Critical effects of long non-coding RNA on fibrosis diseases
Experimental & Molecular Medicine
Critical effects of long non-coding RNA on fibrosis diseases
The expression or dysfunction of long non-coding RNAs (lncRNAs) is closely related to various hereditary diseases, autoimmune diseases, metabolic diseases and tumors. LncRNAs were also recently recognized as functional regulators of fibrosis, which is a secondary process in many of these diseases and a primary pathology in fibrosis diseases. We review the latest findings on lncRNAs in fibrosis diseases of the liver, myocardium, kidney, lung and peritoneum. We also discuss the potential of diseaserelated lncRNAs as therapeutic targets for the clinical treatment of human fibrosis diseases. Experimental & Molecular Medicine (2018) 50, e428; doi:10.1038/emm.2017.223; published online 19 January 2018
Fibrosis is the formation of excess fibrous connective tissue in
an organ or tissue.1 This process may be reactive or reparative
and benign or pathological. The effect of fibrosis when it occurs
in response to injury is known as scarring, and the fibrotic mass
is known as a fibroma when the fibrosis originates from a single
cell. The physiological outcome of deposited connective tissue,
particularly when excessive, may be an obliteration of the
architecture and function of the underlying organ or tissue,
which is a pathological state. The pathological accumulation of
extracellular matrix (ECM) proteins in fibrosis ultimately
causes scarring and a thickening of the affected tissue, which
involves stimulated fibroblasts laying down connective tissue,
including collagen and glycosaminoglycans.2
The process of fibrosis is initiated when immune cells, such as
macrophages, release soluble factors that stimulate fibroblasts.
The most well-characterized pro-fibrotic mediator is tumor
growth factor-beta (TGF-?), which is released by macrophages
and any damaged tissue between interstitial surfaces. Other
soluble mediators of fibrosis include connective tissue growth
factor (CTGF), platelet-derived growth factor (PDGF) and
interleukin 4 (IL-4). These factors initiate signal transduction
pathways, such as the AKT/mTOR3 and SMAD,4 which lead to
the proliferation and activation of fibroblasts for the deposition
of ECM into the surrounding connective tissue. This process of
tissue repair is complex and requires tight regulation of ECM
synthesis and degradation to ensure the maintenance of normal
tissue architecture (and function). The entire process is
necessary, but it may lead to a progressive irreversible fibrotic
response if the tissue injury is severe or repetitive or the wound
healing response itself becomes deregulated.2
Recent studies demonstrated that epigenetic mechanisms
are also involved in the regulation of the fibrosis process.5?7
Long non-coding RNAs (lncRNAs) are RNA segments
4200 nucleotides in length that lack protein-coding
capacity.8?10 Some lncRNAs are regulators of fibrosis.11?13
LncRNAs mediate various normal biological processes and
exhibit dose compensation effects in the epigenetic regulation
of the cell cycle and cells.14,15 The dysregulation of lncRNAs
may produce serious detrimental effects on human health.
These molecules are associated with the pathogenesis of various
human diseases, such as cancer and neurodegenerative
disorders.16?18 LncRNAs are unlike microRNAs (miRNAs),
which are RNA segments ~ 22 nucleotides in length that
regulate ~ 60% of human genes19 and function exclusively at
the post-transcriptional level. LncRNAs participate in the
transcriptional and post-transcriptional regulation of genes.
The present review summarizes the latest advances in our
understanding of lncRNA regulation of fibrosis and focuses on
the mechanisms of fibrosis in the liver, myocardium, kidney,
lung and peritoneum. We also discuss the potential of
lncRNAbased therapies for these fibrosis diseases.
A variety of inducers of chronic liver damage, including viral
infection, chemical exposure, physical injury and autoimmune
hepatitis, may cause liver fibrosis. The condition itself is
characterized by an excessive accumulation of ECM and liver
dysfunction. Sustained liver fibrosis is key to the development
of a broad range of chronic liver diseases, from cirrhosis to
cancer.18 The lncRNAs involved in liver fibrosis are
Alu-mediated p21 transcriptional regulator and long
intergenic non-coding RNA-p21 regulate the p21-mediated
progression of liver fibrosis
Animal cells synthesize and secrete ECM, which is distributed
along the cell surface or between cells. An array of primary
and/or secondary causes of ECM synthesis and an imbalance
between ECM synthesis and degradation may induce fibrosis.
Functioning as a ceRNA for miR-222, increasing
Repressing DUSP5/ERK1/2, increasing
ND ? in Ang II treated cardiac fibroblasts
Functioning as a ceRNA for miR-24, upregulat- ? in mouse myocardial infarction model, and
ing TGF-?1 expression cardiac fibroblasts treated with serum or Ang II
ND ? in kidney tissue from db/db mice, and MMCs
cultured in high glucose
Unclear, but can recruit cyp4a12a ? in kidney tissue from db/db mice, and MMCs
cultured in high glucose
Unclear, but is TGF/Smad3-dependent ? in Smad3 knockout UUO mouse model and
anti-GBM GN mouse model
Functioning as a ceRNA for miR-17 that targets ? in TGF-?2-induced fibrosis of HK-2 human
fibronectin proximal tubular epithelial cells and
induced renal fibrosis in vivo
Functioning as ceRNAs for miR-29b-3p and let- ? in bleomycin-induced pulmonary fibrosis rat
7i-5p, respectively, up-regulating N4bp2 and model
Plxna4 that are the targets of miR-29b-3p and
Possible functioning as a ceRNA to suppress
miR-489 that targets MyD88 and Smad3
Abbreviations: Anti-GBM GN, immunologically induced anti-glomerular basement membrane glomerulonephritis; ?, Inhibition or decrease; MMCs, mouse mesangial cells;
ND, not detected in the referred literature; ?, Promotion or increase; UUO, Smad3 knockout mouse models of unilateral ureteral obstructive nephropathy.
Hepatic stellate cells (HSCs) are the predominant producers of
ECM during liver fibrogenesis.20,21 Current studies suggest that
the activation of HSCs, such as by liver injury, and the
subsequent secretion of ECM are key mechanisms in the
initiation and progression of liver fibrosis.22?24 However, this
process reverts to the original (non-fibrotic) state after removal
of the liver damage stimulus.25,26
Collagen is the main constituent of a fibrotic scar, and
TGF-? promotes its expression in HSC myofibroblasts.27?29
Negishi et al.30 recently performed a small-interfering
(si)RNA screen of human lncRNAs to identify the molecules
that contribute to cell proliferation. Alu-mediated p21
transcriptional regulator (APTR) was identified as an lncRNA
target, and it acted in trans to repress the promoter of
the CDKN1A/p21 tumor suppressor gene and promote cell
proliferation independently of p53. A detailed molecular
analysis revealed that APTR recruited polycomb repressive
complex 2 (PRC2) to repress the activity of the p21 promoter
and inhibit p21 expression30 (Figure 1). Another study
demonstrated increased APTR levels in serum and liver biopsy
samples and activated HSCs from patients with liver cirrhosis.31
Knockdown of APTR inhibited HSC activation, mitigated the
accumulation of collagen, and abrogated the TGF-?1-induced
upregulation of ?-smooth muscle actin (?-SMA) in HSCs.
However, treatment with p21 siRNA attenuated the inhibition
of cell cycling and cell proliferation that occurred in primary
HSCs following APTR knockdown.31
Other reports indicated that long intergenic non-coding
RNA (lincRNA)-p21 inhibited liver fibrosis via promotion of
p21 expression.32 Studies demonstrated that lincRNA-p21
induced apoptosis in mouse cell models,31,33 and its expression
is decreased in tumors.34 Zheng et al.32 recently reported that
the targeting the tumor suppressor gene p21 markedly reduced
lincRNA-p21 expression in mouse liver fibrosis models and
human cirrhotic liver (Figure 1). Liver cirrhosis patients,
especially patients with decompensated cirrhosis, exhibited
significantly lower serum lincRNA-p21 levels compared to
healthy subjects. Overexpression of lincRNA-p21 in vitro
upregulated p21 mRNA and protein levels, inhibited cell cycle
progression and the proliferation of primary HSCs and
reversed the activation of HSCs to their quiescent phenotype.
Lentivirus-mediated lincRNA-p21 transfer into these mice
decreased the severity of liver fibrosis.32 These studies
collectively revealed a new biological role of APTR and lincRNA-p21
in liver fibrogenesis and suggest the potential of these
molecules as biomarkers or therapeutic targets to clinically
address liver fibrosis via the targeting of a common tumor
suppressor gene, p2131,32 (Figure 1; Table 1).
Inhibitory effects of lncRNA MEG3 in liver fibrosis
Maternally expressed gene 3 (MEG3) is an imprinted gene
located at 14q32 that encodes an lncRNA correlated with
several human cancers.35 MEG3 does not encode any protein,
and it functions at the RNA level.36,37 A
methylationdependent downregulation of MEG3 was described in liver
cancers.35 Braconi et al.38 reported that the forced expression
of MEG3 in hepatocellular carcinoma cells significantly
decreased anchorage-dependent and anchorage-independent
cell growth and induced apoptosis. He et al.13 recently
investigated the role of MEG3 in the development of liver
fibrosis and TGF-?1-induced HSC activation. These authors
demonstrated that MEG3 levels were remarkably decreased
in carbon tetrachloride (CCl4)-induced mouse liver fibrosis
models and human fibrotic livers. MEG3 expression was
downregulated in the human HSC line LX-2 in response to
TGF-?1 stimulation, and this effect was dose- and
timedependent. This downregulation of MEG3 expression was
likely mediated by hypermethylation of the MEG3 promoter,
which was identified using methylation-specific PCR.
Inhibition of methylation by treatment with 5-aza-2-deoxycytidine or
siRNA targeted to DNA methyltransferase 1 (DNMT1)
robustly increased MEG3 expression in TGF-?1-induced
LX-2 cells, which activated p53, mediated cytochrome c release,
and induced caspase-3-dependent apoptosis13 (Figure 1;
Growth arrest-specific transcript 5 inhibits liver fibrogenesis
Growth arrest-specific transcript 5 (GAS5) is a crucial mediator
of cell proliferation and growth in various cancer cells,
including breast, gastric and prostate, and T cells.39?43
Yu et al.44 reported that GAS5 was a target of miR-222 and
demonstrated that miR-222 inhibited GAS5 expression.
MiR-222 is involved in liver fibrosis, and MiR-222 expression
increases with the progression of liver fibrosis severity.45 The
underlying mechanisms likely include the direct inhibition of
miR-222 on tumor suppressor p27 gene expression,46 which
was demonstrated in liver fibrosis and glioblastomas
Notably, Yu et al.44 also found that GAS5 increased p27
protein levels by functioning as a competing endogenous RNA
(ceRNA) for miR-222, which inhibited the activation and
proliferation of HSCs. GAS5 overexpression further suppressed
the activation of primary HSCs in vitro and alleviated the
accumulation of collagen in fibrotic liver tissues in vivo.
However, Yu et al. reported reduced GAS5 expression in
mouse, rat and human fibrotic liver samples and activated
HSCs, which supports the hypothesis of the pivotal inhibitory
roles of GAS5 in liver fibrosis and reveals a new regulatory
circuitry in liver fibrosis in which RNAs cross talk by
competing for shared miRNAs44 (Figure 1; Table 1). These
insights represent a potential new therapeutic strategy for the
treatment of liver fibrosis.
Cardiac fibrosis is a major factor in the progression of
myocardial infarction and heart failure,48?50 which is
characterized by an excessive deposition of ECM proteins that impair
organ function.51?53 Cardiac fibroblasts (CFs) are primarily
responsible for the homeostatic maintenance of tissue ECM,
particularly healing after injury.54?57 Activated fibroblasts
exhibit increased protein synthesis, including collagens, other
ECM proteins, certain cytokines and ?-SMA (a contractile
protein and marker of profibrogenic CF activation).58,59
Numerous regulatory factors also exert substantial effects on
fibrosis and may be responsible for the inter-organ variability
of fibrotic manifestations.53,60,61 However, there is no therapy
for this disease because of our limited understanding of the
basic underlying mechanisms of cardiac fibrosis. Recent
investigations demonstrated that the expression of distinct
ncRNAs, including lncRNAs, strongly correlated with the
genesis, progression and treatment of cardiac fibrosis.62
LncRNA H19 control of the dual-specificity phosphatase 5/
ERK1/2 axis contributes to cardiac fibrosis
LncRNA H19 is a 3-kb ncRNA that is expressed in the nucleus
and cytoplasm. H19 is activated in embryonic cells, and it is
highly expressed during embryogenesis. H19 expression is
significantly reduced after birth, but it may significantly
increase in disease conditions.63 The primary function of
H19 is the upregulation of cell activation.64 The
downregulation of dual-specificity phosphatase 5 (DUSP5) increased cell
proliferation,65 and this effect was mediated via epigenetic
events involving lncRNA H19 in a human choriocarcinoma cell
line.66 Tao et al.10 recently demonstrated the ability of H19 to
negatively regulate DUSP5 gene expression in cardiac fibroblast
and fibrosis tissues. These authors also demonstrated an
upregulation of H19 expression in response to TGF-?1
treatment in freshly isolated rat cardiac fibroblasts, which
correlated with the gradual decrease in DUSP5 expression.
Decreased DUSP5 expression was the consequence of at least a
partial repression of DUSP5/ERK1/2. H19 ectopic
overexpression reduced DUSP5 abundance and increased the proliferation
of cardiac fibroblasts, and H19 silencing induced opposite
effects. Therefore, the collective literature suggests a broader
perspective for H19 beyond its roles in tumor cells, with
functional contributions to cardiac fibroblast proliferation and
fibrosis (Figure 1; Table 1).
LncRNA-NR024118 and Cdkn1c in adult rat cardiac
Angiotensin II (Ang II) increases blood pressure via stimulation
of the Gq protein in vascular smooth muscle cells (VSMCs),
which activates an IP3-dependent mechanism to increase
intracellular calcium levels, induce blood vessel contraction,
and increase blood volume and pressure.67 Ang II also plays
numerous roles in cardiac fibroblasts, including the stimulation
of cardiac fibroblasts proliferation and ECM synthesis and the
promotion of cytokine secretion, which eventually leads to
Recent research indicates that Ang II regulates specific
lncRNAs in the pathogenesis of cardiac fibrosis. Jiang et al.70
analyzed the expression profile of lncRNAs in Ang II-treated
cardiac fibroblasts using lncRNAs arrays to investigate the role
of lncRNAs in cardiac fibrosis. These authors found that 282 of
the 4376 detected lncRNAs exhibited a 42-fold differential
expression in response to 24-h Ang II (100 nm) treatment.
Twenty-two of the lncRNAs exhibited a greater than four-fold
change. Ang II also induced broad expression changes in
protein-coding genes in cardiac fibroblasts. Quantitative
realtime PCR confirmed the changes of six lncRNAs (AF159100,
BC086588, MRNR026574, MRAK134679, NR024118 and
AX765700) and nine mRNAs (IL6, RGS2, PRG4, TIMP1,
Cdkn1c, TIMP3, Col I, Col III and fibronectin) in cardiac
fibroblasts. The Ang II-induced decrease in lncRNA-NR024118
and Cdkn1c was mediated by an Ang II receptor type I
(AT1)-dependent pathway and not an AT2
receptordependent pathway, as demonstrated using AT1 and AT2
blockers, respectively70 (Figure 1; Table 1). These results
provide a foundational understanding of the molecular
mechanisms of Ang II receptors in adult rat cardiac fibroblasts.
Myocardial infarction-associated transcript is a pro-fibrotic lncRNA in cardiac fibrosis in post-infarct myocardium
Myocardial infarction-associated transcript (MIAT) confers a
risk of myocardial infarction (MI).71 Qu et al.72 recently
elucidated the pathophysiological role and the underlying
mechanisms of MIAT in the regulation of cardiac fibrosis.
MIAT was remarkably upregulated in a mouse model of
MI and cardiac fibroblasts treated with serum or Ang II, and
this upregulation was accompanied by cardiac interstitial
fibrosis. MIAT upregulation in MI was accompanied by a
deregulation of some fibrosis-related regulators, namely,
miR-24 (downregulated) and furin and TGF-?1 (upregulated).
However, siRNA-mediated knockdown of endogenous MIAT
reduced the cardiac fibrosis and restored the deregulated
expression of the fibrosis-related regulators. These changes in
the expression of regulators promoted fibroblast proliferation
and collagen accumulation, and the siRNA-mediated
knockdown of MIAT or overexpression of miR-24 via delivery of its
mimic abrogated the fibrogenesis.
Qu et al.72 also confirmed that MIAT absorbed miR-24 via
its sponge-like action as a ceRNA. MiR-24 is a regulator of
TGF-?1 activation,73 and the mechanism of miR-24 promotion
of heart fibrosis may form a new fibrosis-regulatory modality
in which the increased expression of MIAT will cause
downregulation of miR-24 and ultimately induce cardiac fibrosis
(Figure 1; Table 1). The Qu et al.72 study identified MIAT as
the first profibrotic lncRNA in the heart and characterized
the role of MIAT in the pathogenesis of MI. This mechanism
may contribute to other cardiac pathological processes
associated with fibrosis. These collective findings suggest the
normalization of MIAT levels as a therapeutic option for the
treatment of MI-induced cardiac fibrosis and the associated
LncRNA protects mesangial cells from proliferation and
Diabetic nephropathy (DN) is an important microvascular
complication of diabetes. The incidence of end-stage renal
disease as a result of DN continues to increase annually.74,75
DN is characterized by a series of abnormal characteristics,
including glomerular hypertrophy, thickening of the
glomerular basement membrane, mesangial expansion and the
accumulation of ECM. Wang et al.76,77 recently investigated
the effects of lncRNAs on DN pathogenesis using lncRNA
microarrays to detect altered expression in three cases of kidney
tissue from db/db mice, which is a genetic model of early stage
type 2 DN. A total of 1018 lncRNAs exhibited differential
expression (42 fold-change); 221 lncRNAs were upregulated,
and 797 lncRNAs were downregulated compared to control
(db/m) mice. CYP4B1-PS1-001 was significantly
downregulated in early DN in the in vitro and in vivo model systems, and
CYP4B1-PS1-001 overexpression inhibited mesangial cell (MC)
proliferation and fibrosis.76
ENSMUST00000147869 and Cyp4a12a expression decreased
in a dose-dependent manner in mouse MCs (MMCs) under
different glucose conditions.77 Overexpression of
ENSMUST00000147869 in MMCs impeded proliferation and fibrosis
and reversed the proliferation rate of MMCs under
highglucose conditions. Cyp4a12a is a neighboring gene locus to
ENSMUST00000147869, and it is a target gene for this
lncRNA, which results in downregulation and recruitment
during ENSMUST00000147869 overexpression. However,
whether Cyp4a12a participates in proliferation and fibrosis of
MMCs is not known. These preliminary data suggest potential
roles for CYP4B1-PS1-001 and ENSMUST00000147869 in the
proliferation and fibrosis of MCs, particularly MMCs. These
two processes are prominent features during the early stage of that H19 upregulation contributes to renal fibrosis, and H19
DN (Figure 1; Table 1). These findings extend the relationship inhibition may represent a novel anti-fibrotic treatment in
between lncRNAs and DN and suggest possible therapeutic renal diseases (Figure 1; Table 1).
targets and molecular biomarkers for this disease.
LncRNAs associate with TGF-?/Smad3-mediated renal
TGF-?/Smad signaling plays a critical role in renal fibrosis and
inflammation in chronic kidney diseases, and Smad3 is a
key mediator of downstream TGF-?/Smad signaling, which
mediates renal inflammation and fibrosis via several
miRNAs.78?80 Zhou et al.81 recently identified the
Smad3dependent lncRNAs related to renal inflammation and fibrosis
in Smad3 knockout mouse models of unilateral ureteral
obstructive (UUO) nephropathy and immunologically induced
anti-glomerular basement membrane glomerulonephritis
(anti-GBM GN). A total of 151 lncRNAs in UUO kidney
and 413 lncRNAs in anti-GBM GN kidneys were significantly
altered in the Smad3 knockout mice compared to wild-type
mice. Twenty-one novel lncRNAs were co-expressed in both
disease models. Twenty-one lncRNAs were upregulated in wild
type but downregulated in Smad3 knockout mice. The kidneys
in both disease models exhibited progressive renal
inflammation and fibrosis and beneficial effects following Smad3 gene
deletion or suppression. The pool of lncRNAs that are
differentially expressed in the UUO kidney may be related to
fibrogenesis because progressive renal fibrosis in the UUO
kidney is Smad3-dependent.80,82,83 Real-time PCR confirmed
these findings and revealed a functional link between the
Smad3-dependent lncRNA np_5318/np_17856 and progressive
kidney injury (Figure 1; Table 1). This study suggested that the
identification and characterization of functional lncRNAs
associated with kidney disease represent a promising research
direction for renal disorders and may lead to the development
of new lncRNA-based therapies.
LncRNA-H19 promotes renal fibrosis
Renal fibrosis is the final outcome of many renal diseases.84
Aberrant lncRNA expression is involved in renal development,
renal cell carcinoma and renal inflammation.81,85,86 For
example, H19 plays an important role in renal development.86,87 Xie
et al.88 recently demonstrated a significant upregulation of H19
expression in vivo, TGF-?2-induced fibrosis of HK-2 human
proximal tubular epithelial cells and UUO-induced renal
fibrosis. Knockdown of H19 significantly attenuated renal
fibrosis in vitro and in vivo. A previous study had suggested
that miR-17 retarded tissue growth and inhibited fibronectin
expression.89 Xie et al. found that the increased H19 levels
alleviated the miR-17 repressive effect and increased the
expression of fibronectin, which is a target gene of miR-17.
These results suggest that H19 functions as a ceRNA targeting
miR-17.88 These authors also confirmed the upregulated H19
expression and downregulated miR-17 expression in early and
advanced animal models of renal fibrosis.88 Therefore,
lncRNA-H19, miR-17 and fibronectin form a ceRNA
regulatory network that is involved in renal fibrosis, which indicates
Pulmonary fibrosis is an age-related lung disease that was
once regarded as simply a chronic inflammatory process
with few treatment options. However, environmental triggers
(behavioral and occupational) were identified, including
cigarette smoke, various dust particles and hazardous chemicals.90,91
Dysregulation of lncRNAs may play crucial roles in the
presence of chronic lung infection and/or inflammation.92
The epithelial?mesenchymal transition (EMT) of alveolar
epithelial cell transformation is likely an important pathogenic
mechanism of idiopathic fibrosis. Therefore, the lncRNAs
involved in the development of EMT play a crucial role in
the progression of pulmonary fibrosis, and several lncRNAs are
involved in pulmonary fibrosis.
LncRNAs MRAK088388 and MRAK081523 as ceRNAs in
Song et al.93 evaluated the functions of lncRNAs in pulmonary
fibrosis by searching portions of lncRNAs that were adjacent or
homologous to protein-coding genes in the UCSC genome
bioinformatics database (https://genome.ucsc.edu/). The authors
selected two differentially expressed lncRNAs, MRAK088388 and
MRAK081523, for detailed examination of their regulatory
mechanisms. Both lncRNAs were analyzed as lincRNAs and
identified as orthologues of mouse lncRNAs AK088388 and
AK081523, respectively, which are significantly upregulated in
the bleomycin-induced pulmonary fibrosis mouse model, which
was evidenced using quantitative reverse transcription-PCR and
in situ hybridization assays. These authors also found that
MRAK088388 and N4bp2 (a Bcl-3 binding protein) shared
miRNA response elements for miR-200, miR-429, miR-29 and
miR-30, and MRAK081523 and Plxna4 (a tumor-promoting
protein) shared miRNA response elements for miR-218,
miR-141, miR-98 and let-7.93 The expression levels of N4bp2
and Plxna4 increased significantly in fibrotic rats and highly
correlated with MRAK088388 and MRAK081523 expression,
respectively. MiR-29b-3p and let-7i-5p were decreased in
the model group and negatively correlated with MRAK088388
and MRAK081523 expression, respectively. MRAK088388
and MRAK081523 regulate N4bp2 and Plxna4 expression via
sponging miR-29b-3p and let-7i-5p, respectively, and exhibited
regulatory functions as ceRNAs.93 The resulting insights of this
study into the functional interactions of lncRNAs, miRNAs and
mRNAs may lead to new theories on the pathogenesis and
treatment of pulmonary fibrosis (Figure 1; Table 1).
LncRNA CHRF promotes silica-induced pulmonary fibrosis
via targeting of miR-489
Silicosis is an incurable occupational disease associated with
inflammation, fibroblast proliferation and an accumulation of
ECM in lung tissues.94 Ji et al.95 reported decreased expression
levels of miR-489 in lung tissues of silica-induced pulmonary
fibrosis detected using miRNA microassay screening. the normal function of ion channels. The collective data also
Wu et al.96 examined the role of miR-489 in a mouse model suggest that these lncRNAs represent novel therapeutic targets
of silicosis and found reduced miR-489 levels in silica-exposed for cystic fibrosis.
macrophages and TGF-?1-exposed fibroblasts. The results
of in vivo miR-489 overexpression were consistent with its
anti-fibrotic role of attenuating inflammation and fibrotic
progression. The underlying molecular mechanisms include
miR-489 inhibition of silica-induced pulmonary fibrosis, which
occurs primarily via repression of its target genes MyD88 and
Smad3. However, upregulation of the lncRNA cardiac
hypertrophy-related factor (CHRF) in the mouse model
reversed the inhibitory effect of miR-489 on MyD88 and
Smad3 to trigger the inflammation and fibrotic signaling
pathways96 (Figure 1; Table 1). Therefore, the
CHRFmiR-489-MyD88 Smad3 signaling axis appears to exert key
functions in silica-induced pulmonary fibrosis and may
represent a novel therapeutic target for silicosis.
LncRNA uc.77 and 2700086A05Rik regulate EMT in
Sun et al.98 established a mouse model of pulmonary injury
and progressive interstitial fibrosis using an intraperitoneal
injection of paraquat, which is a widely used herbicide that
causes pulmonary fibrosis in humans. These authors used
transcriptome sequencing and microarray analysis to identify
513 upregulated and 204 downregulated lncRNAs in
paraquatinduced fibrotic lung tissues. The evolutionally conserved target
genes of two upregulated lncRNAs, uc.77 and 2700086A05Rik,
as Zeb2 and Hoxa3, respectively, were identified, and both of
these factors are important modulators of EMT.
Overexpression of uc.77 in cells increased Zeb2 expression, and
overexpression of 2700086A05RiK suppressed Hoxa3 in human
lung epithelial cells. Zeb2 is an EMT-activating transcription
factor, and Hoxa3 modulates tissue remodeling via coordinated
changes in epithelial and endothelial cell gene expression and
behavior during wound repair.99,100 The overexpression of
uc.77 or 2700086A05Rik in human lung epithelial cells
consistently induced EMT, which was demonstrated as changes
in gene and protein expression of various EMT markers and
cell morphology.98 Collectively, these results revealed a crucial
role for lncRNAs in the regulation of EMT during lung fibrosis
and provide potential avenues for the discovery of novel
molecular markers and therapeutic targets for interstitial
pulmonary fibrosis (Figure 1; Table 1).
LncRNA BGas regulates cystic fibrosis
Cystic fibrosis is a lethal multisystem, autosomal recessive
disorder, but the detailed mechanisms of this disease are not
known. McKiernan et al.92 defined the expression profile of
30 586 lncRNAs using a microarray assessment of bronchial
cells isolated from endobronchial brushings of cystic fibrosis
and non-cystic fibrosis individuals. A total of 1063 lncRNAs
exhibited differential expression, and gene ontology
bioinformatics analysis highlighted that the numerous over-represented
processes in the cystic fibrosis bronchial epithelium were
related to inflammation. TLR8 natural antisense lncRNA (the
1349-bp TLR8-AS1 transcript) was downregulated in cystic
fibrosis bronchial epithelium and exhibited low-level
expression in three of the nine non-cystic fibrosis controls and only
one of seven cystic fibrosis bronchial epithelial samples (absent
in all other samples). However, this study did not further
examine how TLR8-AS1 contributed to the molecular
pathogenic processes of cystic fibrosis.
The root cause of cystic fibrosis is heritable recessive
mutations that affect the cystic fibrosis transmembrane
conductance regulator (CFTR) gene and the subsequent expression
and activity of encoded ion channels at the cell surface.97
Saayman et al.9 confirmed that lncRNA BGas contributed to
cystic fibrosis pathogenesis via regulation of CFTR gene
expression. These authors demonstrated that CFTR was
regulated transcriptionally by the actions of lncRNA BGas,
which emanates from intron 11 of the CFTR gene and is
expressed in the antisense orientation relative to the
proteincoding sense strand.9 BGas functions in concert with several
proteins, including HMGA1, HMGB1 and WIBG, to modulate
the local chromatin and DNA architecture of intron 11 of the
CFTR gene, which affects transcription. Suppression of BGas or
its associated proteins results in a gain of CFTR expression and
chloride ion function9 (Figure 1; Table 1). These observations
highlighted the possible effects of certain lncRNAs on cystic
fibrosis pathogenesis, such as the involvement of TLR8-AS1 in
the chronic infection and inflammation that exist in the lungs
of people with cystic fibrosis and the involvement of BGas in
Liu et al.101 examined lncRNA, mRNA and miRNA expression
profiles and their potential roles in the process of peritoneal
fibrosis using normal control peritoneum and fibrotic
peritoneum from a mouse model (peritoneal dialysis fluid
induction). A total of 232 lncRNAs (127 upregulated and
105 downregulated), 154 mRNAs (87 upregulated and 67
downregulated) and 15 miRNAs (14 upregulated and 1
downregulated) were differentially expressed in the fibrotic
peritoneum compared to the normal controls. Nine of the
differentially expressed lncRNAs and five miRNAs were
validated using real-time reverse-transcription PCR. Pathway
analysis demonstrated that the Jak-STAT, TGF-? and MAPK
signaling pathways were closely related to peritoneal fibrosis.
Gene co-expression network analysis identified many genes,
including JunB, HSP72 and Nedd9; lncRNAs, including
AK089579, AK080622 and ENSMUST00000053838; and
miRNAs, including miR-182 and miR-488. All of these species
potentially play key roles in peritoneal fibrosis (Figure 1;
Table 1). These results provide a foundation and an expansive
view of the roles and mechanisms of ncRNAs in peritoneal
dialysis fluid-induced peritoneal fibrosis, but the exact roles
and the detailed mechanisms require further investigation to
fully understand the contribution of ncRNAs, including
lncRNAs, to peritoneal fibrosis.
This review summarized the mechanisms of fibrosis influenced
by lncRNAs. The exact role and underlying mechanisms of
most of the identified lncRNAs are not known, but the
knowledge to date is key to understanding fibrosis diseases in
its various forms. Thereafter, we could target and influence
lncRNA changes using pharmacological or genetic
interventions to treat the spectrum of pathogenic fibroses.
Development of inhibitors for the treatment of fibrosis is promising,
and systematic study of the clinical application of these
inhibitors will lead to further insights into the overall disease
processes and allow more effective and specific treatment
strategies. LncRNA inhibitors will likely be effective, but the
problem of targeting lncRNA effectively must be solved before
this benefit may be realized. Combination therapies of lncRNA
inhibitors and other chemotherapeutic drugs may also be
useful. LncRNAs represent a heterogeneous class of transcripts
that are incompletely annotated, and challenges in the
investigation of these lncRNAs remain. Continued investigations
that build on the existing knowledge presented herein will
certainly overcome these challenges and significantly impact
the field of human fibrosis diseases.
TGF-? also exhibits a wide potential influence on cell
growth, differentiation, ECM aggregation and the immune
response, and it is one of the most widespread and profound
cytokines for various organ fibrosis in the body.102 TGF-?
regulates the proliferation, migration and adhesion of cancer
cells, and it creates a favorable environment for tumor
development.103,104 Hepatic fibrosis is characterized by the
excessive deposition of ECM, and it is caused by chronic liver
injury from various sources. Hepatic fibrosis is a necessary
stage for the development of chronic liver disease to cirrhosis
and hepatocellular carcinoma, which suggests a link between
fibrosis and carcinogenesis. Recent studies revealed that the
pro-fibrosis roles of MEG3, MIAT, lnc-H19 and np_5318/
np_17856 were related to TGF-?, which suggests that
these lncRNAs also contribute to the related carcinogenesis.
Therefore, the targeting of these lncRNAs would be beneficial
to fibrosis and potentially helpful in the prevention of
CONFLICT OF INTEREST
The authors declare no conflict of interest.
This work was supported by grants from the Major State Basic
Research Development Program of China (no. 2013CB531503), the
National Foundation of China (no. 81502728), the Anhui Provincial
Natural Science Foundation (no. 1408085MH149) and the Research
Program of Foundation Science and Application Technology of
Chongqing (nos. cstc2015jcyjA10105 and cstc2015jcyjA10119). The
funders had no role in the study design, data analysis, or decision to
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