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MicroRNA-34a: A Novel Therapeutic Target in Fibrosis

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Fibrosis can occur in many organs, and severe cases leading to organ failure and death. No specific treatment for fibrosis so far. In recent years, microRNA-34a (miR-34a) has been found to play a role in fibrotic diseases. MiR-34a is involved in the apoptosis, autophagy and cellular senescence, also regulates TGF-β1/Smad signal pathway, and negatively regulates the expression of multiple target genes to affect the deposition of extracellular matrix and regulate the process of fibrosis. Some studies have explored the efficacy of miR-34a-targeted therapies for fibrotic diseases. Therefore, miR-34a has specific potential for the treatment of fibrosis. This article reviews the important roles of miR-34a in fibrosis and provides the possibility for miR-34a as a novel therapeutic target in fibrosis.
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MicroRNA-34a: A Novel Therapeutic
Target in Fibrosis
Min Zhao
1
, Qin Qi
2
,
3
, Shimin Liu
2
,
3
, Rong Huang
2
, Jiacheng Shen
2
, Yi Zhu
3
, Jing Chai
2
,
Handan Zheng
2
,
3
, Huangan Wu
2
,
3
* and Huirong Liu
2
,
3
*
1
Department of Acupuncture-Moxibustion, LongHua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine, Shanghai, China,
2
Key Laboratory of Acupuncture and Immunological Effects,
Shanghai University of Traditional Chinese Medicine, Shanghai, China,
3
Shanghai Research Institute of Acupuncture and
Meridian, Shanghai, China
Fibrosis can occur in many organs, and severe cases leading to organ failure and death. No
specic treatment for brosis so far. In recent years, microRNA-34a (miR-34a) has been
found to play a role in brotic diseases. MiR-34a is involved in the apoptosis, autophagy
and cellular senescence, also regulates TGF-β1/Smad signal pathway, and negatively
regulates the expression of multiple target genes to affect the deposition of extracellular
matrix and regulate the process of brosis. Some studies have explored the efcacy of
miR-34a-targeted therapies for brotic diseases. Therefore, miR-34a has specic potential
for the treatment of brosis. This article reviews the important roles of miR-34a in brosis
and provides the possibility for miR-34a as a novel therapeutic target in brosis.
Keywords: microRNA-34a, brosis, apoptosis, autophagy, senescence, TGF-β1/Smad signal pathway, target genes
INTRODUCTION
Fibrosis (FB) is an excessive repair reaction of the body to external injury, resulting in
structural damage and dysfunction of normal tissues and organs, which affects the patients
physical and mental health and quality of life seriously (Jun and Lau, 2018;Henderson et al.,
2020). It is a high-burden diseases, and the annualized incidence of major brosis-related
conditions is nearly 1/20 (Tsou et al., 2014;Zhao et al., 2020). At present, the treatment
methods are limited. In the early stage, drug therapy merely alleviate inammation and
symptoms; in the late stage, only surgery or organ transplantation can be selected. However,
the cure rate is still low and the recurrence rate is high (Rieder et al., 2012;Villac Adde et al.,
2018;Ramos et al., 2019;Cai et al., 2020). Some researches has investigated a variety of
regulator (such as microRNA, TGF-β,interleukins,IFN-γ) for the treatment of FB, which only
acertainefcacy (Ghosh et al., 2013;Richeldi et al., 2017;Gieseck et al., 2018;Weiskirchen
et al., 2019). As the signal transduction network of FB is complex, the current researches on
therapeutic targets is not sufcient to support the clinical practice of FB. We need to further
clarify the specic function of various signal molecules in brosis to guide the clinical therapy.
Recently, many studies have found that microRNA-34a (miR-34a) plays a role in a variety of
brotic diseases by regulating cell proliferation, differentiation, apoptosis and other processes (Chen
and Hu, 2012;Alivernini et al., 2014;Zhou et al., 2017;Li et al., 2018)(Table 1). It has been found that
miR-34a can regulate the extracellular matrix (ECM) deposition by acting on the processes of
apoptosis, senescence and autophagy in epithelial/endothelial cells and broblasts (Tian et al., 2016;
Cui et al., 2017a;Zhu et al., 2019), and also promote transforming growth factor-β1 (TGF-β1)-
induced broblasts activation by targeting Smad4 (Huang et al., 2014;Qi et al., 2020); while the miR-
34a inhibitor can improve collagen deposition and attenuate brosis by regulating cell apoptosis and
Edited by:
Zhihong Yang,
Université de Fribourg, Switzerland
Reviewed by:
Paul J. Higgins,
Albany Medical College, United States
Amr M. Abdelhamid,
October University for Modern
Sciences and Arts (MSA), Egypt
*Correspondence:
Huangan Wu
wuhuangan@126.com
Huirong Liu
lhr_tcm@139.com
Specialty section:
This article was submitted to
Integrative Physiology,
a section of the journal
Frontiers in Physiology
Received: 13 March 2022
Accepted: 30 May 2022
Published: 20 June 2022
Citation:
Zhao M, Qi Q, Liu S, Huang R, Shen J,
Zhu Y, Chai J, Zheng H, Wu H and
Liu H (2022) MicroRNA-34a: A Novel
Therapeutic Target in Fibrosis.
Front. Physiol. 13:895242.
doi: 10.3389/fphys.2022.895242
Frontiers in Physiology | www.frontiersin.org June 2022 | Volume 13 | Article 8952421
REVIEW
published: 20 June 2022
doi: 10.3389/fphys.2022.895242
differentiation through Bcl-2, TGF-β1, and PPARγ(Zhou et al.,
2014;Li et al., 2015;Song et al., 2019).
According to current researches, miR-34a may be exploited as
a potential target for anti-brosis therapy in the future. In this
paper, we review studies on the involvement of miR-34a in
brotic diseases in order to reveal the possible mechanism of
miR-34a as a therapeutic target for FB.
Role of MicroRNA-34a in Various Molecular
Pathways of Fibrosis
MicroRNA are a class of small non-coding RNA containing about
1822 nucleotides that regulate gene expression at the post-
transcriptional level through completely or partially
complementary base binding to their target mRNAs (Tang
et al., 2015). MiR-34a is a member of miRNA family, which is
widely expressed in mammals (Hermeking, 2010). It has been
found that miR-34a affects the occurrence and development of
brotic diseases by regulating cell activities, including apoptosis,
autophagy, cellular senescence, the expression of related target
genes and TGF-β1/Smad signaling pathway (Figure 1).
Role of MicroRNA-34a in Apoptosis
Apoptosis is a process of programmed cell death in multicellular
organisms, which plays an important role in the development of
brosis (Zhang et al., 2001;Docherty et al., 2006). After injury,
cell apoptosis induce the recruitment of immune cells with
amplication of inammatory response and probrogenic
factors, enhance broblast proliferation, and then promotes
the regeneration of granulation tissue, which eventually leads
to the development of brotic lesions (Uhal, 2002;Bhandary
et al., 2012;Jun and Lau, 2018). MiR-34a has been found to play
an important role in the process of brosis by regulating
apoptosis.
MiR-34a is the direct transcription target of p53, and can
negatively regulate sirtuin 1(SIRT1), resulting in increased p53
acetylation. P53 and SIRT1 are typical genes involved in apoptosis
regulation (Yamakuchi et al., 2008;Li et al., 2011), and p53 is a
major contributor to the onset and progression of brotic diseases
(Yang et al., 2010;Sutton et al., 2013;Overstreet et al., 2014;
Valentijn et al., 2021;Fu et al., 2022;Li et al., 2022). Therefore, the
miR-34a SIRT1/p53 signaling pathway forms a positive feedback
loop that has a vital role in cell proliferation and apoptosis
(Tarasov et al., 2007;Kumamoto et al., 2008;Kim et al., 2015).
It was found that the expression level of miR-34a was positively
correlated with the severity of liver injury (Castro et al., 2013). In
liver tissue of rats with hepatic brosis, it has been observed that
miR-34a and acetyl-p53 were up-regulated and SIRT1 was down-
regulated; nevertheless, SIRT1 activator signicantly reduced the
levels of miR-34a and acetyl-p53, and inhibited brosis, which
suggested that miR-34a/SIRT1/p53 signaling pathway was
activated in brosis; in vitro, it was further conrmed that
miR-34a/SIRT1/p53 signaling pathway was activated in
epithelial cells to induce apoptosis, which activate hepatic
stellate cells (HSCs) and accelerate the process of liver brosis
(Tian et al., 2016). In addition, in the lung tissues of patients and
mice with pulmonary brosis, the apoptosis levels of alveolar
epithelial cells (AECs) were increased, the expression of acetyl-
p53, PAI-1, and miR-34a was increased, and the expression of
SIRT1 was decreased; however, the above process could be
reversed by knockout of the miR-34a gene (Shetty et al.,
2017). It can be seen that miR-34a/SIRT1/p53 is also involved
in the apoptosis of pulmonary epithelial cells and the induction of
pulmonary brosis.
Bcl-2 is an important antiapoptosis gene and one of the target
genes of miR-34a. MiR-34a can promote apoptosis by inhibiting
bcl-2 expression (Bommer et al., 2007). Tubular epithelial cells
apoptosis is one of the mechanisms of tubular atrophy and
TABLE 1 | MiR-34a acts on various organ brosis.
Tissue Species Target Mechanism References
Liver Rat, hepatocyte, mice, intrahepatic biliary epithelial cells,
HSCs, human
SIRT1, p53; caspase2 apoptosis Tian et al. (2016),Meng et al. (2012)
ACSL1; PPAR-γ;
RXRa
target genes Yan et al. (2015);Yan. (2016),Oda et al. (2014);Li
et al. (2015)
Smad4, Smad3 TGF-β1/Smad
pathway
Feili et al. (2018),Song et al. (2019)
p16p21CCL2
PAI-1
Cellular senescence Wan et al. (2017)
Kidney Mice, rat, renal tubular epithelial cells, renal interstitial
broblasts
Bcl-2 apoptosis Zhou et al. (2014);Li et al. (2019)
Klotho; Notch1 target genes Liu et al. (2019),Du et al. (2012)
SIRT1 autophagy Xue et al. (2018),Zhu et al. (2019)
Heart Rat, myocardial broblasts, mice C-Ski; PNUTS target genes Zhang et al. (2018),Boon et al. (2013)
Smad4 TGF-β1/smad
pathway
Huang et al. (2014)
PI3K/AKT autophagy Liu et al. (2018)
Lung Human, mice, type II alveolar epithelial cells SIRT1, p53 apoptosis Shetty et al. (2017)
nectin-1Abca3 target genes Takano et al. (2017)
E2F1c-Myc
CCNE2
Celluar senescence Disayabutr et al. (2016);Cui et al. (2017b)
Skin mice c-Met target genes Simone et al. (2014)
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Zhao et al. MicroRNA-34a: Therapeutic Target in Fibrosis
tubulointerstitial brosis (Docherty et al., 2006). In the study of
rats and mice with renal interstitial brosis, miR-34a was released
from mesenchymal broblasts and transferred to proximal
tubular epithelial cells, where it promoted apoptosis of renal
tubular epithelial cells by inhibiting the transcription and
translation of Bcl-2, further aggravating renal interstitial
brosis (Zhou et al., 2014;Li et al., 2019).
Furthermore, caspase-2 is also the target gene of miR-34a,
which helps to enhance apoptosis and plays a role in cell
remodeling and tissue repair (Madesh et al., 2009). In the
study of alcoholic liver disease, miR-34a was found to regulate
apoptosis of hepatocytes and intrahepatic biliary epithelial cells
by targeting caspase 2, affecting cell survival and migration, and
regulating the release of matrix metalloproteinases (MMPs).
Therefore, miR-34a plays a role in the repair of liver injury
and liver brosis (Meng et al., 2012). The above results
indicate that miR-34a participates in organ brosis by
regulating apoptosis-related signal molecules.
Role of MicroRNA-34a in Autophagy
Autophagy is a conserved lysosomal degradation process in
eukaryotic cells that plays an important role in maintaining
homeostasis in cells and tissues. Autophagy disorders
participate in the development of organ brosis. It has
been conrmed that autophagy promote the clearance of
damaged proteins and organelles, and accelerate the
degradation of extracellular matrix proteins (Ding and
Choi, 2014;Lv et al., 2017;Jesus et al., 2019); in addition,
intracellular autophagy ux can increases the energy needed
for extracellular matrix protein formation (Kota et al., 2017).
Some studies have found that autophagy mediates brotic
diseases regulated by miR-34a.
A study of epidural scar hyperplasia after laminectomy has
found that the expression of miR-34a and autophagy-related
molecules (beclin-1, ATG5, LC3B-2/1, p53) were changed,
which suggests that the disorder of miR-34a and autophagy
level may be involved in the formation of brosis (Wang B. B.
et al., 2017). The PI3K/Akt signaling pathway is a classical
autophagy regulatory pathway involved in the regulation of
cell proliferation, migration and differentiation (Zundler et al.,
2016;Aoki and Fujishita, 2017;Shi et al., 2017). This signaling
pathway is concerned in the study of myocardial brosis. In the
rat model of myocardial brosis induced by thyroid hormone,
miR-34a expression and PI3K and Akt proteins were found to be
upregulated, while autophagy related proteins (ATG5, Atg7,
Atg16L1, Beclin1, LC3A) were signicantly downregulated,
and MMPs/TIMPs ratios appeared imbalance. This study
suggested that myocardial brosis might be related to miR-
34a-mediated regulation of the PI3K/Akt signaling pathway
and inhibition of autophagy (Liu et al., 2018).
In addition, miR-34a indirectly interferes with the extension of
autolysosomes by inhibiting SIRT1(Yang et al., 2013). SIRT1 is
not only a molecule involved in autophagy activation, but also an
important component of the EMT, which plays an important role
in the process of organ brosis (Salminen and Kaarniranta, 2009;
Simic et al., 2013). It has been found that miR-34a-5p is up-
regulated accompanied by the corresponding down-regulation of
SIRT1 in the renal tissue of mice with diabetic nephropathy. MiR-
34a-5p was positively correlated with the expression of
bronectin (FN), type I collagen (COL 1), and TGF-β1; then
the cell experiments further identied that miR-34a-5p directly
suppressed SIRT1 to increase the probrogenic effects of TGF-β1
by targeting the 3-UTR of SIRT1; it has also been found that
miR-34a-5p inhibitor increases the expression of SIRT1 and
FIGURE 1 | Schematic diagram of miR-34a involved in brosis process. MiR-34a is involved in the apoptosis, autophagy and senescence, regulates TGF-β1/Smad
signal pathway, and negatively regulates the expression of multiple target genes to affect the process of organ brosis.
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Zhao et al. MicroRNA-34a: Therapeutic Target in Fibrosis
decreases the level of TGF-β1, FN, and COL 1, then a small
interfering RNA (siRNA) targeting SIRT1 enhanced the
expression of TGF-β1 and FB-related genes, indicating that
miR-34a-5p could promote renal brosis by inhibiting SIRT1
(Xue et al., 2018). In diabetic cardiomyopathy, miR-34a was also
found to aggravate myocardial injury related to inhibition of
SIRT1 transcription (Zhu et al., 2019). According to the current
research, we found that miR-34a is involved in the brosis process
by inhibiting autophagy-related molecules. Unfortunately, there
is insufcient evidence to explore the role of miR-34a in brosis
by regulating autophagy at present, further research is needed to
ll in this theory in the future.
Role of MicroRNA-34a in Cellular
Senescence
Cellular senescence is a process in which cells undergo irreversible
cell cycle arrest and is considered to play a key role in damage repair.
Fibroblast senescence is one of the important factors of brosis
pathology (Waters et al., 2018). It has been found that broblasts
derived from brotic tissue have a variety of senescence-related
characteristics. Myobroblasts senescence stop synthesizing collagen
and other ECM proteins, and secrete ECM protein-degrading
enzymes to improve matrix deposition and limit the
accumulation of brotic tissue (Harding et al., 2005;
Krizhanovsky et al., 2008;Jun and Lau, 2010;Álvarez et al.,
2017). Besides, epithelial cells senescence indirectly promotes the
differentiation of broblasts into myobroblasts, resulting in the
excessive deposition of collage (Lehmann et al., 2017).
As a downstream transcription target of p53, a cell cycle regulator,
miR-34a is closely related to cell senescence (Kyle et al., 2009;Harries,
2014). It has been proved that miR-34a can regulate cell cycle and
senescence by targeting multiple genes, such as SIRT1, cyclin E2,
cyclin D1, and E2F3 (Cui et al., 2017a). AECs are the main senescent
cells of pulmonary brosis. In the lung tissues and puried AECs of
patients with idiopathic pulmonary FB (IPF), the relative levels of
miR-34a, miR-34b and miR-34c were signicantly increased, the
activity of p16, p21, p53, and SA-β-gal was increased, and the
expression of miR-34 targets (E2F1, c-myc, and CCNE2) was
downregulated, these changes stimulated the senescence of AECs,
promoted myobroblast transdifferentiation and induced IPF
(Disayabutr et al., 2016;Cui et al., 2017b). In the study of hepatic
brosis, the same results were obtained. MiR-34a was up-regulated in
the patients with hepatic brosis, which promoting the senescence of
hepatocytes and inducing hepatic brosis by reducing the senescence
of HSCs; however, miR-34a inhibitor (morpholino) obstructed this
process and improved hepatic brosis, which indicating that miR-34a
plays a role in promoting hepatocytes senescence and reducing HSCs
senescence (Wan et al., 2017). Not only can miR-34a regulates
epithelial cell senescence and induce broblast to differentiate into
myobroblast, but also inhibits broblast senescence, promotes
broblast proliferation, and aggravates the brosis process.
Therefore, cell senescence plays an important role in the process of
miR-34a participating in brosis.
Regulation MicroRNA-34a on Typical
Target Genes
MiRNA-34a regulates growth, differentiation and metabolism by
negatively regulating typical target genes. Previous studies have
revealed that miR-34a can combined with multiple target genes to
regulate brosis in many ways.
ACSL1 is a member of Acyl-CoA synthetase long-chain
(ACSL) family. ACSL1 is an important gene in liver lipid
metabolism. The luciferase reporter assay conrmed that
ACSL1 was the target gene of miR-34a (Li et al., 2011). In the
research of hepatic brosis, miR-34a specically bound to the 3-
UTR of ACSL1, which negatively regulated the expression of
ACSL1 mRNA and protein, promoted the activation and
proliferation of HSCs, and lead to upregulation of ECM-
related indicators (COL 1, a-SMA); in contrast, silencing of
the miR-34a gene increased the expression of ACSL1,
decreased the expression of ECM-related proteins, and affected
HSCs activation (Yan et al., 2015;Yan, 2016). Thus, ACSL1 is one
of the factors by which miR-34a promotes hepatic brosis.
Protooncogene c-ski, a transcriptional corepressor, is a
negative regulator of TGF-β/Smad signaling (Cunnington
et al., 2009), and can inhibit TGF-β1-induced activation of
cardiac broblasts and ECM deposition (Wang J. et al., 2017).
In vitro and in vivo studies on myocardial brosis in rats, it was
found that miR-34a could target and inhibit the expression of
c-ski, and the levels of collagen I and aSMA were signicantly
increased; Inhibition of miR-34a signicantly increased the
expression of c-ski protein and decreased the levels of COL
one and a-SMA protein (Zhang et al., 2018). It can be seen
c-ski mediates miR-34a to promote the proliferation and ECM
deposition of TGF-β1-induced primary cultured rat cardiac
broblasts, which contribute to myocardial brosis.
Klotho, a specic antiaging protein of kidney, is mainly
expressed in renal tubular epithelial cells and has a signicant
anti-brosis effect (Guan et al., 2014;Ding et al., 2019). The
luciferase reporter assay showed that miR-34a directly down-
regulated the expression of Klotho. In renal brosis, the increased
expression of miR-34a is accompanied by the sharp
downregulation of Klotho, the increase of aSMA and
bronectin, and the decrease of E-cadherin, which promote
the process of epithelial mesenchymal transformation (EMT);
however, the expression of Klotho was signicantly increased and
EMT was inhibited in miR-34a/mice, so miR-34a negatively
regulates Klotho to promote EMT and induce renal brosis (Liu
et al., 2019).
In addition, there were other miR-34a target genes, including
PPAR-γ, PNUTS, RXRa, Notch1, c-Met, nectin-1, and Abca3,
have been found to affect the brosis process by regulating cell
proliferation, the EMT process and collagen synthesis (Du et al.,
2012;Boon et al., 2013;Oda et al., 2014;Simone et al., 2014;Li
et al., 2015;Takano et al., 2017). In various organ brosis, miR-
34a affects the process of brosis by targeting different protein-
coding genes.
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Zhao et al. MicroRNA-34a: Therapeutic Target in Fibrosis
Role of MicroRNA-34a in Transforming
Growth Factor-β1/Smad Signaling Pathway
Transforming growth factor-β1 (TGF-β1) is a key cytokine
involved in the formation of brosis (Ghosh et al., 2013) that
not only plays an important role in the transdifferentiation of
broblasts into myobroblasts but also triggers the EMT,
mesothelial-to-mesenchymal transition (MMT) and
endothelial-to-mesenchymal-transition (EndoMT) processes,
controls the extracellular matrix (ECM) synthesis, and
participates in the pathogenesis of brosis (Wu et al., 2013;
Weiskirchen et al., 2019). There is a certain correlation
between miR-34a disorders and TGF-βpathway in brotic
diseases (Xie et al., 2011;Zhang et al., 2014;Zhang J. et al., 2021).
Firstly, Bin Zhou found that eight miRNAs and seven mRNA
were involved in TGF-βsignal pathway, including miR-34a, in
systemic sclerosis (SSc) by Gene Expression Omnibus (GEO)
analysis (Zhou et al., 2017), this was a direct evidence that miR-
34a targets brosis through TGF-βsignaling pathway. Smad
transcription factors are the core of TGF-βpathway
(Massague et al., 2005). TGF-β1/Smad signaling pathway has
been widely recognized as a typical pathway in brosis (Zhang
et al., 2019;Lv et al., 2020). The expression of miR-34a was
increased in mice with cardiac brosis, and the degree of brosis
was inhibited by miR-34a antagonist; miR-34a directly targets
Smad4 mRNA according to luciferase reporter assay; when the
broblasts are transfected with Smad4 siRNA, the expression of
type I collagen, TGF-β1 and a-SMA was suppressed. The study
indicated that TGF-β1 induces the expression of miR-34a, which
in turn promotes the activation of TGF-β1-induced myocardial
broblasts and the formation of cardiac brosis by targeting
Smad4 (Huang et al., 2014). In carbon tetrachloride (CCl4)-
induced hepatic brosis mice, miR-34a imbalance was also found
to promote liver brosis via targeting Smad4 and activation TGF-
β1/Smad3 pathway (Feili et al., 2018).
Besides, miR-34a/SIRT1/p53 loop is also involved in the EMT
mediated by TGF-β1/Smad signaling pathway. Activated p53 (ac-
p53 and p-p53) combines with Smad3 to form a multiprotein
complex to promote TGF-β1-induced EMT process (Piccolo,
2008;Termén et al., 2013). In rat model of hepatic brosis, it
was found that miR-34a was overexpressed, SIRT1 was down-
regulated, p53 and ac-p53 were increased, with activated TGF-β1/
Smad signal pathway; miR-34a inhibitor and p53 siRNA
signicantly prevented TGF-β1-induced EMT in hepatocytes,
and alleviated the degree of hepatic brosis (Song et al., 2019).
Therefore, these results suggest that TGF-β1/Smad signaling
pathway mediates the process of miR-34a-induced brosis.
MIRNA-34A AS THERAPEUTIC TARGETS
OF FIBROSIS
As described, miR-34a is a key regulator of FB-related molecules.
In recent years, miR-34a or miR-34a-targeted gene have been
used as new intervention targets in the treatment of FB, which
have better effectiveness. Therefore, the regulation of miR-34a
and related molecules are expected to be new therapeutic targets
for FB (Table 2).
MicroRNA-34a Inhibitors
In most studies, miR-34a inhibitors were used to improve the
degree of brosis. At the cellular level, miR-34a inhibitor was
transfected into renal tubular cells incubated with TGF-β1to
induce the upregulation of Bcl-2, inhibit the apoptosis of
renal tubular cells and improve the degree of renal brosis
(Zhou et al., 2014). Transfection of miR-34a silencing vector
using Lipofectamine2000 into activated HSCs increased the
expression of ACSL1 and promoted lipogenesis, thereby
inhibiting HSCs activation and hepatic brosis (Yan et al.,
2015). MiR-34a inhibitor was also found to increase PPAR γ,
decrease a-SMA, and improve the process of liver brosis (Li
et al., 2015). Transfection of miR-34a inhibitor in primary
hepatocytes increased SIRT1 and p65/p53 deacetylation
levels, decreased the expression of proinammatory
cytokines and improved liver inammatory response (Kim
et al., 2015). MiR-34a inhibitor could reduce the EMT process
and brosis activity of human intrahepatic biliary epithelial
cells, and improved liver brosis (Pan et al., 2021). In cardiac
broblasts, a miR-34a antagonist improved cardiac brosis
by inhibiting TGF-β1 signaling (Huang et al., 2014). In vivo
study, Subcutaneous injection of locked nucleic acid (LNA)-
antimiR-34a (initial dose 25 mg/kg, maintenance dose
10 mg/kg every other day, 3 times a week for 6 weeks) can
improved the cardiac function of female mice with dilated
cardiomyopathy, characterized by attenuated heart
enlargement and lung congestion, inhibit the expression of
cardiac stress genes, and alleviate myocardial brosis
(Bernardo et al., 2016). Besides, miR-34a inhibitors can
improve myocardial brosis and reduce scar area in
myocardial infarction rats (ZhangF.etal.,2021). In the
mice of CCl4-induced liver brosis, miR-34a siRNA
signicantly reduced the express of TGF-β,a-SMA, and
MCP-1, further inhibited the brosis of HSCs (Zhang
J. et al., 2021). It has also been found that ablation of miR-
34a protected aged animals from developing experimental
lung brosis (Cui et al., 2017b).
In addition, there are some compounds acting on miR-34a to
intervene in FB. Hydrogen sulde and astragaloside IV(AS-IV)
were found to reverse myocardial brosis, which may be related
to the down-regulation of miR-34a to activate autophagy (Liu
et al., 2018;Zhu et al., 2019). Prunella vulgaris aqueous extract
(PVAE) can downregulate miR-34a level, inhibit the activation of
HSCs, and regulate the expression of TIMP-1, MMP-2, and
MMP-13, promoting the degradation of collagen, and
alleviating hepatic brosis (Hu et al., 2016); Paclitaxel has
been applied to treat brosis by downregulating miR-34a,
upregulating SIRT1, and inhibiting p53 activation and TGF-
β1/Smads signal pathway (Song et al., 2019). Atorvastatin also
inhibited miR-34a and upregulated SIRT1 to improve myocardial
brosis (Tabuchi et al., 2012). Therefore, the above study shows
that the downregulation of miR-34a has therapeutic effect on FB.
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Zhao et al. MicroRNA-34a: Therapeutic Target in Fibrosis
The Biological Agents of
MicroRNA-34a-Related Molecules
The target gene of miR-34a has been used as the therapeutic
target for brosis in some researches. SRT1720, the
SIRT1activator, inhibited hepatocyte apoptosis and improved
liver brosis by reducing the expression of miR-34a and the
acylation of p53 (Tian et al., 2016). Resveratrol, another SIRT1
activator, was often used as an inhibitor in brosis researches
(Chávez et al., 2008;Hong et al., 2010;Li et al., 2010). P53
inhibitor, pithrina(PFT), decreased the level of miR-34a and
played a protective role in hepatic ischemia/reperfusion mice
(Kim et al., 2015). In addition, PPAR γactivators blocked the
activation of HSCs in hepatic brosis (Attia et al., 2013;Sharvit
et al., 2013). Smad4 siRNA downregulated the mRNA and
protein expression of Col I, a-SMA, and TGF-β1, and
inhibited myocardial brosis (Huang et al., 2014). Jagged1
siRNA and Notch 1 siRNAs effectively inhibited EMT in renal
tubular epithelial cells (Du et al., 2012). LGR4 is the direct target
of miR-34a, LGR4 siRNA signicantly inhibited the proliferation
and migration of retinal pigmented epithelial cell line ARPE-19
(Hou et al., 2016). As a novel direct miR-34a target, PNUTS
improved the functional recovery after acute myocardial
infarction by reducing telomere shortening, DNA damage
response and cardiomyocyte apoptosis (Boon et al., 2013).
These results suggest that miR-34a-related molecules also plays
an important role in the treatment of FB, which may provide
guiding signicance for clinical research.
LIMITATION OF MICRORNA-34A AS
THERAPEUTIC TARGETS OF FIBROSIS
Currently there are no FDA-approved miRNAs, but many
miRNA therapies have achieved substantial preclinical efcacy,
even entered in clinical trials (Wang et al., 2021;Smith et al., 2022;
Zogg et al., 2022). For example, miravirsen (miR-122 inhibitor)
has completed Phase II clinical trials for the treatment of
Hepatitis C (Janssen et al., 2013;Panigrahi et al., 2022). The
Phase I clinical trials of MRG-110 (miR-92a inhibitor) to improve
wound healing has been completed (Gallant-Behm et al., 2018;
Abplanalp et al., 2020). A Phase I/IIa clinical trial has
demonstrated the potential of RG-125 (AZD4076) (miR-103/
107 inhibitor) for the treatment of type 2 diabetes and non-
alcoholic fatty liver disease (Rottiers and Naar, 2012). A Phase 1b
clinical trial of RGLS4326 (miR-17 inhibitor) in patients with
autosomal dominant polycystic kidney disease is under way (Kim
and Park, 2016). A Phase I clinical trials have shown that
CDR132L inhibits miR-132 in patients with heart failure (Ucar
et al., 2012). Moreover, TargomiRs, a miR-16 mimic, has been
considered as a second- or third-line treatment for recurrent
malignant pleural mesothelioma and non-small cell lung cancer
(van Zandwijk et al., 2017). Therefore, the therapeutic potential of
miRNAs is limitless.
Based on the existing research, miR-34a plays a complex and
important role in brotic diseases. It will be a new target for the
treatment of FB, but there are still many practical problems for
miR-34a as a therapeutic target. At present, the anti-brosis effect
of miR-34a and its target molecules have been explored mainly at
the cellular level in vitro, perhaps because of the functional
complexity of miR-34a and the non-target effect in vivo. There
are still some problems in the preparation of miR-34a inhibitors.
Although liposome transfection has been used in some
experiments, it has the disadvantage of immunogenicity
(Simone et al., 2014;Yan et al., 2015). Viral delivery enables
long-term, persistent, and high expression of miRNAs, but it also
has the disadvantage of nonspecic binding, so it cannot
transport miRNAs to the designated site. Microvesicles, a new
cell signaling vector for short- or long-range delivery, contains
TABLE 2 | the biological agents of miR-34a and related molecules for brosis.
Type Biologics Target Tissue/Cell References
miR-34a inhibitor MiR-34a inhibitor miR-34a renal tubular epithelial cells, intrahepatic biliary
epithelial cells, HSCs, hepatocyte, Cardiac
broblasts, heart, liver, lung
Zhou et al. (2014),Yan et al. (2015),Li et al. (2015),
Kim et al. (2015),Huang et al. (2014),Bernardo
et al. (2016),Pan et al. (2021),Zhang et al. (2021a),
Zhang et al. (2021b),Cui et al. (2017b)
Hydrogen sulde (H
2
S) heart Liu et al. (2018)
Astragaloside-IV(AS-IVA) cardiomyocytes Zhu et al. (2019)
Aqueous extract from
Prunella Vulgaris (PVAE)
HSCs Hu et al. (2016)
Pterostilbene hepatocyte Song et al. (2019)
Atorvastatin endothelial cell Tabuchi et al. (2012)
Preparation of miR-
34a-related molecules
SRT1720 SIRT1 hepatocyte Tian et al. (2016)
Resveratrol SIRT1 liver, kidney Chávez et al. (2008);Hong et al. (2010);Li et al.
(2010)
pithrin -αp53 hepatocyte Kim et al. (2015)
PPARγagonist PPARγHSCs Attia et al. (2013);Sharvit et al. (2013)
Smad4 siRNA Smad4 cardiac broblast Huang et al. (2014)
Jagged1 siRNAs Jagged1 renal tubular epithelial cells Du et al. (2012)
Notch1siRNAs Notch1 renal tubular epithelial cells Du et al. (2012)
LGR4 siRNA LGR4 retinal pigment epithelial cells Hou et al. (2016)
PNUTS PNUTS heart Boon et al. (2013)
Frontiers in Physiology | www.frontiersin.org June 2022 | Volume 13 | Article 8952426
Zhao et al. MicroRNA-34a: Therapeutic Target in Fibrosis
protein, mRNA and miRNA (Martins et al., 2013;Recep et al.,
2017). In a study of renal brosis, it has been found that (Zhou
et al., 2014;Li et al., 2019) renal interstitial broblasts can secrete
microvesicles containing miR-34a to transport to renal tubular
epithelial cells and promote their apoptosis; then the
microbubbles in broblasts can be extracted and injected into
cells or mice to imitate the mechanism of miR-34a in renal
brosis. With the development of science and technology, other
better biological agents will likely be found in the future, further
improving the treatment of FB.
CONCLUSION
In summary, although there have been many studies on the
pathogenesis of brosis, there are still many deciencies in the
treatment of brosis. Various types of brosis, such as pulmonary
brosis, cardiac brosis, liver brosis, renal brosis, etc., involve
the same or different internal signal network. Therefore, it is very
difcult to nd the common target of brosis. Although there
were two drugs (pirfenidone and nintedanib) have been approved
for the treatment of idiopathic pulmonary brosis, they can only
improve lung capacity and survival rate, and do not show
benecial histological changes in pulmonary brosis (Martinez
et al., 2017). Therefore, it is urgent to develop new anti-brosis
therapy for other brotic diseases. MiR-34a can regulate the
expression of many genes and proteins, and participate in
complex signal mechanism. Compared with traditional
cytokines and signal molecules, miR-34a is more suitable as a
common target for the regulation of organ FB. MiR-34a is a key
regulator of brosis, which is involved in the regulation of
apoptosis, senescence, autophagy, and TGF-β1 signaling
pathway in epithelial cells and broblasts to affect the
excessive repair; moreover, target genes of miR-34a also
regulate the process of brosis in many ways; the application
of miR-34a inhibitor has also been found to signicantly improve
the degree of brosis. So miR-34a is expected to become a new
target for the treatment of brosis. However, those vivo or clinical
studies on the treatment of brosis with miR-34a are still little and
incomplete, so the specic mechanism and efcacy need to be
further veried.
AUTHOR CONTRIBUTIONS
MZ wrote the manuscript. QQ, SL, and RH collect related
literature; JS, YZ, JC, and HZ revised the manuscript; HW and
HL contributed to conception and design of the article. All the
authors reviewed the manuscript and agreed for submission.
FUNDING
This study supported by the National Natural Sciences
Foundation of China (81873374); the Science and Technology
Commission of Shanghai (21ZR1460000); Shanghai Sailing
Program (20YF1445400), and Shanghai Clinical Research
Center for Acupuncture and Moxibustion (No. 20MC1920500).
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A liver-specific microRNA, miR-122, anneals to the HCV genomic 5’ terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full length RNAs with specific mutations in the 5’ UTR can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having EMCV IRES-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication when compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by amount of viral RNA delivered. HCV RNAs replicating independent of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of a miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection, and also supports new replication complex formation during ongoing infection and after infected cell division. IMPORTANCE: The mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as potential HCV therapy.
Article
Background: Previous studies have confirmed that MicroRNA (miRNA) is a key regulator exhibiting different effects in human liver fibrosis. However, the function of miR-34a in liver fibrosis has not been reported. Hence, this study aimed to investigate the regulatory mechanism of miR-34a in liver fibrosis. Methods: The expression of miR-34a was measured in fibrosis tissues via the quantitative real-time PCR (qRT-PCR) assay. Subsequently, 30 male C57BL/6J mice were divided into control and treatment groups and used to establish animal models of liver fibrosis to explore the expression level of miR-34a. Moreover, Cell Counting Kit 8 (CCK-8) and transwell assays were preformed to identify the regulatory mechanism of miR-34a in cells. The effect of miR-34a on the activity of transforming growth factor-β (TGF-β) pathway was observed by western blot. Results: Up-regulation of miR-34a was detected in fibrosis cells. Moreover, the cellular phenotype was suppressed by miR-34a down-regulation in a primary culture of hepatic stellate cells (HSCs). Besides, it was found that increased miR-34a could significantly promote the invasion and migration of HSCs. Moreover, miR-34a activates HSCs through transforming TGF-β, α-smooth muscle actin (α-SMA), and Monocyte chemoattractant protein-1 (MCP-1), which further affects liver fibrosis. Conclusions: MiR-34a promotes the fibrosis of HSCs as well as cell proliferation, migration, and invasion.
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The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.