has several binding sites for
transcription factors, including E2F, SP1, and MYC, which are involved
in the regulation of pri-miR-221/222 expression. Additionally, there are
three poly-A sequences found downstream of pre-miR-221 and two types of
canonical TATA boxes at 550 and 190 bp upstream of pre-miR-222 in the
miR-221/222 promoter region. Pre-miR-221 and pre-miR-222 are created as
a result of the nuclear processing of pri-miR-221/222 that is mediated
by Drosha and the RNA-binding protein DGCR8. These two miRNAs are 110
nucleotides long and are transported out of the nucleus by the
exportin-5 transporter. Dicer cleaves the miR-221 molecule into its
mature form. The RNA-induced silencing complex (RISC), made up of the
mature miR-221 and several other mature miRNAs, is created by their
binding to an Argonaute (AGO) protein (Figure 1 ) (Di Martino et
al., 2022; Markovic, Sharma, & Balakrishnan, 2020; Visone et al.,
2007). MiR-221 contributes to the expression of specific genes,
participates in the regulation of the cell cycle, and is involved in
several biological mechanisms like cell differentiation and development
(Gao et al., 2023), immune responses (Du et al., 2018; Mikami et al.,
2021), metabolism (Y.-T. Wang, Tsai, Liao, Hsu, & Juo, 2013), and
carcinogenesis (Guo et al., 2021), epigenetic regulators of immune cells
reprogramming (Seeley et al., 2018). Moreover, miR-221 significantly
raises the level of proinflammatory cytokines (D. Zhao, Zhuang, Ding,
Kang, & Shi, 2016).