Review Article
Ophthalmic Res 2022;65:481–492 Received: August 9, 2021
DOI: 10.1159/000523878
Biomarkers in the Occurrence
and Development of Pterygium
Siying He Zhaoxia Wu
Clinical Lab, Jinhua Hospital of Zhejiang University, Jinhua, China
Keywords
Pterygium · Biomarkers · Genetics · Epigenetics · Proteomics
Abstract
Pterygium is a kind of common conjunctival degeneration.
The pathogenesis of pterygium is complex, and various bio-
markers provide new targets for treatment and prognosis.
Currently, the most common treatment for pterygium is sur-
gical excision, but it is invasive risk and has a high recurrence
rate. Since the development of sequencing, gene chip tech-
nology, and proteomics technologies has been rapid, re-
search on the internal mechanism of disease has been facili-
tated. This review focuses on recent advances in the discov-
ery of biomarkers from the fields of genetics, proteomics, and
epigenetics and their likely functional mechanisms and clini-
cal applications in pterygium. © 2022 The Author(s).
Published by S. Karger AG, Basel
Introduction
Pterygium is a common ocular disease. Epidemiologi-
cal studies worldwide indicate that the prevalence rates of
pterygium range from 0.3% to 37.46% [1, 2]. Pterygium
is characterized by hyperplastic, centripetally directed
growth of altered limbal epithelial cells accompanied by
Bowman’s layer dissolution and epithelial-mesenchymal
Karger@karger.com © 2022 The Author(s).
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This is an Open Access article licensed under the Creative Commons
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mercial purposes requires written permission.
Accepted: February 18, 2022
Published online: April 11, 2022
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transition (EMT) [3]. Pterygium is usually located on the
nasal side, affecting patients’ appearance, generating a
foreign body sensation, and even causing blindness [4].
Pterygium is widely considered a chronic inflamma-
tion and is associated with prolonged exposure to out-
door ultraviolet (UV) light and dust [5]. Records of pte-
rygium date back to 770 BC, and the disease is derived
from the syndrome of wind-heat and damp-heat [6]. Pte-
rygium is widely considered to be caused by joint genetic
and environmental factors [7], such as human papilloma-
virus [8], allergens [9], and cholesterol metabolism [10].
A brief history of hypotheses on the etiology of pterygium
is presented in Figure 1.
Currently, the most common treatment for pterygium
is surgical excision with conjunctival autografts [11].
However, postoperative use of adjuvant agents, such as
mitomycin C and 5-flurouracil, can effectively reduce the
recurrence rate [12]. Nonetheless, there are still many dif-
ficulties associated with therapy, such as operative risks,
postoperative scarring, and a high postoperative recur-
rence rate [13, 14]. These problems have led many clini-
cians to devote themselves to the study of the pathogen-
esis and treatment of both primary and recurrent pteryg-
ium. Therefore, the identification of biomarkers for the
occurrence and development of primary pterygium is im-
portant to deepen the understanding of pterygium patho-
genesis and provide new biomarkers for therapeutics and
recurrence prevention.
Correspondence to:
Siying He, hesiying @ whu.edu.cn
 Syndrome of
wind-heat and Inflammatory
damp-heat response Apoptosis
Vascular Oncogenic
EMT proteins: p53
dysplasia
BC770 1893 1954 1956 1966 1971 1975 1982 1984 1994 1997 1999 2000 2004 2008
Ultraviolet Oxidative
light damage
HPV
Hereditary Immunologic
mechanism
Fig. 1. The history of hypotheses for the etiology of pterygium. EMT, epithelial-mesenchymal transition; HPV,
human papillomavirus; Pax6, paired box protein 6.
Genetic Biomarkers of Pterygium
Both gene mutations and single nucleotide polymor-
phisms involve changes in gene structure or expression
levels. The use of next-generation sequencing and DNA
microarrays has provided new strategies for research on
the mechanism of pterygium.
The first genetic biomarker of pterygium, heparin
binding-epidermal growth factor (HB-EGF), was identi-
fied in 2003; its mRNA was elevated 6.8-fold at 6 h after
irradiation [15]. HB-EGF is a potent mitogen that is sig-
nificantly induced by UV radiation in pterygium-derived
epithelial cells, suggesting that HB-EGF is positively cor-
related with the progression of pterygium and that UV
irradiation might participate in inducing pterygium
pathogenesis.
Early research has shown that both the expression and
function of p53 are dysregulated in pterygium [16, 17].
Mutations within exons 4–8 in p53 are detected in the
pterygium epithelium, but only 15.7% (8 of 51) of pte-
rygium have p53 mutations [17]. Mutation in the p53
gene leads to increased protein stability, allowing more
pronounced immunohistochemical detection [18]. UV
light activates survivin to suppress the biological function
of p53, leading to abnormal cell cycle, apoptosis, and
DNA repair [19]; therefore, the possibility of restoring
482 Ophthalmic Res 2022;65:481–492
DOI: 10.1159/000523878
Matrix
metalloproteinase
(MMPs)
Pax6
Pterygium
Limbal
stem cells
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Cholesterol
metabolism
p53 function offers hope for more effective pterygium
treatment.
Unlike p53, Kirsten rat sarcoma viral oncogene homo-
logue (K-ras) is one of the most frequently mutated on-
cogenes in cancer. Mutated K-ras leads to continual K-ras
activation, and disordered signal transduction results in
cell proliferation. The K-ras mutation rate at codon 12 is
significantly higher in patients with recurrent pterygium
and young patients [20], while the K-ras codon 61 muta-
tion frequency is significantly higher in primary and bi-
lateral pterygium tissues [21]. However, the number of
specimens in both studies was too small to obtain a con-
clusion with certainty, but it may be speculated that K-ras
is associated with a recurrent risk of pterygium.
Differentially expressed genes were first identified
from the DNA microarray and further characterized by
real-time polymerase chain reaction, western blot, and
immunohistochemistry. Thus, neutrophil gelatinase-as-
sociated lipocalin and matrix metalloproteinase 9
(MMP9) were upregulated, while insulin-like growth fac-
tor-binding protein 3 was downregulated in pterygium
[22, 23]. Neutrophil gelatinase-associated lipocalin and
MMP9 account for extracellular matrix (ECM) accumu-
lation and a chronic inflammatory reaction, and low ex-
pression of insulin-like growth factor-binding protein 3
leads to uncontrolled cell proliferation.
He/Wu
Table 1. The changes of DNA methylation in pterygium
Gene DNA methylation Phenotypes affected Initiator
p16 ↑ Proliferation DNMT3b
E-cadherin ↑ EMT DNMT3b
TGM2 ↑ ECM remodeling – used to provide novel insights into the potential regula-
MMP2 ↓ ECM remodeling – tory mechanisms of pterygium. Among the differentially
CD24 ↓ ECM remodeling
MDM2 ↓ Proliferation DNMT3a
LATS1/LATS2 ↑ Apoptosis – were mainly involved in two biological functions: ECM
CD24, cluster of differentiation 24; DNMT3a/3b, DNA methyl-
transferase 3a/3b; ECM, extracellular matrix; EMT, epithelial-mesen-
chymal transition; LATS1/2, large tumor suppressor kinase 1/2;
MDM2, mouse double minute 2; MMP2, matrix metalloproteinase 2;
TGM2, transglutaminase 2.
There is a restriction fragment length polymorphism
in intron 16 of angiotensin-converting enzyme (ACE)
based on its presence (insertion I) or absence (deletion D)
that leads to three genotypes: DD homozygote, II homo-
zygote, and ID heterozygote. Detection of the ACE poly-
morphism genotype has been performed in Sardinian pa-
tients, and the D and DD genotypes are associated with a
higher risk of developing pterygium, while the I allele
plays a protective role in pterygium occurrence [24]; the
DD genotype activates more circulating ACE to promote
vasoconstriction, cell proliferation, and inflammatory re-
sponses.
A missense variant in cysteine-rich transmembrane
bone morphogenetic protein regulator 1 (CRIM1)
(NM_016441.2: c.1235A>C (H412P)) has been identified
in a family affected by pterygium [25]. CRIM1 is a widely
expressed gene in the eye and plays a significant role in
cell migration, differentiation, and angiogenesis. Mutat-
ed CRIM1 loses its activation in extracellular single-reg-
ulated kinase phosphorylation, leading to excessive cell
proliferation and inhibition of apoptosis. Although the
CRIM1 mutation was discovered in an Irish family, larger
sample sizes are needed to verify the hypothesis that
CRIM1 may serve as a predictive biomarker for evaluat-
ing the pterygium recurrence rate.
The SNP (rs1060043) in the SLC1A5 gene was signifi-
cantly associated with conjunctival UV autofluorescence
[26]. The SLC1 gene family has been widely detected in
the human cornea, so the role of SLC1A5 in pterygium
deserves further study.
A recent study showed that allelic frequency analysis
of MMP9 rs3918242 showed no significant difference in
the distribution of allelic frequencies between the pteryg-
Review Based on Genetic, Epigenetic, and
Proteomic Biomarkers in Pterygium
ium and control groups [27]. Therefore, the role of the
MMP9 SNP in determining personal susceptibility to pte-
rygium is still open to debate.
With the development of science and technology,
weighted gene coexpression network analysis has been
expressed genes, 200 upregulated genes in pterygium
and cell adhesion or migration. The 139 downregulated
genes were enriched in inflammation pathways [28].
These differentially expressed genes are mainly involved
in ECM-receptor interactions, the phosphoinositide 3-ki-
nase (PI3K)-protein kinase B (Akt) signaling pathway,
and an endoplasmic reticulum-related pathway.
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Epigenetic Biomarkers in Pterygium
Epigenetics, including DNA methylation, histone
modification, nucleosome localization, and noncoding
RNA editing, is based on the genetic changes in gene ex-
pression but without changes in nucleotide sequences.
Abnormal changes have been identified in DNA meth-
ylation and microRNA (miRNA) expression in pterygi-
um.
DNA Methylation Biomarkers of Pterygium
DNA methylation refers to the covalent binding of a
methyl group at the 5′ C site of the cytosine in genomic
CpG dinucleotides due to the action of DNA methyl-
transferases. In general, CpG dinucleotides in “useless”
sequences are relatively rare and always in a methylated
state, while most coding genes are always unmethylated
[29]. Changes in DNA methylation in pterygium report-
ed to date are shown in Table 1.
The protein expression of p16 is downregulated in pte-
rygium, which is due to the high methylation of the p16
promoter in pterygium caused by DNA methyltransfer-
ase 3b [30]. As a tumor suppressor, p16 participates in the
regulation of the cell cycle. Staining results have shown
that p16 is limited to the nuclei of the epithelial layer, in-
dicating that high methylation of the p16 promoter par-
ticipates in initiating the development of pterygium.
In 2011, researchers detected the methylation level of
29 genes encoding ECM proteins in pterygium [31].
Transglutaminase 2 was highly methylated in pterygium,
while matrix metalloproteinase 2 (MMP2) and cluster of
differentiation 24 (CD24) had low methylation levels. De-
creased transglutaminase 2 attenuated cell adhesion and
Ophthalmic Res 2022;65:481–492 483
DOI: 10.1159/000523878
facilitated the migration of pterygium tissue, while MMP2
and CD24 participated in ECM remodeling and EMT
promotion. Furthermore, CD24 has been verified to play
a role in neovascularization [32]. However, E-cadherin, a
surface marker of epithelial cells, has a hypermethylated
promoter region, suggesting the presence of EMT in pte-
rygium [33].
Previous studies have demonstrated that p53 is differ-
entially expressed in pterygium [16, 17], and mouse dou-
ble minute 2 (MDM2) acts as an E3 ubiquitin protein li-
gase in the degradation of p53 [34]. Compared to that of
control conjunctiva, the methylation rate of the MDM2
promoter in pterygium is significantly lower [34, 35]. It is
controversial whether MDM2 suppresses p53 transcrip-
tional activity despite abundant p53 in pterygium.
Early studies have demonstrated that large tumor sup-
pressor kinases 1 and 2 (LATS1 and LATS2) are common
tumor suppressor genes in the DNA damage response
pathway induced by UV radiation [36]. Najafi et al. [36]
found that the LATS1 and LATS2 methylation levels are
too high to resist the effects of UV DNA damage. Thus,
methylation levels of LATS1 and LATS2 are related to the
risk of recurrence.
Histone Modification Biomarkers of Pterygium
Histone modification refers to the process by which
histones undergo methylation, acetylation, adenylation,
ubiquitination, or ADP ribosylation through related en-
zymes [37]. Among the histone modifications, methyla-
tion is the most stable, while acetylation is highly dynam-
ic, and the modification level correlates with the degree
of gene silencing and activation. Thus far, no research has
confirmed the actual role of histone modification in the
development of pterygium, but some researchers have
speculated that pterygium may be related to histone mod-
ification.
Koga et al. [38] found that butyrate and phenylbutyr-
ate may be used as histone deacetylase inhibitors to in-
hibit the expression of fibrosis-related proteins in pteryg-
ium, such as α-smooth muscle actin, collagen I/III, and
matrix metalloproteinase 1. This research suggests that
histone acetylation may be involved in the occurrence
and development of pterygium. However, the specific
biomarkers involved require further study and explora-
tion.
Biomarkers from Noncoding RNA Regulation in
Pterygium
Noncoding RNAs are a type of RNA that includes
miRNAs, long noncoding RNAs (lncRNA), and circular
484 Ophthalmic Res 2022;65:481–492
DOI: 10.1159/000523878
RNAs (circRNA), which do not encode proteins but reg-
ulate translation. Noncoding RNAs have also been exten-
sively studied in pterygium. The abnormal expression of
noncoding RNAs in pterygium is shown in Table 2.
miRNA Biomarkers in Pterygium
miRNAs are a class of small noncoding RNAs that are
approximately 22 nt in length and are known to be pow-
erful regulators of gene expression. miRNAs bind to the
3′ untranslated region of target genes and induce gene
silencing or degradation.
Some miRNAs Are Associated with Cell Proliferation or
Apoptosis in Pterygium. Compared to control conjuncti-
val tissues, miR-221 expression is upregulated, and miR-
215 expression is downregulated in pterygium tissues.
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miR-221 suppresses the expression of the cyclin-depen-
dent kinase inhibitor p27 kinase protein 1 to drive the
transformation from G1 phase to S phase [39]. Further-
more, miR-221 levels were significantly higher in the
fleshly and intermediate groups than in the atrophic
group, indicating that miR-221 is positively related to
pterygium safety. miR-215 targets minichromosome
maintenance protein 10 and cell division cycle 25A, and
both of these genes promote cell proliferation by partici-
pating in G1/S and G2/M phase transitions [40]. For this
reason, it was speculated that miR-215 could be used as a
therapeutic target in pterygium in the future.
miR-21 is reported to activate the Akt signaling path-
way in various cancers by inhibiting phosphatase and ten-
sin homologue [41, 42]. Li et al. [43] have found that the
miR-21 inhibitor suppresses pterygium fibroblast prolif-
eration and promotes apoptosis via phosphatase and ten-
sin homologue-PI3K/Akt signaling, indicating that an in-
hibitor of miR-21 may be a novel agent used for treat-
ment.
miR-145 has been found to be significantly downregu-
lated in the head part of the pterygium [44]. p53 plays an
agonist role in triggering the transcription of various ap-
optosis proteins, while MDM2 binds to p53 to initiate the
ubiquitin-mediated degradation of p53 [45]. Therefore,
the miR-145-MDM2-p53 axis may serve as a potential
target pathway for pterygium therapy.
The expression of miR-122 decreases in pterygium,
whereas the expression of the targeted gene, B-cell lym-
phoma-w (Bcl-w), is upregulated [46]. miR-122 functions
as a tumor suppressor by targeting Bcl-w, and overex-
pressed miR-122 arrests the cell cycle at the G1 phase and
activates the caspase-3/7 signaling pathway [47]. Oleic
acid-based nanoparticles successfully transfer miR-122
into hepatocytes in mice to effectively suppress Bcl-w ex-
He/Wu
 Table 2. The abnormal expression of noncoding RNA in pterygium

Noncoding RNA Expression Target genes Phenotypes affected

miR-215 ↓ Cdc25A, Mcm10 Proliferation

miR-221 ↑ p27Kip1 Proliferation
miR-21 ↑ PTEN Proliferation and apoptosis
miR-145 ↓ MDM2 Cell growth and apoptosis
miR-122 ↓ Bcl-w Apoptosis
miR-3175 ↑ Smad7 EMT
miR-218-5p ↓ EGFR Migration and proliferation
miR-200a ↓ ZEB1/ZEB2 EMT
miR-145 ↓ – Severity degree
miR-200 ↓ – EMT
miR-143-3p, miR-181a-2-3p ↑ – Pathogenesis
miR-377-5p, miR-411a-5p
PISRT1, LOC283761, FOXD2-AS1 ↑ – Proliferation
↑

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linc-9432 – Differentiation
circ-LAPTM4B ↑ – Proliferation, apoptosis, and migration

Bcl-w, B-cell lymphoma-w; Cdc25A, cell division cycle 25A; circ-LAPTM4B, circular RNA-lysosomal associated pro-
tein transmembrane 4b; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; FOXD2-
AS1, long noncoding RNA-forkhead box d2 adjacent opposite strand RNA 1; Mcm10, minichromosome maintenance
protein 10; MDM2, mouse double minute 2; p27Kip1, p27 kinase protein 1; PISRT1, long noncoding RNA-polled in-
tersex syndrome regulated transcript 1; PTEN, phosphatase and tensin homologue; Smad7, drosophila mothers
against decapentaplegic protein 7; ZEB1/2, zinc finger E-box binding homeobox 1.

pression [48], which indicates the feasibility of miR-122
in pterygium treatment.
Some miRNAs Are Associated with Cell Migration or
EMT of Pterygium. In a recent study, upregulated miR-
3175 was identified in patients with pterygium and di-
rectly inhibited the expression of Drosophila mothers
against decapentaplegic protein 7 to promote prolifera-
tion, migration, invasion, and EMT in human conjuncti-
val epithelial cell lines [49]. miR-3175 promotes patho-
logical phenotypes of pterygium in normal conjunctival
cells, which might be used in clinical therapy.
Aberrant epidermal growth factor receptor (EGFR)
expression or function has been detected in several eye
diseases, including angiogenesis, ECM disorder, and
EMT [50, 51]. In pterygium epithelial cells, miR-218-5p
suppresses the expression of EGFR and inhibits the down-
stream PI3K/Akt/mTOR pathway to promote cell migra-
tion and proliferation [52]. This research shows the sig-
nificance of EGFR in EMT of pterygium and suggests a
possible therapeutic candidate, as agents against EGFR
have been developed in various cancers [53].
miR-200a is significantly lower in pterygium than in
conjunctiva controls, and further tests have shown that
the expression level of miR-200a is negatively associated
with zinc finger E-box binding homeobox (ZEB) 1/2.
ZEB1 and ZEB2 are classified as the main regulators of
EMT by inhibiting p53 [54, 55], and p53 is the down-
stream molecule of both miR-200a and miR-145.
Additionally, Some miRNAs Are Associated with Pte-
rygium Severity. The severity grade of pterygium is based
on a comprehensive assessment of three aspects of slit-
lamp images: extension, vascularity, and thickness of the
pathological tissues. In a study by Chien et al. [56], miR-
145 expression was negatively correlated with pterygium
severity and was significantly higher in primary pterygi-
um tissues than in recurrent tissues, which suggests the
prognostic value of miR-145.
miRNA and mRNA microarray results revealed the
important regulatory capacity of the miR-200 family in
pterygium [57]. Members of the miR-200 family are all
downregulated in pterygium, while the predicted targets
of the miR-200 family, including a large number of ECM-
related proteins, are upregulated [57], suggesting that the
miR-200 family initiates EMT in pterygium. Lee et al. [58]
suggested that, compared to normal fibroblasts, miR-
143a-3p, miR-181a-2-3p, miR-377-5p, and miR-411a-5p
are overexpressed in pterygium fibroblasts. However,
these studies lacked further exploration, so their clinical
applications require further research.

Review Based on Genetic, Epigenetic, and Ophthalmic Res 2022;65:481–492 485

Proteomic Biomarkers in Pterygium DOI: 10.1159/000523878
 LncRNA Biomarkers in Pterygium
LncRNAs are a class of noncoding RNAs with a length
greater than 200 nucleotides. Studies have shown that ln-
cRNAs play important roles in many physiological ac-
tivities, such as cell cycle and differentiation regulation,
and have become a research hotspot in epigenetics.
The results of lncRNA microarrays can provide a new
focus for pterygium. Researchers have found that ln-
cRNA-polled intersex syndrome regulated transcript 1,
LOC283761, and lncRNA-forkhead box d2 adjacent op-
posite strand RNA 1 are upregulated in pterygium and
promote cell proliferation, while lncRNA-lipoprotein(a)
like 2 and lncRNA-small nucleolar RNA host gene 1 are
downregulated in pterygium and suppress cell apoptosis
[59]. These lncRNAs hold great promise for clinical ap-
plication.
A novel lncRNA, linc-9432, is upregulated in pterygi-
um and may regulate 30 differentiation-related genes. In
pterygium fibroblasts, linc-9432 participates in inhibiting
differentiation-induced cell death, promoting the expres-
sion of stem cell and EMT markers [60]. Linc-9432 is pos-
itively related to the process of cell differentiation in pte-
rygium, which may be used as an indicator of progression.
CircRNA Biomarkers in Pterygium
CircRNAs are a special class of noncoding RNA mol-
ecules and are the most recent research focus in the RNA
field. A circRNA molecule has a closed and stably ex-
pressed ring structure that protects it from RNA exonu-
cleases. CircRNAs are rich in miRNA binding sites and act
as miRNA sponges to block the effects of the miRNAs; this
is called the competitive endogenous RNA mechanism.
CircRNA microarrays have indicated that circular RNA-
lysosomal associated protein transmembrane 4b (circ-
LAPTM4B) is upregulated in pterygium. Inhibiting the ex-
pression of circ-LAPTM4B in pterygium fibroblasts and
epithelial cells suppresses cell viability and proliferation but
promotes apoptosis [61]. Thus, circ-LAPTM4B may be a
valuable new therapeutic agent that is more stable.
Biomarkers from Proteomic Analysis in Pterygium
Proteomics refers to the large-scale study of protein
characteristics, including protein expression level, post-
translational modification, and protein-protein interac-
tion, and therefore provides a comprehensive under-
standing of disease at the protein level. Many studies have
investigated the protein profile of pterygium using pro-
teomic technology.
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DOI: 10.1159/000523878
Overexpressed peroxiredoxin-2 (PRDX2) has been
found in pterygium using a proteomic approach [62].
PRDX2 is a cytoplasmic enzyme involved in decreasing
intracellular reactive oxygen species levels and protecting
cells from oxidative stress induced by UV irradiation. Up-
regulated PRDX2 reduces peroxide-induced apoptosis
and necrosis and leads to aberrant cell proliferation and
EMT. The PRDX2 expression level indicates the cause of
the disease in that excessive UV exposure promotes the
occurrence of pterygium.
Among the 230 differentially expressed proteins in
pterygium, aldehyde dehydrogenase 3 family member
A1, protein disulfide isomerase A3, and PRDX2 were sig-
nificantly overexpressed and even increased in recurrent
pterygium. These three proteins are protective factors
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that protect against UV-induced oxidative stress, such as
apoptosis suppression and over-proliferation [63]. These
three biomarkers demonstrate the predominance of oxi-
dative stress in pterygium formation and may be used to
evaluate prognosis.
Based on primary pterygium and conjunctival fibro-
blasts, a collection of differentially expressed proteins has
identified that a large part of the 433 detected proteins are
ECM and fibroblast-secreted proteins [64]. The collagen
family is overexpressed in the pterygium, and the over-
sedimentary collagen produced by pterygium fibroblasts
facilitates pterygium growth. The upregulation of fibulin
1 and the downregulation of serpin family E member 1
assemble elastic matrix fibers and inactivate tissue plas-
minogen activator, leading to ECM changes.
In a recent study, Linghu et al. [65] identified 156 pro-
teins differentially expressed between pterygium and
normal conjunctival tissues; among these genes, matrix
metalloproteinase 10 (MMP10) and cluster of differentia-
tion 34 (CD34) were significantly upregulated in pteryg-
ium. MMP10 is a significant factor in denaturing base-
ment membrane components to participate in pterygium
invasion, while CD34 is recognized as a surface biomark-
er of hematopoietic progenitor cells and stem cells to
evaluate angiogenesis. MMP10 and CD34 may regulate
invasion and neovascularization in pterygium and may
be used for prognosis evaluation.
Discussion
In the period of DNA sequencing development, genet-
ics has become a hotspot in the study of disease biomark-
ers. With advancements in chip technology, RNA se-
quencing, mass spectrometry, epigenetics, and pro-
He/Wu
Table 3. The disordered source and
phenotypes affected of biomarkers
teomics have gradually become the core of mechanistic
research. All the mentioned biomarkers in our review
have been listed in Table 3.
Pterygium is a multifactorial disease with a high inci-
dence and recurrence rate. The most common treat-
Review Based on Genetic, Epigenetic, and
Proteomic Biomarkers in Pterygium
Biomarker Disordered Expression Phenotypes affected
source
HB-EGF Genomics ↑ Proliferation
p53 Progression related Proliferation and apoptosis
K-ras ↑ Proliferation
NGAL ↑ ECM remodeling
MMP9 ↑ Inflammatory
IGFBP3 ↓ Proliferation
ACE ↑ Vasoconstriction
CRIM1 ↓ Differentiation
SLC1A5 ↑ Further study
p16 Epigenetics ↑ Proliferation
E-cadherin ↑ EMT
TGM2 ↑ ECM remodeling
MMP2 ↓ ECM remodeling
CD24 ↓ ECM remodeling
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MDM2 ↓ Proliferation
LATS1/LATS2 ↑ Apoptosis
miR-221-p27Kip1 ↑ Proliferation
miR-215-Cdc25A/ ↓ Proliferation
Mcm10
miR-21-PTEN ↑ Proliferation and apoptosis
miR-145-MDM2 Progression related Proliferation and apoptosis
miR-122-Bcl-w ↓ Apoptosis
miR-3175 ↑ EMT
miR-218-5p-EGFR ↓ Migration and proliferation
miR-200a-ZEB1/ZEB2 ↓ EMT
linc-9432 ↑ Differentiation
Circ-LAPTM4B ↑ Proliferation and apoptosis
PRDX2 Proteomics ↑ Necrosis and EMT
ALDH3A1 ↑ Apoptosis
PDLA3 ↑ Apoptosis
FN1 ↑ ECM remodeling
SERPINE1 ↓ ECM remodeling
MMP10 ↑ Invasion
CD34 ↑ Neovascularization
ALDH3A1, aldehyde dehydrogenase 3 family member A1; Bcl-w, B-cell lymphoma-w;
CD24, cluster of differentiation 24; CD34, cluster of differentiation 34; Cdc25A, cell division
cycle 25A; circ-LAPTM4B, circular RNA-lysosomal associated protein transmembrane 4b;
ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-mesen-
chymal transition; FN1, fibulin 1; LATS1/2, large tumor suppressor kinase 1/2; Mcm10, mini-
chromosome maintenance protein 10; MDM2, mouse double minute 2; MMP2, matrix me-
talloproteinase 2; MMP10, matrix metalloproteinase 10; p27Kip1, p27 kinase protein 1;
PDLA3, protein disulfide isomerase A3; PISRT1, long noncoding RNA-polled intersex syn-
drome regulated transcript 1; PRDX2, peroxiredoxin-2; PTEN, phosphatase and tensin ho-
mologue; SERPINE1, serpin family 1; TGM2, transglutaminase 2; ZEB1/2, zinc finger E-box
binding homeobox 1; NGAL, neutrophil gelatinase-associated lipocalin; IGFBP3, insulin-like
growth factor-binding protein 3.
ment for pterygium is surgical excision, and many ad-
junctive agents may be used, such as doxycycline, mito-
mycin C, and 5-fluorouracil [66]. However, these agents
have toxicity and side effects and are only used postop-
eratively.
Ophthalmic Res 2022;65:481–492 487
DOI: 10.1159/000523878
 Epigenetics links genetics to the environment; thus,
the importance of epigenetics in environmental respons-
es should be well established in pterygium to better pre-
vent the occurrence of disease. Primary pterygium patho-
genesis is mainly associated with UV light exposure, and
some biomarkers support this conclusion. LATS1 and
LATS2 act as effectors against UV-induced DNA damage
and participate in regulating the cell cycle and apoptosis
[67]. In addition, aberrant methylation of p16 is specu-
lated to be associated with UV exposure [30].
As a neoplasm-like disease, cancer includes changes
similar to those in pterygium. p16 and p53 are both tumor
suppressors that induce growth arrest or apoptosis; p16
acts as a stabilizer of p53 to interact with the E3 ubiquitin-
protein ligase MDM2 [68]. Both p16 and p53 share a
common function in controlling the G1 phase of the cell
cycle. In contrast, K-ras possesses intrinsic GTPase activ-
ity, and mutated K-ras induces transcriptional silencing
of tumor suppressor genes [69]. Therefore, some antican-
cer therapies targeting cancer genes may also be feasible
for pterygium treatment. For example, siRNA or shRNAs
can knockdown mutant p53 to restore activity, gentami-
cin can induce readthroughs of premature termination
codons, and CDB3 can restore sequence-specific DNA
binding and transcriptional activity [70]. In addition,
MDM2 small-molecule inhibitors have advanced into
human clinical trials [71], which may also be taken into
consideration for therapy in the future.
It is worth noting that p53 is ectopically expressed in
pterygium. miR-145 is predominantly expressed in the
basal pterygium epithelium, whereas oncogene MDM2
expression is abundant in pterygium epithelium and stro-
ma [44]. Ectopic expression of miR-145 in pterygium
cells induces G1 arrest, downregulates MDM2 and ele-
vates p53 expression.
In addition to the tumor-related proteins, many ECM
proteins are abnormally expressed in pterygium. The
most notable result from the WGCNA was the identifi-
cation of fibulin 1, one of the five hub genes that serves
as a potential regulator of epithelial cell migration, ECM
deposition, and EMT and has also been verified in pro-
teomic findings [28, 64]. Members of the MMP family,
including MMP2, MMP9, and MMP10, are overex-
pressed in the epithelial layer of the pterygium to acti-
vate fibroblasts and promote EMT(22, 32, 65). These
profiling findings point to the core role of ECM remod-
eling in the disease progression, suggesting an impor-
tant research prospect for ECM remodeling and reversal
of EMT in pterygium treatment. Biomarkers identified
in genetics, epigenetics, and proteomics studies were
488 Ophthalmic Res 2022;65:481–492
DOI: 10.1159/000523878
classified as potential mechanisms and shown in a net-
work (Fig. 2).
Some core molecules are observed in the complicated
biomarker network. The first central point is p53, whose
expression levels and functions are regulated by various
factors [16, 17, 19]. First, the mutation of p53 is partly
regulated by UV light [19]. Second, levels of MDM2
methylation are also involved in p53 expression because
MDM2 acts as an E3 ubiquitin protein ligase to degrade
p53 [72]. Third, miR-145 can regulate p53 via the miR-
145-MDM2-p53 axis [44]. Furthermore, p16 is a protec-
tive factor for p53, whereas abnormally activated K-ras
inhibits p53 expression. Teng et al. [44] found that miR-
145 expression is lower in the head of pterygium than in
the body, whereas Chien et al. [56] indicated that miR-
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145 is negatively correlated with pterygium severity. To
the best of our knowledge, these two conclusions are not
contradictory. The head of pterygium is affected at the
beginning of disease development; at this stage, the low
expression of miR-145 in cells promotes rapid cell pro-
liferation. An abnormal increase in cell proliferation
leads to increased disease severity and a poor prognosis.
The above research demonstrated that the miR-
145-MDM2-p53 axis may be a new target for prognosis
or therapy.
miRNA microarrays have been used to identify new
study targets. The latest study performed by Liu et al. [73]
mainly focused on the expression patterns of mRNAs, ln-
cRNAs, and circRNAs. However, much of the informa-
tion was listed rather than verified. Based on research us-
ing these microarrays, miR-143-3p lies at the intersection
[40, 46, 57, 58]. miR-143-3p has been reported as a tumor
suppressor that suppresses proliferation, migration, and
invasion, and promotes apoptosis in various tumors [74,
75]. The use of a miR-143-3p mimic has provided a new
strategy for pterygium therapy.
Due to their invertibility, epigenetic biomarkers may
be more applicable in clinical settings. Small molecule
drugs for DNA methyltransferases and histone deacety-
lases are in the developmental stage and have made some
achievements in tumor treatment. Furthermore, the use
of the miR-122 antagonist in patients with hepatitis C has
entered phase III clinical trials [76]. This application in-
dicates the prospect of miRNA antagonists and activators
being used in the clinic and provides a possibility for non-
invasive treatment of pterygium. The first studies using
proteomics in pterygium were performed in 2006, and
their study specimens were tears from patients with pte-
rygium [77]. Although many genetic biomarkers and
proteomic biomarkers lack deep exploration, noninva-
He/Wu
 miR– miR–
181a– 143a– miR–
2-3p 3p 221 miR–
122
miR– miR– miR–
miR– 377– 145 21
TIMP 411a– 5p miR–
2/3 fibuli 5p 21
n1 miR– FOX
215 D2–
miR– circ– AS1
3175 Pathogenesis LAPT
/Severity M4B LOC
MMP SNH
TGM 2 2837
G1
2 61
miR– Migration Proliferation LPAL
200a/ 2
/EMT /Apoptosis PISR
b
T1
E– MD
cadhe

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p16 M2
rin MMP Others CRI
10 PRD M1
CD24 X2
PDL LAS
miR– A3 T1/2
218–
5p linc– K-ras
SERP 9432 ACE
INE1 CD34 ALD p53
H3A1

CTL ZNF2
A4 05

Fig. 2. The mechanism network of biomarkers in pterygium. EMT, epithelial-mesenchymal transition; “others”
include neovascularization, cell differentiation, and fibrosis.

Clinical
applications
Upregulated Downregulated

ACE, MMP2, CD24,

PRDX2, ALDH3A1, miR-145, TGM2,
Severity PDIA3, fibulin 1, E-cadherin, SERPINE1
MMP10, CD34

Prognosis
prediction
HB-EGF, K-ras, NGAL,
CRIM1, IGFBP3,
Recurrence MMP9, Linc-9432,
LATS1/LATS2
VEGFA, VEGFC

MDM2, miR-3175, p53, p16, miR-218-5P,

Therapeutic miR-21, miR-221, miR-145, miR-122,
development circ-LAPTM4B, miR-200a, miR-215,
Semaphorin 7a FGF21

Fig. 3. Clinical applications of biomarkers in pterygium.

Review Based on Genetic, Epigenetic, and Ophthalmic Res 2022;65:481–492 489

Proteomic Biomarkers in Pterygium DOI: 10.1159/000523878
sive detection may be used to evaluate prognosis in the
future. The probable clinical applications of these bio-
markers are shown in Figure 3.
In addition to biomarkers from genetics, epigenetics,
and proteomics, other biomarkers may also be used clin-
ically. A recent study demonstrated that serum fibroblast
growth factor 21, which is a target for neovascularization
reduction, is lower in patients with pterygium [78]. Fur-
thermore, fibroblast growth factor 21 is negatively related
to cholesterol, triglyceride, and LDL levels; therefore, im-
paired lipid metabolism should be considered for thera-
py. Essential biomarkers in tears, including interleukin-6,
interleukin-8, and vascular endothelial growth factor
(VEGF), are positively correlated with disease severity,
and may also be used for postoperative monitoring [79].
Conclusion
In summary, this review introduced multiple bio-
markers in pterygium identified from genetics, epi-
genetics, and proteomics studies. It was concluded that
these biomarkers might play critical roles in severity de-
gree judgement, recurrence risk prediction, and adjuvant
therapy in pterygium. Among these biomarkers, it is
noteworthy that p53 is involved in pterygium by abnor-
mal changes in various pathways and even has different
phenotypes in different development stages. The abnor-
mal changes of the cell cycle dominated by p53 may be a
new target for pterygium therapy.

Downloaded from http://karger.com/ore/article-pdf/65/5/481/4021749/000523878.pdf by guest on 05 November 2023

Han et al. [80] found that semaphorin 7a is upregulated Conflict of Interest Statement
in pterygium tissues, and the level in recurrent pterygium
The authors have no conflicts of interest to declare.
is even higher than that in primary pterygium. Semapho-
rin 7a shows a positive association with some angiogenic
factors, such as VEGFA and VEGFR, and migration-pro-
Funding Sources
moting factors, such as β1-integrin. Based on the malig-
nant nature of semaphorin 7a in pterygium development This manuscript did not receive any funding.
and recurrence, its inhibitor may act as a new target for
prognosis.
Author Contributions

Siying He contributed to the conception and collected the data

for the work; while Zhaoxia Wu drafted the work and revised it.

References
1 Zhong H, Cha X, Wei T, Lin X, Li X, Li J, et al.
Prevalence of and risk factors for pterygium
in rural adult Chinese populations of the Bai
nationality in Dali: the Yunnan Minority Eye
Study. Invest Ophthalmol Vis Sci. 2012;
53(10):6617–21.
2 Chen YF, Hsiao CH, Ngan KW, Yeung L, Tan
HY, Yang KH, et al. Herpes simplex virus and
pterygium in Taiwan. Cornea. 2008; 27(3):
311–3.
3 Chui J, Coroneo MT, Tat LT, Crouch R, Wake-
field D, Di Girolamo N. Ophthalmic pterygi-
um: a stem cell disorder with premalignant fea-
tures. Am J Pathol. 2011;178(2):817–27.
4 Clearfield E, Muthappan V, Wang X, Kuo IC.
Conjunctival autograft for pterygium. Co-
chrane Database Syst Rev. 2016;2:CD011349.
5 Garzon-Chavez DR, Quentin E, Harrison SL,
Parisi AV, Butler HJ, Downs NJ. The geospa-
tial relationship of pterygium and senile cata-
ract with ambient solar ultraviolet in tropical
Ecuador. Photochem Photobiol Sci. 2018;
17(8):1075–83.
6 Pang Y, Rose T. Rapid growth of pterygium
after photorefractive keratectomy. Optome-
try. 2006;77(10):499–502.
7 Liu T, Liu Y, Xie L, He X, Bai J. Progress in the
pathogenesis of pterygium. Curr Eye Res.
2013;38(12):1191–7.
8 Tsai YY, Chang CC, Chiang CC, Yeh KT,
Chen PL, Chang CH, et al. HPV infection and
p53 inactivation in pterygium. Mol Vis. 2009;
15:1092–7.
9 Pinkerton OD, Hokama Y, Shigemura LA. Im-
munologic basis for the pathogenesis of pteryg-
ium. Am J Ophthalmol. 1984;98(2):225–8.
10 Peiretti E, Dessì S, Putzolu M, Fossarello M.
Hyperexpression of low-density lipoprotein
receptors and hydroxy-methylglutaryl-coen-
zyme A-reductase in human pinguecula and
primary pterygium. Invest Ophthalmol Vis
Sci. 2004;45(11):3982–5.
11 Hacioglu D, Erdol H. Developments and cur-
rent approaches in the treatment of pterygi-
um. Int Ophthalmol. 2017;37(4):1073–81.
12 Hacıoğlu D, Erdöl H. Developments and cur-
rent approaches in the treatment of pterygi-
um. Int Ophthalmol. 2017;37(4):1073–81.
13 Wang G, Dong N, Wang Y, Li J, Dong F, Jey-
alatha V, et al. Epithelial dysplasia in pterygi-
um postoperative granuloma. Exp Eye Res.
2018;175:199–206.
14 Zada M, Pattamatta U, White A. Modulation
of fibroblasts in conjunctival wound healing.
Ophthalmology. 2018;125(2):179–92.
15 Nolan TM, DiGirolamo N, Sachdev NH,
Hampartzoumian T, Coroneo MT, Wakefield
D. The role of ultraviolet irradiation and hep-
arin-binding epidermal growth factor-like
growth factor in the pathogenesis of pterygi-
um. Am J Pathol. 2003;162(2):567–74.
16 Schneider BG, John-Aryankalayil M, Rowsey
JJ, Dushku N, Reid TW. Accumulation of p53
protein in pterygia is not accompanied by
TP53 gene mutation. Exp Eye Res. 2006;82(1):
91–8.
17 Tsai YY, Cheng YW, Lee H, Tsai FJ, Tseng SH,
Chang KC. P53 gene mutation spectrum and
the relationship between gene mutation and
protein levels in pterygium. Mol Vis. 2005;11:
50–5.
18 Mahesh M, Mittal SK, Kishore S, Singh A,
Gupta N, Rana R. Expression of p53 and Ki-
67 proteins in patients with increasing sever-
ity and duration of pterygium. Indian J Oph-
thalmol. 2021;69(4):847–50.

490 Ophthalmic Res 2022;65:481–492 He/Wu

DOI: 10.1159/000523878
19 Maxia C, Perra MT, Demurtas P, Minerba L,
Murtas D, Piras F, et al. Expression of survivin
protein in pterygium and relationship with
oxidative DNA damage. J Cell Mol Med. 2008;
12(6A):2372–80.
20 Detorakis ET, Zafiropoulos A, Arvanitis DA,
Spandidos DA. Detection of point mutations
at codon 12 of KI-ras in ophthalmic pterygia.
Eye. 2005;19(2):210–4.
21 Ozturk BT, Yıldırım MS, Zamani A, Bozkurt
B. K-ras oncogene mutation in pterygium.
Eye. 2017;31(3):491–8.
22 John-Aryankalayil M, Dushku N, Jaworski
CJ, Cox CA, Schultz G, Smith JA, et al. Micro-
array and protein analysis of human pterygi-
um. Mol Vis. 2006;12:55–64.
23 Wong YW, Chew J, Yang H, Tan DT, Beuer-
man R. Expression of insulin-like growth fac-
tor binding protein-3 in pterygium tissue. Br
J Ophthalmol. 2006;90(6):769–72.
24 Demurtas P, Orru G, Coni P, Minerba L, Cor-
rias M, Sirigu P, et al. Association between the
ACE insertion/deletion polymorphism and
pterygium in Sardinian patients: a population
based case-control study. BMJ Open. 2014;
4(10):e005627.
25 Kria L, Ohira A, Amemiya T. Immunohisto-
chemical localization of basic fibroblast
growth factor, platelet derived growth factor,
transforming growth factor-beta and tumor
necrosis factor-alpha in the pterygium. Acta
Histochem. 1996;98(2):195–201.
26 Yazar S, Cuellar-Partida G, McKnight CM,
Quach-Thanissorn P, Mountain JA, Coroneo
MT, et al. Genetic and environmental factors
in conjunctival UV autofluorescence. JAMA
Ophthalmol. 2015;133(4):406–12.
27 Tsai CB, Hsia NY, Wang ZH, Yang JS, Hsu
YM, Wang YC, et al. The contribution of
MMP-9 genotypes to pterygium in Taiwan.
Anticancer Res. 2020;40(8):4523–7.
28 Chen Y, Wang H, Jiang Y, Zhang X, Wang Q.
Transcriptional profiling to identify the key
genes and pathways of pterygium. PeerJ.
2020;8:e9056.
29 Robertson KD. DNA methylation and human
disease. Nat Rev Genet. 2005;6(8):597–610.
30 Chen PL, Cheng YW, Chiang CC, Tseng SH,
Chau PS, Tsai YY. Hypermethylation of the
p16 gene promoter in pterygia and its associa-
tion with the expression of DNA methyltrans-
ferase 3b. Mol Vis. 2006;12:1411–6.
31 Riau AK, Wong TT, Lan W, Finger SN,
Chaurasia SS, Hou AH, et al. Aberrant DNA
methylation of matrix remodeling and cell ad-
hesion related genes in pterygium. PLoS One.
2011;6(2):e14687.
32 Lanza M, Benincasa G, Costa D, Napoli C.
Clinical role of epigenetics and network anal-
ysis in eye diseases: a translational science re-
view. J Ophthalmol. 2019;2019:2424956.
33 Young C-H, Chiu Y-T, Shih T-S, Lin W-R,
Chiang C-C, Chou Y-E, et al. E-cadherin pro-
moter hypermethylation may contribute to
protein inactivation in pterygia. Mol Vis.
2010;16:1047–53.
Review Based on Genetic, Epigenetic, and
Proteomic Biomarkers in Pterygium
34 Arish M, Kordi-Tamandani DM, Sangterash
MH, Poyandeh R. Assessment of promoter
hypermethylation and expression profile of
P14ARF and MDM2 genes in patients with
pterygium. Eye Contact Lens. 2016;42(1):e4–
7.
35 Cao D, Ng TK, Yip YWY, Young AL, Pang
CP, Chu WK, et al. p53 inhibition by MDM2
in human pterygium. Exp Eye Res. 2018; 175:
142–7.
36 Najafi M, Kordi-Tamandani DM, Arish M.
Evaluation of LATS1 and LATS2 promoter
methylation with the risk of pterygium for-
mation. J Ophthalmol. 2016;2016:5431021.
37 Bannister AJ, Kouzarides T. Regulation of
chromatin by histone modifications. Cell Res.
2011;21(3):381–95.
38 Koga Y, Maeshige N, Tabuchi H, Uemura M,
Aoyama-Ishikawa M, Miyoshi M, et al. Sup-
pression of fibrosis in human pterygium fi-
broblasts by butyrate and phenylbutyrate. Int
J Ophthalmol. 2017;10(9):1337–43.
39 Wu CW, Cheng YW, Hsu NY, Yeh KT, Tsai
YY, Chiang CC, et al. MiRNA-221 negatively
regulated downstream p27Kip1 gene expres-
sion involvement in pterygium pathogenesis.
Mol Vis. 2014;20:1048–56.
40 Lan W, Chen S, Tong L. MicroRNA-215 regu-
lates fibroblast function: insights from a hu-
man fibrotic disease. Cell Cycle. 2015;14(12):
1973–84.
41 Cui M, Liu W, Zhang L, Guo F, Liu Y, Chen
F, et al. Over-expression of miR-21 and lower
PTEN levels in Wilms’ tumor with aggressive
behavior. Tohoku J Exp Med. 2017; 242(1):
43–52.
42 Wu Y, Song Y, Xiong Y, Wang X, Xu K, Han
B, et al. MicroRNA-21 (MiR-21) promotes
cell growth and invasion by repressing tumor
suppressor PTEN in colorectal cancer. Cell
Physiol Biochem. 2017;43(3):945–58.
43 Li X, Dai Y, Xu J. MiR-21 promotes pterygium
cell proliferation through the PTEN/AKT
pathway. Mol Vis. 2018;24:485–94.
44 Teng Y, Yam GH, Li N, Wu S, Ghosh A, Wang
N, et al. MicroRNA regulation of MDM2-p53
loop in pterygium. Exp Eye Res. 2018; 169:
149–56.
45 Levine AJ, Oren M. The first 30 years of p53:
growing ever more complex. Nat Rev Cancer.
2009;9(10):749–58.
46 Cui YH, Li HY, Gao ZX, Liang N, Ma SS,
Meng FJ, et al. Regulation of apoptosis by
miR-122 in pterygium via targeting Bcl-w. In-
vest Ophthalmol Vis Sci. 2016;57(8):3723–30.
47 Ma J, Wu Q, Zhang Y, Li J, Yu Y, Pan Q, et al.
MicroRNA sponge blocks the tumor-sup-
pressing functions of microRNA-122 in hu-
man hepatoma and osteosarcoma cells. Oncol
Rep. 2014;32(6):2744–52.
48 Wang X, Yu B, Ren W, Mo X, Zhou C, He H,
et al. Enhanced hepatic delivery of siRNA and
microRNA using oleic acid based lipid
nanoparticle formulations. J Control Release.
2013;172(3):690–8.
Ophthalmic Res 2022;65:481–492
DOI: 10.1159/000523878
49 Zhong X, Tang J, Li H, Shi X, Wu Y, Xia D, et
al. MiR-3175 promotes epithelial-mesenchy-
mal transition by targeting Smad7 in human
conjunctiva and pterygium. FEBS letters.
2020 Apr;594(7):1207–17.
50 Di Girolamo N, Coroneo M, Wakefield D.
Epidermal growth factor receptor signaling is
partially responsible for the increased matrix
metalloproteinase-1 expression in ocular epi-
thelial cells after UVB radiation. Am J Pathol.
2005;167(2):489–503.
51 Balasoiu AT, Ciurea RN, Manescu MR, Mo-
canu CL, Stepan AE, Balasoiu M, et al. Assess-
ment of VEGF and EGFR in the study of an-
giogenesis of eyelid carcinomas. Rom J Mor-
phol Embryol. 2016;57(4):1229–34.
52 Han S, Chen Y, Gao Y, Sun B, Kong Y. Mi-
croRNA-218-5p inhibit the migration and
proliferation of pterygium epithelial cells by
Downloaded from http://karger.com/ore/article-pdf/65/5/481/4021749/000523878.pdf by guest on 05 November 2023
targeting EGFR via PI3K/Akt/mTOR signal-
ing pathway. Exp Eye Res. 2018;178:37–45.
53 Vecchione L, Jacobs B, Normanno N, Ciardi-
ello F, Tejpar S. EGFR-targeted therapy. Exp
Cell Res. 2011;317(19):2765–71.
54 Berx G, Raspé E, Christofori G, Thiery JP, Sl-
eeman JP. Pre-EMTing metastasis? Recapitu-
lation of morphogenetic processes in cancer.
Clin Exp Metastasis. 2007;24(8):587–97.
55 Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon
YJ, Volinia S, et al. p53 regulates epithelial-
mesenchymal transition through microRNAs
targeting ZEB1 and ZEB2. J Exp Med. 2011;
208(5):875–83.
56 Chien KH, Chen SJ, Liu JH, Woung LC, Chen
JT, Liang CM, et al. Correlation of microR-
NA-145 levels and clinical severity of pteryg-
ia. Ocul Surf. 2013;11(2):133–8.
57 Engelsvold DH, Utheim TP, Olstad OK, Gon-
zalez P, Eidet JR, Lyberg T, et al. miRNA and
mRNA expression profiling identifies mem-
bers of the miR-200 family as potential regula-
tors of epithelial-mesenchymal transition in
pterygium. Exp Eye Res. 2013;115:189–98.
58 Lee JH, Jung SA, Kwon YA, Chung JL, Kim
US. Expression of microRNAs in fibroblast of
pterygium. Int J Ophthalmol. 2016;9(7):967–
72.
59 Liu J, Ding X, Yuan L, Zhang X. Identification
of pterygium-related long non-coding RNAs
and expression profiling by microarray analy-
sis. Int J Mol Med. 2016;38(2):529–36.
60 Lan W, Hou A, Lakshminarayanan R, Lim
YP, Tong L. Linc-9432 is a novel pterygium
lincRNA which regulates differentiation of fi-
broblasts. FEBS Lett. 2018;592(7):1173–84.
61 Li XM, Ge HM, Yao J, Zhou YF, Yao MD, Liu
C, et al. Genome-wide identification of circu-
lar RNAs as a novel class of putative biomark-
ers for an ocular surface disease. Cell Physiol
Biochem. 2018;47(4):1630–42.
62 Bautista-de Lucio VM, Lopez-Espinosa NL,
Robles-Contreras A, Perez-Cano HJ, Mejia-
Lopez H, Mendoza G, et al. Overexpression of
peroxiredoxin 2 in pterygium. A proteomic
approach. Exp Eye Res. 2013;110:70–5.
491
63 Kim SW, Lee J, Lee B, Rhim T. Proteomic
analysis in pterygium; upregulated protein
expression of ALDH3A1, PDIA3, and
PRDX2. Mol Vis. 2014;20:1192–202.
64 Hou A, Law KP, Tin MQ, Lim YP, Tong L. In
vitro secretomics study of pterygium-derived
fibroblasts by iTRAQ-based quantitative pro-
teomics strategy. Exp Eye Res. 2016; 153: 14–
22.
65 Linghu D, Guo L, Zhao Y, Liu Z, Zhao M,
Huang L, et al. iTRAQ-based quantitative
proteomic analysis and bioinformatics study
of proteins in pterygia. Proteomics Clin Appl.
2017;11(7–8.
66 Young AL, Cao D, Chu WK, Ng TK, Yip
YWY, Jhanji V, et al. The evolving story of
pterygium. Cornea. 2018;37 Suppl 1:S55–7.
67 Takahashi Y, Miyoshi Y, Takahata C, Irahara
N, Taguchi T, Tamaki Y, et al. Down-regula-
69 Serra RW, Fang M, Park SM, Hutchinson L,
Green MR. A KRAS-directed transcriptional
silencing pathway that mediates the CpG is-
land methylator phenotype. Elife. 2014; 3:
e02313.
70 Kanasty R, Dorkin JR, Vegas A, Anderson D.
Delivery materials for siRNA therapeutics.
Nat Mater. 2013;12(11):967–77.
71 Wang S, Zhao Y, Aguilar A, Bernard D, Yang
CY. Targeting the MDM2-p53 protein-pro-
tein interaction for new cancer therapy: prog-
ress and challenges. Cold Spring Harb Per-
spect Med. 2017;7(5):a026245.
72 Manfredi JJ. The Mdm2-p53 relationship
evolves: Mdm2 swings both ways as an onco-
gene and a tumor suppressor. Genes Dev.
2010;24(15):1580–9.
73 Liu X, Zhang J, Nie D, Zeng K, Hu H, Tie J, et
al. Comparative transcriptomic analysis to
75 He Z, Yi J, Liu X, Chen J, Han S, Jin L, et al.
MiR-143-3p functions as a tumor suppressor
by regulating cell proliferation, invasion and
epithelial-mesenchymal transition by target-
ing QKI-5 in esophageal squamous cell carci-
noma. Mol Cancer. 2016;15(1):51.
76 Janssen HL, Reesink HW, Lawitz EJ, Zeuzem
S, Rodriguez-Torres M, Patel K, et al. Treat-
ment of HCV infection by targeting microR-
NA. N Engl J Med. 2013;368(18):1685–94.
77 Zhou L, Beuerman RW, Foo Y, Liu S, Ang LP,
Tan DT. Characterisation of human tear pro-
teins using high-resolution mass spectrome-
try. Ann Acad Med Singap. 2006;35(6):400–7.
78 Yaghoobi G, Shokoohi-Rad S, Jafarzadeh H,
Abdollahi E. Serum fibroblast growth factor
21 in patients with and without pterygia. J
Ophthalmic Vis Res. 2020;15(1):38–44.
79 Van Acker SI, Haagdorens M, Roelant E, Roz-

Downloaded from http://karger.com/ore/article-pdf/65/5/481/4021749/000523878.pdf by guest on 05 November 2023

tion of LATS1 and LATS2 mRNA expression
by promoter hypermethylation and its asso-
ciation with biologically aggressive pheno-
type in human breast cancers. Clin Cancer
Res. 2005;11(4):1380–5.
68 Schafer KA. The cell cycle: a review. Vet
Pathol. 1998;35(6):461–78.
identify the important coding and non-cod-
ing RNAs involved in the pathogenesis of pte-
rygium. Front Genet. 2021;12:646550.
74 Chen J, Chen X. MYBL2 is targeted by miR-
143-3p and regulates breast cancer cell prolif-
eration and apoptosis. Oncol Res. 2018;26(6):
913–22.
ema J, Possemiers T, Van Gerwen V, et al. Pte-
rygium pathology: a prospective case-control
study on tear film cytokine levels. Mediators
Inflamm. 2019;2019:9416262.
80 Han YF, Liu Z, Wang B, Zhu W, Li JZ, Qi YQ,
et al. Semaphorin 7a participants in pterygi-
um by regulating vascular endothelial growth
factor. Int J Ophthalmol. 2019;12(6):892–7.

492 Ophthalmic Res 2022;65:481–492 He/Wu

DOI: 10.1159/000523878