·Review·Current
Issue· ·Achieve· ·Search Articles· ·Online Submission· ·About IJO· PMC
Aberrant expression of genes and
proteins in pterygium and their implications in the pathogenesis
Qing-Yang Feng1, Zi-Xuan Hu2, Xi-Ling Song2,
Hong-Wei Pan1,2,3
1Department of
Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou
510630, Guangdong Province, China
2Department of Public
Health and Preventive Medicine, Jinan University, Guangzhou 510632, Guangdong
Province, China
3Institute of
Ophthalmology, School of Medicine, Jinan University, Guangzhou 510632,
Guangdong Province, China
Correspondence
to: Hong-Wei
Pan. Department of Ophthalmology, the First Affiliated Hospital of Jinan
University, 613 West Huangpu Avenue, Guangzhou 510630, Guangdong Province,
China. panhongwei@hotmail.com
Received:
2016-11-14
Accepted: 2017-03-11
Pterygium is a
common ocular surface disease induced by a variety of factors. The exact
pathogenesis of pterygium remains unclear. Numbers of genes and proteins are
discovered in pterygium and they function differently in the occurrence and
development of this disease. We searched the Web of Science and PubMed
throughout history for literatures about the subject. The keywords we used
contain pterygium, gene, protein, angiogenesis, fibrosis, proliferation,
inflammation, pathogenesis and therapy. In this review, we summarize the
aberrant expression of a range of genes and proteins in pterygium compared with
normal conjunctiva or cornea, including growth factors, matrix
metalloproteinases and tissue inhibitors of metalloproteinases, interleukins,
tumor suppressor genes, proliferation related proteins, apoptosis related
proteins, cell adhesion molecules, extracellular matrix proteins, heat shock
proteins and tight junction proteins. We illustrate their possible mechanisms
in the pathogenesis of pterygium as well as the related intervention based on
them for pterygium therapy.
KEYWORDS: pterygium;
growth factors; matrix metalloproteinases; tissue inhibitors of
metalloproteinases; interleukins; tumor suppressor genes; proliferation and
apoptosis; cell adhesion molecules; extracellular matrix proteins
DOI:10.18240/ijo.2017.06.22
Citation: Feng QY, Hu
ZX, Song XL, Pan HW. Aberrant expression of genes and proteins in pterygium and
their implications in the pathogenesis. Int J Ophthalmol 2017;10(6):973-981
Pterygium, one
of the most common ocular surface diseases, is characterized by the invasive
growth of fibrovascular conjunctiva tissue extending on the corneal surface,
which leads to the reduction of visual acuity[1].
Surgery is the traditional treatment for this disease. Despite pterygium has
been extensively studied, the accurate pathogenesis remains a mystery. Epidemiological studies
have found that the etiology of
pterygium is relevant to chronic stimulations caused by ultraviolet and dust, etc[2]. Whereas numerous studies[3-5] provide the evidence that various molecules, such as
growth factors, matrix metalloproteinases (MMPs) and interleukins (ILs), have
close relation to angiogenesis, fibrosis, proliferation and inflammation, which
constitute the pathology of pterygium.
We searched
literatures concerning the keywords pterygium, gene, protein, angiogenesis,
fibrosis, proliferation, inflammation, pathogenesis and therapy from the Web of
Science and PubMed throughout history. In this review, we compare pterygium
with normal ocular surface tissues and summarize the aberrant expression of
some genes and proteins in pterygium (Table 1). In addition, we indicate the
possible functions of these molecules involved in the pathogenesis of pterygium
and demonstrate some therapeutic implications for pterygium according to these
molecules.
Table 1
Aberrant expression of some genes and proteins in pterygium
Genes/proteins |
Upregulated |
Downregulated |
Invariant |
Growth
factors |
VEGF, VEGFR-2, VEGFR-3, TGF-β,
bFGF, IGFBP2, NGF, TrkA, CTGF |
TGFR-β1, TGFR-β2, IGFBP3 |
|
MMPs and
TIMPs |
MMP-1, MMP-2, MMP-3, MMP-8, MMP-9,
MMP-10, MMP-13, TIMP-1, TIMP-3 |
|
|
ILs |
IL-1, IL-4, IL-6, IL-8, IL-10,
IL-17 |
|
|
Tumor
suppressor genes |
P53, p63, p16 |
P27 |
|
Proliferation
related proteins |
Ki-67, PCNA, cyclin D1 |
|
|
Apoptosis
related proteins |
Survivin, Bcl-2, Bcl-w |
|
Bax |
CAMs |
ICAM-1, VCAM-1, E-cadherin,
integrin |
|
|
Extracellular
matrix proteins |
Keratin, tropoelastin, collagen
type II |
|
|
HSPs |
Hsp27, Hsp70, Hsp90 |
|
|
Tight
junction proteins |
|
Claudin-1 |
|
Growth
Factors Growth factors, a type of
molecules that stimulate cell growth, have the ability to promote mitosis and
proliferation in cell cycle. Numbers of growth factors, such as vascular
endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β),
basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), nerve
growth factor (NGF) and connective tissue growth factor (CTGF) have been
discovered in pterygium[6].
Firstly, VEGF
is one of the most important growth factors in ocular diseases. The VEGF family
control pathological angiogenesis and increase vascular permeability in eye
sicknesses[7]. Compared with normal conjunctiva,
pterygium presented higher levels of VEGF and
vascular endothelial growth factor receptor (VEGFR)-2, -3[8-9]. Gharaee et al[10]
discovered VEGF mRNA expression was much higher in atopic pterygium patients
than in non-atopic individuals. Upregulation of VEGF-C mRNA level probably
leaded to lymphangiogenesis in pterygium, especially in recurrent pterygium[11-12]. Lately, it was clarified TNF-α
mediated the expression of VEGF-C[13]. Increased
expression of VEGF leads to angiogenesis and lymphangiogenesis, which may
influence the normal metabolism of conjunctiva cells and promote them to become
pterygium cells. 5-fluorouracil, a new-trend treatment for preventing pterygium
recurrence, was recently reported to be unable to affect VEGF expression in
pterygium[14]. As we all know, anti-VEGF
medicines like ranibizumab and bevacizumab have been extensively applied in
healing ocular maladies. Nevertheless, current evidence didn’t advocate the use
of anti-VEGF drugs in pterygium surgery[15].
Secondly,
TGF-β regulates many of the processes common to both tissue repair and disease,
including fibroblast proliferation, angiogenesis, controlled synthesis and
degradation of matrix proteins like collagen and fibronectin[16]. With reverse transcription polymerase
chain reaction (RT-PCR), Zhong et al[17]
discovered TGF-β1 and TGF-β2 were upregulated while transforming growth
factor-beta receptor 1, 2 (TGFR-β1, -β2) were downregulated in pterygium
compared to normal bulbar conjunctival tissues. Bianchi et al[18] elucidated TGF-β was expressed moderately in the
epithelial and stromal layers of pterygium, yet weakly in normal conjunctiva.
In consistent with VEGF, the expression of TGF-β1 was obviously higher in
atopic pterygium patients compared to non-atopic ones[19]. It was found by Tan et al[20] that Tafazzin (TAZ) protein adjusted conjunctiva
epithelial cell propagation by suppressing TGF-β signaling. Pirfenidone
and tranilast were newly reported to be effective in decreasing the expression
of TGF-β in pterygium and might be safe adjuvants for pterygium surgery to
avoid recurrence[21-22]. In
addition, amniotic membrane grafting was shown to inhibit the signaling of
TGF-β[23]. Thus, inhibiting the expression of
TGF-β seems to be effective in preventing pterygium occurrence.
Thirdly, bFGF,
also known as fibroblast growth factor 2 (FGF2), participates in angiogenesis,
wound healing and various endocrine signaling pathways. The expression of bFGF
was found to be increased in infiltrating mast cells, epithelium and blood
vessels of pterygium, moreover, mast cells might serve as an additional source
of bFGF[24-25]. Detorakis et
al[26] measured the mRNA level of FGF2 in
pterygium and normal conjunctiva with qRT-PCR, obtaining the result that higher
FGF2 was expressed in pterygium. FGF2 was able to induce the expression of
cyclooxygenase-2 (COX-2), which was absent in normal conjunctiva[27] but present in human pterygium fibroblasts[28]. COX-2 is the key enzyme for inflammatory
cytokine-induced angiogenesis, thus FGF2 can induce inflammation and
angiogenesis in pterygium. Recent study[29] found
mycophenolic acid changed bFGF expression in pterygium and exhibited an
inhibitory effect on fibroblasts proliferation.
Fourthly, IGF,
capable of promoting cell mitosis, stimulating cell proliferation and
inhibiting apoptosis, contributes to the growth of pterygium[30].
According to the study of Solomon et al[31],
insulin-like growth factor binding protein-2 (IGFBP2) was found to be
overexpressed in pterygium body fibroblasts. However, insulin-like growth
factor binding protein-3 (IGFBP3) was notably decreased in pterygium compared
to normal conjunctiva[32]. Downregulation of
IGFBP3 is closely associated with the occurrence of cancer[33],
in other words, low level of IGFBP3 may be relevant to the out of control cell
proliferation, which means downregulation of IGFBP3 is linked to the continuing
growth of pterygium possibly.
Fifthly, NGF,
a neurotrophic factor, mainly regulates growth, proliferation and survival of
certain cells. Expression of NGF was strong in epithelia, fibroblasts and
vascular endothelial cells of pterygium, while weak in epithelia and
fibroblasts of normal conjunctiva[34]. Ribatti et
al[35] observed that endothelial cells in
human pterygium were immunoreactive to both NGF and its receptor TrkA. These
two molecules were related to microvascular density. Thus increased level of
NGF and TrkA seem to accelerate vascularization in pterygium.
Last but not
least, CTGF, which is involved in cell adhesion, migration and chemotaxis,
belongs to the CCN family of proteins. The CCN family is a complicated family
of multifunctional proteins including six members designated CCN1 to CCN6. The
CCN abbreviation was introduced from the names of the first three members of
the family to be discovered: cysteine-rich protein 61 (Cyr61), CTGF and
nephroblastoma overexpressed gene (NOV)[36]. van
Setten et al[37] illustrated that CTGF was
present in the epithelium of pterygium, however, it appeared to be absent in
normal conjunctiva. Therefore, it is possible that only pterygium can express
CTGF, while normal conjunctiva can’t.
Matrix Metalloproteinases
and Tissue Inhibitors of Metalloproteinases MMPs are a multigene family of over
25 secreted and cell surface enzymes that process
or degrade lots of extracellular matrix[38],
which can be divided into five subgroups based on substrate preference:
collagenases (MMP-1, MMP-8, MMP-13), gelatinases (MMP-2, MMP-9),
stromelysins
(MMP-3, MMP-10), membrane-associated MMPs (MT1-MMP, MT2-MMP) and others (e.g.
MMP-12, MMP-19, MMP-20)[39]. Tissue inhibitors of
metalloproteinases (TIMPs) bind to and deter the activities of most MMPs. The
relationship between pterygium and these two groups of proteins has been a
focus for exploring the pathogenesis of pterygium for a long time.
MMP-1, MMP-2,
MMP-3, TIMP-1 and TIMP-3 were detected in increased amounts in pterygium
tissues and cultured pterygium epithelial cells and fibroblasts compared with
conjunctiva[40-41]. Siak et
al[42] found TNF-α activated the nuclear
factor kappa B (NF-κB) pathway in pterygium fibroblasts, thereby upregulated
the expressions of MMP-1, MMP-2 and MMP-3. The extracellular signal-regulated
kinase 1/2 mitogen-activated protein kinase intracellular pathway was involved
in the UVB induction of MMP-1 expression in pterygium[43].
Bevacizumab was lately demonstrated to reduce the level of MMP-1 in human
Tenon's fibroblasts cultured from primary and recurrent pterygium[44]. Yao et al[45]
indicated that higher MMP-3 and MMP-8 were expressed in pterygia than in normal
tissues. MMP-3 and secreted protein acidic and rich in cysteine (SPARC) were
reported to be upregulated and colocalized in the epithelium of pterygium,
indicating they might collaborate to account for the diverse phenotypes of
pterygium[46]. Recent study[47]
shown cyclosporine A had the capability to lower MMP-3 and MMP-13 expression in
cultured pterygium fibroblasts. Precursor and active forms of MMP-7 exist in
epithelium and blood vessels of pterygium, but they are absent in conjunctival
vessels[48]. Tsai et al[4]
reported that the immune-positive rate for MMP-9, MMP-10 and TIMP-1 were 35.4%,
34.1% and 72.0% respectively among the 82 pterygium samples, and the invasion
and migration ability of cells were increased in TIMPs knockdown pterygium
epithelia. The results above came to a conclusion that MMP-9 and MMP-10
contributed to pterygium formation, whereas TIMPs inhibited pterygium invasion.
Early study[49] suggested the expression of MMP-9
was similar in both pterygium and normal Tenon’s capsule. However, further
research conducted by Yang et al[50]
pointed out MMP-9 and activated MMP-2 were not expressed in early-stage
pterygium tissues and cultured fibroblasts until pterygium head passed the
pupillary region. MMPs produced by pterygium cells had the ability of
dissolving Bowman's layer, leading to the growth stimulation of stromal
fibroblasts[51]. Moreover, MMPs seemed to be
active in other ocular surface disorders, for example, MMP-1 and MMP-3 were overexpressed
in cultured conjunctival fibroblasts and surgical samples from patients who
suffered from superior limbic keratoconjunctivitis[52].
The expression
of MMPs and TIMPs vary in different stages of pterygium. We consider the
disruption of the balance between MMPs and TIMPs may be responsible for the
progression or recurrence of pterygium.
Interleukins ILs are a group of secreted proteins
and signal molecules that were first seen to be expressed by white blood cells[53]. White blood cells play vital roles in the process of
inflammation, thus ILs ought to be closely related to pterygium.
In a previous
study[54], the expression of IL-1α, IL-1β, IL-1β
RA and IL-1β precursor proteins in primary pterygium and normal conjunctival
epithelium were detected via immunofluorescence. It turned out that
enhanced level of IL-1 family proteins were present only in pterygium. Likewise,
Huang et al[55] found IL-1α was expressed
higher not only in primary but also in recurrent pterygium. According to a
research carried out by Kuo et al[56],
IL-4 was transcriptionally elevated in recurrent pterygium tissues. Moreover,
it was localized to perivascular tissues and endothelial cells in the stroma of
the subconjunctiva of pterygium. As important proinflammatory cytokines, IL-6
and IL-8 proteins were strongly expressed in the epithelium of pterygium in
comparison to normal cornea, conjunctiva and limbus. Besides, in contrast with
nonirradiated pterygium, IL-6 and IL-8 proteins were significantly elevated in
UVB-treated pterygium, suggesting UVB might induce the secretion of these two
ILs[57]. IL-8 is able to induce vascularization
of cornea directly[58]. A recent study[59] indicated that mitomycin C (MMC) increased the
secretion of IL-8 concentration-dependently in human Tenon's capsule
fibroblasts (HTFs), whereas dexamethasone reversed the HTFs proliferation
through inhibiting the MMC-induced IL-8 secretion. It was reported that IL-10
and Foxp3 were expressed more abundantly in pterygium than in the normal
conjunctiva[60]. The level of IL-17 was recently
found to be upregulated in ocular surface inflammatory pathologies, such as
pterygium, inflamed juvenile conjunctival nevus and ocular demodicosis[61-62]. Subbarayal et al[63] suggested IL-17 promoted ocular surface autoimmunity
partly via enhancing B cell proliferation, differentiation and plasma
cell generation.
Tumor
Suppressor Genes Tumor suppressor genes
protect cells from converting to cancer cells and regulate the growth of cells
along with the proto-oncogene. P53, one of the most common tumor suppressor
genes, has been widely studied. Ueda et al[64]
found mutant p53 existed in Japanese and Tunisian pterygium tissues. In
addition, they suggested that damage caused by p53-dependent programmed cell
death of pterygium cells may lead to mutations in other genes, which may allow
the progressive multistep development of limbal tumors. Therefore mutant
p53-positive pterygia can possibly develop into limbal tumors. Tsai et al[65] reviewed all immunohistochemical studies on pterygium
from Medline and indicated over 20% of all pterygium samples in the literatures
were positive for p53 expression. Weinstein et al[66]
performed immunohistochemical staining on 13 pterygium specimens and 2 normal
conjunctiva specimens, and the result showed that 54% of pterygia were positive
for abnormal p53 expression, whereas no pathological staining was observed in
conjunctiva. In the studies from other countries, p53 likewise had greater
immunoreactivity in pterygium than conjunctiva[67-68]. Recently it was known that the p53 protein had
positive correlation with Ki-67 protein, a marker of proliferative cellular
activity, in pterygium[69]. Surprisingly, the
increased expression of p53 in pterygium didn’t block cell proliferation or
cause apoptosis, implying these normal mechanisms of p53 were inactivated in
pterygium[70]. According to Rodrigues et al[71], abnormal expression of p53, p53 codon 72
polymorphisms and human papillomavirus (HPV) DNA were necessary co-factors for
the progression of pterygium. It was demonstrated HPV 16/18 E6 oncoprotein was
involved in p53 inactivation in the pathogenesis of HPV-mediated pterygium[72]. It seems to us that the aberrant expression of p53
promotes cell proliferation and slows apoptosis in pterygium, thereby
accelerates the development of this disease.
Besides p53,
there are some homeotic tumor suppressor genes like p63, p16 and p27
functioning in pterygium as well. P63 expressed increasingly in the basal and
parabasal layers of primary pterygium, and in the full thickness of the
epithelium in recurrent pterygium. Increased expression of p16 protein was
observed in pterygium. Yet p63 and p16 seemed to express rarely in normal
conjunctiva[73]. Atkinson et al[74] also found p63 overexpressed in pterygium. To our
astonishment, the p16 gene promoter was hypermethylated in pterygium, which
might cause the suppression of p16 protein[75].
As a member of tumor suppressor genes, p27 was detected with low nuclear
immunoreactivity in pterygium tissues, which differed from other tumor
suppressor genes[76].
Proliferation
Related Proteins Proliferation related
proteins, such as Ki-67, proliferating
cell nuclear antigen (PCNA) and cyclin D1, play important roles in the process
of cell growth. One of the most significant characters of pterygium is
proliferation, so proliferation related proteins ought to function actively in
the progress of this disease.
The Ki-67
protein is known as a cellular marker for proliferation extensively[77]. Konuk et al[78]
demonstrated that the expression of Ki-67 increased in both primary and
recurrent pterygium, which supported the proliferative nature of pterygium.
Ohara et al[79] suggested Ki-67 might be a
sensitive marker for ocular malignant tumor. As we know, pterygium seems to
have a few features similar to tumor, so Ki-67 may be a marker for pterygium
likewise.
PCNA is a DNA
clamp and achieves its processivity by encircling the DNA, where it acts as a
scaffold to recruit proteins involved in DNA replication, DNA repair, chromatin
remodeling and epigenetics[80]. It was reported
that the expression of PCNA and Ki-67 was significantly higher in pterygium
than normal conjunctiva[81]. It seems to us that
the synergy of PCNA and Ki-67 may consolidate the cell proliferation in
pterygium pathogenesis.
Cyclin D1 is a
protein required for progression through the G1 phase of the cell cycle[82]. Recent study[83] found
PCNA and cyclin D1 were overexpressed in limbal part of pterygium epithelial
cells compared with normal conjunctivas, which might lead to the limbal
micro-environmental anomaly such as hyper-proliferation of resident epithelial
cells. This may explain how these two proteins promote the initiation of this
disease. Tung et al[84] indicated
β-catenin expressed in nuclei/cytoplasm could increase cyclin D1 protein
expression, which contributed to proliferation of pterygium cells. In addition,
PCNA was overexpressed in cultured human pterygium fibroblasts in vitro
and ahylysantinfarctase could inhibit its expression at a dose-dependent manner[85]. Moreover, DK2, a peroxisome proliferator-activated
receptor γ agonist, was found to be capable of inducing the apoptosis and
suppressing the expression of PCNA mRNA and protein in human pterygium
fibroblasts[86].
Apoptosis
Related Proteins Apoptosis related
proteins, such as survivin, Bcl-2, Bax and Bcl-w, are suggested to be involved
in the regulation of cell apoptosis.
Survivin, an
important member of the apoptosis inhibitors family, is capable of inhibiting
caspases activation, leading to negative regulation of apoptosis. Xu et al[87] revealed that survivin was strongly expressed in
pterygium tissues and located in both nucleus and cytoplasm of epithelial
cells, however, it was only weakly expressed in the cytosol of normal
conjunctival epithelium. Furthermore, knockdown of survivin suppressed
propagation of pterygium epithelial cells, along with downregulation of p63 and
upregulation of p57 and p21 expressions. It was demonstrated that oxidative
stress could cause activation of survivin expression, inducing a
hyperproliferative condition, which might be a crucial event in the growth of
pterygium[88]. Survivin had an essential
connection with COX-2 in primary pterygium, suggesting that pterygium might
originate via an anti-apoptotic mechanism[89].
Bcl-2, a
protein encoded in humans by the Bcl-2 gene, is the founding member of the
Bcl-2 family that controls apoptosis by either inducing or inhibiting apoptosis[90-91]. Bax, known as an apoptotic
activator protein, comes from the Bcl-2 gene family as well. Apparent
expression of Bcl-2 was observed in the basal epithelial layer of all pterygium
epithelial cells, while normal conjunctiva showed no evidence of Bcl-2. Bax
came from the same family as Bcl-2, so the expression of Bax might be
upregulated in theory. But the truth was that its expression seemed to be
similar in both pterygium and normal conjunctiva[92].
Zheng et al[93] got the same results as
the previous study concerning these two proteins. Ahylysantinfarctase was shown
to inhibit the Bcl-2 expression in cultured human pterygium fibroblasts[85]. Bcl-w, a member of Bcl-2 family, protects cell from
apoptosis[94]. Recently it was reported that
Bcl-w was overexpressed in pterygium and the decrease of miR-122 could result
in abnormal apoptosis in pterygium via its regulation of the Bcl-w
expression[95].
Cell
Adhesion Molecules Cell adhesion molecules
(CAMs) are proteins located on the cell surface and involved in binding with
other cells or with the extracellular matrix in the process called cell
adhesion, including selectin, syndecan, cadherin and integrin[96].
Beden et al[97] found the expression of intercellular adhesion molecule-1
(ICAM-1) was present in pterygium, while absent in normal conjunctival
epithelium. van de Stolpe and van der Saag[98]
indicated that ICAM-1 stimulated antigen-presenting cells to activate MHC class
II restricted T-cells, and other cell types in association with MHC class I to
activate cytotoxic T-cells. And ICAM-1 was able to promote migration of
leukocytes to sites of inflammation. Thus, pterygium epithelial cells
participated in the inflammatory process by expressing ICAM-1. Tekelioglu et
al[99] demonstrated ICAM-1, vascular cell
adhesion molecule-1 (VCAM-1) was upregulated in pterygium compared with normal
conjunctival tissue, along with higher levels of CD4 and CD8 lymphocytes. This
means ICAM-1 and VCAM-1 may elevate the levels of T-lymphocyte infiltration,
thereby promote the pathogenesis of pterygium.
Selectin and
syndecan are less investigated for their involvement in pterygium, thus we pay
more attention to cadherin and integrin. Kase et al[100]
indicated E-cadherin was present in diverse epithelial cells in pterygium, but
deficient in normal cornea and conjunctiva. E-cadherin, a transmembrane
glycoprotein mediates cell-to-cell adhesion[101],
may advance the adhesion of epithelial and vascular cells in pterygium and
accelerate the pathogenesis. Integrin functions interactions between cells and
the extracellular matrix and hence promote cell migration, tissue stability and
a stable cellular environment for stem cells[102].
In our opinion, increased integrin may disturb the steady status of limbal
cells, influence the adhesion and migration of conjunctiva cells, which would
cause the occurrence and recurrence of pterygium. Recent study[103] revealed that doxycycline treatment could evidently
reduce the expression of integrin in pterygium.
Extracellular
Matrix Proteins Extracellular matrix
proteins contain keratin, elastin, collagen, fibroin and so on. Some keratins
(K8, K16, K14 and AE3) are found to be present in the full thickness in
pterygium epithelium, but not in normal conjunctiva[104].
Perez-Rico et al[105] indicated that
pterygium shown higher mRNA level and expression of tropoelastin than
conjunctival tissue. The expression of tropoelastin in pinguecular part of
pterygium is increased because of the posttranscriptional modification[106]. Lately, it was found that several extracellular
matrix constituents, such as LOXs, FBN1 and FBLN5, involved in the development
of elastin were overexpressed in pterygium[107],
which meant elastin might be overexpressed likewise. Collagen types I, III and
IV were detected in both pterygium and normal conjunctiva, but collagen type II
only existed in pterygium[108]. Recently it was
reported the use of biodegradable collagen matrix implants following pterygium
excision seemed to lower the risk of pterygium recurrence[109].
Since pterygium is fibrovascular tissue characterized by excessive
extracellular matrix deposition and vascular ingrowth, the aberrant expression
of extracellular matrix proteins seems to be directly associated with the
growth of pterygium.
Heat Shock
Proteins Heat shock proteins (HSPs)
are a family of proteins that are produced by cells in response to exposure to
stressful conditions. Pharmakakis and Assimakopoulou[110]
indicated the expression of Hsp27 was detected in the epithelial cells,
endothelial cells and vascular smooth muscle cells of pterygium while only in
the epithelium of normal conjunctiva. In 10 normal conjunctiva and 15 pterygium
samples, Sebastia et al[111] found
pterygium epithelium expressed more Hsp90 than normal conjunctiva epithelium.
Recently it was shown the expressions of HSPs (Hsp27, Hsp70 and Hsp90) and
hypoxia-inducible factor-1α (HIF-1α) were noticeably increased in pterygium[112]. Hsp90 cooperated with HIF-1α in regulating the
transcription of abundant target genes involved in vascularization, energy
metabolism and apoptosis[113]. In addition, some
members of HSPs were found to be overexpressed in other ocular surface disease
like keratoconjunctivitis[114]. In our opinion,
chronic stimulations caused by UV radiation or dust might lead to the
occurrence of pterygium via elevating the expression of HSPs.
Tight
Junction Proteins Tight junctions are the
intimately associated areas of two cells whose membranes join together forming
an impermeable barrier to fluid. Claudins are indispensable proteins for the
formation and maintenance of tight junctions. Dogan et al[115] used immunohistochemical evaluation and McNemar
test to investigate the tight junction protein claudin-1 expressions in
pterygium with respect to normal conjunctiva. They found the expression of
claudin-1 decreased significantly in pterygium, which meant the loss of
claudin-1 probably contributed to the pathogenesis of pterygium.
With histology
and molecular biology technique, the genes and proteins expression profile of
pterygium was found to be greatly different from normal conjunctiva or cornea.
Moreover, the expression profile also varies with the clinical stage or onset
(primary or recurrent). These genes and proteins can be classified into
different groups according to their major function, and they may play a role in
the diverse biological process and contribute to the initiation and development
of pterygium with interaction. Many proteins that are found to aberrantly expressed
in pterygium need to be studied by further investigation, such as human
cystatin C[116] and COX-2[117],
etc. It is also possible that many important genes and proteins in
pterygium pathogenesis still remain unknown. Further studies should be performed
to understand the mechanisms by which these genes and proteins are involved in
pterygium. Pharmaceutical intervention targeting these molecules that are
proved to be critical in pterygium development might be a promising therapy for
pterygium besides surgical treatment.
Foundations:
Supported
by the National Natural Science Foundation of China (No.81570814); Natural
Science Foundation of Guangdong Province, China (No.2014A030313363).
Conflicts
of Interest: Feng QY, None; Hu ZX, None; Song XL, None; Pan HW,
None.
1 Chui J, Di Girolamo N, Wakefield D, Coroneo MT. The pathogenesis
of pterygium: current concepts and their therapeutic implications. Ocul Surf 2008;6(1):24-43. [CrossRef]
2 Atanasova M, Whitty A. Understanding cytokine and growth factor
receptor activation mechanisms. Crit Rev
Biochem Mol Biol 2012;47(6):502-530. [CrossRef] [PMC free article] [PubMed]
4 Tsai YY, Chiang CC, Yeh KT, Lee H, Cheng YW. Effect of TIMP-1
and MMP in pterygium invasion. Invest
Ophthalmol Vis Sci 2010;51(7): 3462-3467. [CrossRef] [PubMed]
5 Kim KW, Park SH, Kim JC. Fibroblast biology in pterygia. Exp Eye Res 2016;142:32-39. [CrossRef] [PubMed]
6 Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Pathogenesis of
pterygia: role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004;23(2):195-228. [CrossRef] [PubMed]
7 Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular
endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 2003;22(1):1-29. [CrossRef]
8 Gumus K, Karakucuk S, Mirza GE, Akgun H, Arda H, Oner AO.
Overexpression of vascular endothelial growth factor receptor 2 in pterygia may
have a predictive value for a higher postoperative recurrence rate. Br J Ophthalmol 2014;98(6):796-800. [CrossRef] [PubMed]
9 Fukuhara J, Kase S, Ohashi T, Ando R, Dong Z, Noda K, Ohguchi,
Kanda A, Ishida S. Expression of vascular endothelial growth factor C in human
pterygium. Histochem Cell Biol 2013;139(2):381-389.
[CrossRef] [PubMed]
10 Gharaee H, Shayegan MR, Khakzad MR, Kianoush S, Varasteh AR,
Sankian M, Meshkat M. The expression of vascular endothelial growth factor in
pterygium tissue of atopic patients. Int
Ophthalmol 2014;34(6):1175-1181. [CrossRef] [PubMed]
11 Ling S, Liang L, Lin H, Li W, Xu J. Increasing lymphatic
microvessel density in primary pterygia. Arch
Ophthalmol 2012;130(6):735-742. [CrossRef]
12 Ling S, Li Q, Lin H, Li W, Wang T, Ye H, Yang J, Jia X, Sun Y.
Comparative evaluation of lymphatic vessels in primary versus recurrent
pterygium. Eye (Lond) 2012;26(11):1451-1458.
[CrossRef] [PMC free article] [PubMed]
13 Dong Y, Kase S, Dong Z, Fukuhara J, Tagawa Y, Ishizuka ET,
Murata M, Shinmei Y, Ohguchi T, Kanda A, Noda K, Ishida S. Regulation of
vascular endothelial growth factor-C by tumor necrosis factor-α in the
conjunctiva and pterygium. Int J Mol Med 2016;38(2):545-550.
[CrossRef]
14 Hoyama E, Hata Viveiros MM, Shiratori C, de Oliveira DE,
Padovani CR, Selva D, Schellini SA. Expression of vascular endothelial growth
factor (VEGF) in macrophages, fibroblasts, and endothelial cells in pterygium
treated with 5-fluorouracil. Semin
Ophthalmol 2015;30(3): 171-176. [CrossRef] [PubMed]
15 Mak RK, Chan TC, Marcet MM, Choy BN, Shum JW, Shih KC, Wong IY,
Ng AL. Use of anti-vascular endothelial growth factor in the management of
pterygium. Acta Ophthalmol 2017;95(1):20-27.
[CrossRef] [PubMed]
16 Govinden R, Bhoola KD. Genealogy, expression, and cellular
function of transforming growth factor-beta. Pharmacol Ther 2003;98(2):257-265. [CrossRef]
18 Bianchi E, Scarinci F, Grande C, Plateroti R, Plateroti P,
Plateroti AM, Fumagalli L, Capozzi P, Feher J, Artico M. Immunohistochemical
profile of VEGF, TGF-β and PGE2 in human pterygium and normal
conjunctiva: experimental study and review of the literature. Int J Immunopathol Pharmacol 2012;25(3):607-615.
[CrossRef] [PubMed]
19 Shayegan MR, Khakzad MR, Gharaee H, Varasteh AR, Sankian M.
Evaluation of transforming growth factor-beta1 gene expression in pterygium
tissue of atopic patients. J Chin Medical
Assoc 2016; 79(10):565-569. [CrossRef] [PubMed]
21 Lee K, Young Lee S, Park SY, Yang H. Antifibrotic effect of
pirfenidone on human pterygium fibroblasts. Curr
Eye Res 2014;39(7):680-685. [CrossRef] [PubMed]
22 Almeida Junior GC, Arakawa L, Santi Neto DD, Cury PM, Lima
Filho AA, Sousa SJ, Alves MR, Azoubel R. Preoperative tranilast as adjunctive
therapy to primary pterygium surgery with a 1-year follow-up. Arq Bras Oftalmol 2015;78(1):1-5. [CrossRef] [PubMed]
23 Noureddin GS, Yeung SN. The use of dry amniotic membrane in
pterygium surgery. Clin Ophthalmol 2016;10:705-712.
[CrossRef] [PMC free article] [PubMed]
25 Powers MR, Qu Z, O'Brien B, Wilson DJ, Thompson JE, Rosenbaum
JT. Immunolocalization of bFGF in pterygia: association with mast cells. Cornea 1997;16(5):545-549. [CrossRef]
26 Detorakis ET, Zaravinos A, Spandidos DA. Growth factor
expression in ophthalmic pterygia and normal conjunctiva. Int J Mol Med 2010; 25(4):513-516. [CrossRef]
29 Amer R, Rabinowich L, Maftsir G, Puxeddu I, Levi-Schaffer F,
Solomon A. Mycophenolic acid suppresses human pterygium and normal tenon
fibroblast proliferation in vitro. Br J
Ophthalmol 2010;94(10): 1373-1377. [CrossRef] [PubMed]
31 Solomon A, Grueterich M, Li DQ, Meller D, Lee SB, Tseng SC.
Overexpression of insulin-like growth factor-binding protein-2 in pterygium
body fibroblasts. Invest Ophthalmol Vis
Sci 2003;44(2): 573-580.
[CrossRef]
32 Wong YW, Chew J, Yang H, Tan DT, Beuerman R. Expression of
insulin-like growth factor binding protein-3 in pterygium tissue. Br J Ophthalmol 2006;90(6):769-772. [CrossRef] [PMC free article] [PubMed]
33 Yu H, Rohan T. Role of the insulin-like growth factor family in
cancer development and progression. J
Natl Cancer Inst 2000;92(18):1472-1489. [CrossRef]
35 Ribatti D, Nico B, Perra MT, Maxia C, Piras F, Murtas D,
Crivellato E, Sirigu P. Correlation between NGF/TrkA and microvascular density
in human pterygium. Int J Exp Pathol 2009;90(6):615-620.
[CrossRef] [PMC free article] [PubMed]
36 Holbourn KP, Acharya KR, Perbal B. The CCN family of proteins:
structure-function relationships. Trends
Biochem Sci 2008;33(10):461-473. [CrossRef] [PMC free article] [PubMed]
38 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate
cell behavior. Annual Review Cell Dev
Biol 2001;17:463-516. [CrossRef] [PMC free article] [PubMed]
39 Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix
metalloproteinases and diseases of the CNS. Trends
Neurosci 1998; 21(2):75-80. [CrossRef]
42 Siak JJ, Ng SL, Seet LF, Beuerman RW, Tong L. The
nuclear-factor kappaB pathway is activated in pterygium. Invest Ophthalmol Vis Sci 2011;52(1):230-236. [CrossRef] [PubMed]
43 Di Girolamo N, Coroneo MT, Wakefield D. UVB-elicited induction
of MMP-1 expression in human ocular surface epithelial cells is mediated
through the ERK1/2 MAPK-dependent pathway. Invest
Ophthalmol Vis Sci 2003;44(11):4705-4714. [CrossRef] [PubMed]
44 Park YM, Kim CD, Lee JS. Effect of bevacizumab on human tenon's
fibroblasts cultured from primary and recurrent pterygium. Korean J Physiol Pharmacol 2015;19(4):357-363. [CrossRef] [PMC free article] [PubMed]
46 Seet LF, Tong L, Su R, Wong TT. Involvement of SPARC and MMP-3
in the pathogenesis of human pterygium. Invest
Ophthalmol Vis Sci 2012; 53(2):587-595. [CrossRef] [PubMed]
47 Kim YH, Jung JC, Jung SY, Kim YI, Lee KW, Park YJ. Cyclosporine
a downregulates MMP-3 and MMP-13 expression in cultured pterygium fibroblasts. Cornea 2015;34(9):1137-1143. [CrossRef] [PubMed]
49 Schellini SA, Hoyama E, Oliveira DE, Bacchi CE, Padovani CR.
Matrix metalloproteinase-9 expression in pterygium. Arq Bras Oftalmol 2006;69(2):161-164. [CrossRef]
50 Yang SF, Lin CY, Yang PY, Chao SC, Ye YZ, Hu DN. Increased
expression of gelatinase (MMP-2 and MMP-9) in pterygia and pterygium
fibroblasts with disease progression and activation of protein kinase C. Invest Ophthalmol Vis Sci 2009;50(10):4588-4596.
[CrossRef] [PubMed]
51 Reid TW, Dushku N. What a study of pterygia teaches us about
the cornea? Molecular mechanisms of formation. Eye Contact Lens 2010; 36(5):290-295. [CrossRef] [PubMed]
52 Sun YC, Hsiao CH, Chen WL, Hu FR. Overexpression of matrix
metalloproteinase-1 (MMP-1) and MMP-3 in superior limbic keratoconjunctivitis. Invest Ophthalmol Vis Sci 2011;52(6):3701-3705.
[CrossRef] [PubMed]
53 Brocker C, Thompson D, Matsumoto A, Nebert DW, Vasiliou V.
Evolutionary divergence and functions of the human interleukin (IL) gene
family. Hum Genomics 2010;5(1):30-55.
[CrossRef]
56 Kuo CH, Miyazaki D, Yakura K, Araki-Sasaki K, Inoue Y. Role of
Periostin and interleukin-4 in recurrence of pterygia. Invest Ophthalmol Vis Sci 2010;51(1):139-143. [CrossRef] [PubMed]
58 Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner
VM, Elner SG, Strieter RM. Interleukin-8 as a macrophage-derived mediator of
angiogenesis. Science 1992;258(5089):1798-1801.
[CrossRef]
59 Ho WT, Chen TC, Chou SF, Chang SW. Dexamethasone modifies
mitomycin C-triggered interleukin-8 secretion in isolated human Tenon's capsule
fibroblasts. Exp Eye Res 2014;124:86-92.
[CrossRef] [PubMed]
<no>60 Liu YB, Sun X. The expression and
function of Foxp3 and IL-10 in pterygium. <ii>Chinese Journal of Practical
Ophthalmology</ii> 2014;32(8):977-979.</no>
61 Huang Y, He H, Sheha H, Tseng SC. Ocular
demodicosis as a risk factor of pterygium recurrence. <ii>Ophthalmology
</ii>2013;120(7):1341-1347. [CrossRef] [PubMed]
62 Jabarin B, Solomon A, Amer R. Interleukin-17 and
its correlation with vascular endothelial growth factor expression in ocular
surface pathologies: a histologic study. <ii>Eur J Ophthalmol
</ii>2016:26(4):283-286. [CrossRef] [PubMed]
63 Subbarayal B, Chauhan SK, Di Zazzo A, Dana R. IL-17
augments B cell activation in ocular surface autoimmunity. <ii>J Immunol
</ii>2016;197(9): 3464-3470. [CrossRef] [PubMed]
64 Ueda Y, Kanazawa S, Kitaoka T, Dake Y, Ohira A,
Ouertani AM, Amemiya T. Immunohistochemical study of p53, p21 and PCNA in
pterygium. <ii>Acta Histochemica </ii>2001;103(2):159-165. [CrossRef]
65 Tsai YY, Chang KC, Lin CL, Lee H, Tsai FJ, Cheng
YW, Tseng SH. p53 Expression in pterygium by immunohistochemical analysis: a
series report of 127 cases and review of the literature. <ii>Cornea
</ii>2005;24(5): 583-586. [CrossRef]
66 Weinstein O, Rosenthal G, Zirkin H, Monos T,
Lifshitz T, Argov S. Overexpression of p53 tumor suppressor gene in pterygia.
<ii>Eye(Lond) </ii>2002;16(5):619-621. [CrossRef]
<no>67 Zhang LW, Chen BH, Xi XH, Han QQ, Tang
LS. Survivin and p53 expression in primary and recurrent pterygium in Chinese
patients. <ii>Int J Ophthalmol </ii>2011;4(4):388-392.</no>
68 Pelit A, Bal N, Akova YA, Demirhan B. p53
expression in pterygium in two climatic regions in Turkey. <ii>Indian J
Ophthalmol </ii>2009;57(3):
203-206. [CrossRef] [PMC free article] [PubMed]
69 Ljubojevic V, Gajanin R, Amidzic L, Vujkovic Z. The
expression and significance of p53 protein and Ki-67 protein in pterygium.
<ii>Vojnosanit Pregl </ii>2016;73(1):16-20. [CrossRef]
70 Schneider BG, John-Aryankalayil M, Rowsey JJ,
Dushku N, Reid TW. Accumulation of p53 protein in pterygia is not accompanied
by TP53 gene mutation. <ii>Exp Eye Res </ii>2006;82(1):91-98. [CrossRef] [PubMed]
71 Rodrigues FW, Arruda JT, Silva RE, Moura KK. TP53
gene expression, codon 72 polymorphism and human papillomavirus DNA associated
with pterygium. <ii>Genet Mol Res </ii>2008;7(4):1251-1258. [CrossRef]
<no>72 Tsai YY, Chang CC, Chiang CC, Yeh KT,
Chen PL, Chang CH, Chou CH, Lee H, Cheng YW. HPV infection and p53 inactivation
in pterygium. <ii>Mol Vis </ii>2009;15:1092-1097.</no>
73 Ramalho FS, Maestri C, Ramalho LN, Ribeiro-Silva A,
Romao E. Expression of p63 and p16 in primary and recurrent pterygia.
<ii>Graefes Arch Clin Exp Ophthalmol </ii>2006;244(10):1310-1314. [CrossRef] [PubMed]
74 Atkinson SD, Moore JE, Shah S, Sharma A, Best RM,
Leccisotti A, Alarbi M, Rimmer D, Gardiner T, Moore TC. P63 expression in
conjunctival proliferative diseases: pterygium and laryngo-onycho-cutaneous
(LOC) syndrome. <ii>Curr Eye Res </ii>2008;33(7):551-558. [CrossRef] [PubMed]
<no>75 Chen PL, Cheng YW, Chiang CC, Tseng SH,
Chau PS, Tsai YY. Hypermethylation of the p16 gene promoter in pterygia and its
association with the expression of DNA methyltransferase 3b. <ii>Mol
Vis</ii> 2006;12:1411-1416.</no>
76 Tong L. Expression of p27 (KIP1) and cyclin D1, and
cell proliferation in human pterygium. <ii>Br J Ophthalmol
</ii>2008;92(1):157. [CrossRef] [PubMed]
77 Scholzen T, Gerdes J. The Ki-67 protein: from the
known and the unknown. <ii>J Cell Physiol</ii> 2000;182(3):311-322.
[CrossRef]
78 Konuk O, Aktas Z, Erdem O, Konuk EBY, Unal M.
Expression of cyclooxygenase-2 and Ki-67 in primary and recurrent pterygias.
<ii>Turkiye Klinikleri Journal of Medical Sciences
</ii>2011;31(1):115-121. [CrossRef]
79 Ohara M, Sotozono C, Tsuchihashi Y, Kinoshita S.
Ki-67 labeling index as a marker of malignancy in ocular surface neoplasms.
<ii>Jpn J Ophthalmol </ii>2004;48(6):524-529. [CrossRef] [PubMed]
80 Moldovan GL, Pfander B, Jentsch S. PCNA, the
maestro of the replication fork. <ii>Cell </ii>2007;129(4):665-679.
[CrossRef] [PubMed]
<no>81 Liang K, Jiang ZX, Ding BQ, Cheng P,
Huang DK, Tao LM. Expression of cell proliferation and apoptosis biomarkers in
pterygia and normal conjunctiva. <ii>Mol Vis</ii> 2011;17(186-87):1687-1693.</no>
82 Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G.
Cyclin D1 is a nuclear protein required for cell cycle progression in G1.
<ii>Genes Dev </ii>1993;7(5):812-821. [CrossRef]
83 Das P, Gokani A, Bagchi K, Bhaduri G, Chaudhuri S,
Law S. Limbal epithelial stem-microenvironmental alteration leads to pterygium
development. <ii>Mol Cell Biochem </ii>2015;402(1-2):123-139. [CrossRef] [PubMed]
<no>84 Tung JN, Chiang CC, Tsai YY, Chou YY, Yeh
KT, Lee H, Cheng YW. CyclinD1 protein expressed in pterygia is associated with
β-catenin protein localization. <ii>Mol Vis
</ii>2010;16:2733-2738.</no>
<no>85 Mo B, Wang Y, Huang Y. Expression of PCNA
and bcl-2 on cultured human pterygium fibroblasts and the effects of
Ahylysantinfarctase. <ii>Chinese Ophthalmic Research
</ii>2005;23(4):369-372.</no>
86 Zou Y, Zhang M. Inhibitory effect of PPARγ agonist
on the proliferation of human pterygium fibroblasts. <ii>J Huazhong Univ
Sci Technolog Med Sci </ii>2010;30(6):809-814. [CrossRef] [PubMed]
87 Xu YX, Zhang LY, Zou DL, Liu ZS, Shang XM, Wu HP,
Zhou Y, He H, Liu ZG. Differential expression and function of survivin during
the progress of pterygium. <ii>Invest Ophthalmol Vis Sci
</ii>2014;55(12):8480-8487. [CrossRef] [PubMed]
88 Maxia C, Perra MT, Demurtas P, Minerba L, Murtas D,
Piras F, Corbu A, Gotuzzo DC, Cabrera RG, Ribatti D, Sirigu P. Expression of
survivin protein in pterygium and relationship with oxidative DNA damage.
<ii>J Cell Mol Med </ii>2008;12(6A):2372-2380. [CrossRef] [PMC free article] [PubMed]
<no>89 Maxia C, Perra MT, Demurtas P, Minerba L,
Murtas D, Piras F, Cabrera R, Ribatti D, Sirigu P. Relationship between the
expression of cyclooxygenase-2 and survivin in primary pterygium. <ii>Mol
Vis </ii>2009;15:458-463.</no>
90 Cleary ML, Smith SD, Sklar J. Cloning and
structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript
resulting from the t(14;18) translocation. <ii>Cell
</ii>1986;47(1):19-28. [CrossRef]
91 Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce
CM. Cloning of the chromosome breakpoint of neoplastic B cells with the
t(14;18) chromosome translocation. <ii>Science
</ii>1984;226(4678):1097-1099. [CrossRef]
92 Tan DT, Tang WY, Liu YP, Goh HS, Smith DR.
Apoptosis and apoptosis related gene expression in normal conjunctiva and
pterygium. <ii>Br J Ophthalmol </ii>2000;84(2):212-216. [CrossRef]
<no>93 Zheng W, Xu GX, Hu JZ, Lin W, Wang T.
Expression and significance of cell proliferation and apoptosis gene associated
protein in pterygium. <ii>Chinese Journal of Practical Ophthalmology
</ii>2003;21(9):649-651.</no>
94 O'Connor L, Strasser A, O'Reilly LA, Hausmann G,
Adams JM, Cory S, Huang DC. Bim: a novel member of the Bcl-2 family that
promotes apoptosis. <ii>EMBO J </ii>1998;17(2):384-395. [CrossRef] [PMC free article] [PubMed]
95 Cui YH, Li HY, Gao ZX, Liang N, Ma SS, Meng FJ, Li
ZJ, Pan HW. Regulation of apoptosis by miR-122 in pterygium via targeting
Bcl-w. <ii>Invest Ophthalmol Vis Sci </ii>2016;57(8):3723-3730. [CrossRef] [PubMed]
96 Gumbiner BM. Cell adhesion: the molecular basis of
tissue architecture and morphogenesis. <ii>Cell
</ii>1996;84(3):345-357. [CrossRef]
97 Beden U, Irkec M, Orhan D, Orhan M. The roles of
T-lymphocyte subpopulations (CD4 and CD8), intercellular adhesion molecule-1
(ICAM-1), HLA-DR receptor, and mast cells in etiopathogenesis of pterygium.
<ii>Ocul Immunol Inflamm </ii>2003;11(2):115-122. [CrossRef]
98 van de Stolpe A, van der Saag PT. Intercellular
adhesion molecule-1. <ii>J Mol Med (Berl)</ii> 1996;74(1):13-33. [CrossRef]
99 Tekelioglu Y, Turk A, Avunduk AM, Yulug E. Flow
cytometrical analysis of adhesion molecules, T-lymphocyte subpopulations and
inflammatory markers in pterygium. <ii>Ophthalmologica
</ii>2006;220(6):372-378. [CrossRef] [PubMed]
100 Kase S, Osaki M, Sato I, Takahashi S, Nakanishi K,
Yoshida K, Ito H, Ohno S. Immunolocalisation of E-cadherin and beta-catenin in
human pterygium. <ii>Br J Ophthalmol </ii>2007;91(9):1209-1212. [CrossRef] [PMC free article] [PubMed]
<no>101 Takeichi M. The cadherins: cell-cell
adhesion molecules controlling animal morphogenesis. <ii>Development
</ii>1988;102(4):639-655.</no>
102 Boudreau NJ, Jones PL. Extracellular matrix and
integrin signalling: the shape of things to come. <ii>Biochem J
</ii>1999;339 ( Pt 3):481-488. [CrossRef] [PMC free article] [PubMed]
103 Larrayoz IM, de Luis A, Rua O, Velilla S, Cabello
J, Martinez A. Molecular effects of doxycycline treatment on pterygium as
revealed by massive transcriptome sequencing. <ii>PLoS One
</ii>2012;7(6):e39359. [CrossRef] [PMC free article] [PubMed]
<no>104 Zhang M, Liu Z, Xie Y. The study on the
expression of keratin proteins in pterygial epithelium. <ii>Yan Ke Xue
Bao </ii>2000;16(1):48-52.</no>
105 Perez-Rico C, Pascual G, Sotomayor S,
Montes-Mollon MA, Trejo C, Sasaki T, Mecham R, Bellon JM, Bujan J. Tropoelastin
and fibulin overexpression in the subepithelial connective tissue of human
pterygium. <ii>Am J Ophthalmol </ii>2011;151(1):44-52. [CrossRef] [PubMed]
106 Wang IJ, Hu FR, Chen PJ, Lin CT. Mechanism of
abnormal elastin gene expression in the pinguecular part of pterygia.
<ii>Am J Pathol </ii>2000;157(4):1269-1276. [CrossRef]
107 Perez-Rico C, Pascual G, Sotomayor S, Asunsolo A,
Cifuentes A, Garcia-Honduvilla N, Bujan J. Elastin development-associated
extracellular matrix constituents of subepithelial connective tissue in human
pterygium. <ii>Invest Ophthalmol Vis Sci
</ii>2014;55(10):6309-6318. [CrossRef] [PubMed]
108 Dake Y, Mukae R, Soda Y, Kaneko M, Amemiya T.
Immunohistochemical localization of collagen types I, II, III, and IV in
pterygium tissues. <ii>Acta Histochem </ii>1989;87(1):71-74. [CrossRef]
<no>109 Arish M, Nadjafi AN, Jahangard M.
Collagen matrix implantation following pterygium excision: outcomes of a
preliminary tested hypothesis. <ii>Med Hypothesis, Discov Innov Ophthalmol
</ii>2013;2(4):
102-104.</no>
110 Pharmakakis N, Assimakopoulou M.
Immunohistochemical detection of heat shock protein 27 and Ki-67 in human
pterygium. <ii>Br J Ophthalmol </ii>2001;85(11):1392-1393. [CrossRef] [PMC free article] [PubMed]
111 Sebastia R, Ventura MP, Solari HP, Antecka E,
Orellana ME, Burnier MN Jr. Immunohistochemical detection of Hsp90 and Ki-67 in
pterygium. <ii>Diagn Pathol </ii>2013;8:32. [CrossRef] [PMC free article] [PubMed]
<no>112 Pagoulatos D, Pharmakakis N, Lakoumentas
J, Assimakopoulou M. Hypoxia-inducible factor-1α, von Hippel-Lindau protein,
and heat shock protein expression in ophthalmic pterygium and normal
conjunctiva. <ii>Mol Vis </ii>2014;20:441-457.</no>
113 Semenza GL. Regulation of oxygen homeostasis by
hypoxia-inducible factor 1. <ii>Physiology (Bethesda)
</ii>2009;24:97-106. [CrossRef] [PubMed]
114 Leonardi A, Tarrihucone E, Corrao S, Alaibac M,
Corso AJ, Zavan B, Venier P, Conway de Macario E, Macario AJ, Di Stefano A,
Cappello F, Brun P. Chaperone patterns in vernal keratoconjunctivitis are
distinctive of cell and Hsp type and are modified by inflammatory stimuli. <ii>Allergy
</ii>2016;71(3):403-411. [CrossRef] [PubMed]
115 Dogan AS, Onder E, Arikok AT, Bicer T, Gurdal C.
Claudin-1 expressions decrease in pterygium with respect to normal conjunctiva.
<ii>Cutan Ocul Toxicol </ii>2016;35(4):315-318. [CrossRef] [PubMed]
116 Barba-Gallardo LF, Ventura-Juarez J, Kershenobith
Stalnikowitz D, Gutierez-Campos R, Torres-Bernal E, Torres-Bernal LF.
Over-expression of human cystatin C in pterygium versus healthy conjunctiva.
<ii>BMC Ophthalmol </ii>2013;13:6. [CrossRef] [PMC free article] [PubMed]
<no>117 Adiguzel U, Karabacak T, Sari A, Oz O,
Cinel L. Cyclooxygenase-2 expression in primary and recurrent pterygium.
<ii>Eur J Ophthalmol </ii>2007;17(6):879-884.</no>