Download Relation of the Wnt/β-catenin signaling pathway

Turk J Biol
34 (2010) 227-234
© TÜBİTAK
doi:10.3906/biy-0904-24
Relation of the Wnt/β-catenin signaling pathway
with gynecological cancers
Hanife Güler TANIR1, Şayeste DEMİREZEN1, Mehmet Sinan BEKSAÇ2
1
Department of Biology, Faculty of Science, Hacettepe University, Ankara - TURKEY
2Department of Gynecology and Obstetrics, Faculty of Medicine, Hacettepe University, Ankara - TURKEY
Received: 30.04.2009
Abstract: The Wnt signaling pathway is evolutionary conserved and controls many biological processes like cell
proliferation and differentiation. It also provides planar polarity, regulation of the cell cycle, and cell adhesion during both
the embryonic and adult period. However, it has been widely considered in the literature that some pathological
alterations in various biomolecules involved in this pathway, and aberrant activation of signaling have important roles
primarily in the genesis of colorectal and cervical cancer and several other serious diseases. The Wnt signaling pathway
diversifies into 3 types: Wnt/β-catenin signaling pathway, planar cell polarity pathway, and Wnt/calcium (Ca+2) pathway.
Only the Wnt/β-catenin signaling pathway is dealt with in our review, because of its close relation with diseases. In recent
years, numerous studies about the Wnt/β-catenin signaling pathway have led to an explanation of the signal mechanism
and the identification of all components and the relation with the other signaling pathways. All of these studies have
provided crucial contributions to novel diagnostic and therapeutic methods. Gynecological cancers originate in the
female reproductive organs and include cervical, endometrium, ovarian, vulvar, and fallopian cancers. These cancers are
very significant because they are seen in about 45% of women. The most common type of gynecological malignancies
are cervical and ovarian cancers, and their progression may result in death, and so clarifying the mechanisms of
carcinogenesis is very important for producing new targets for therapy methods. Thus, in our review, it is planned to
explain the relation of gynecological cancers, whose mortality is the highest after breast cancer in Turkey and worldwide,
with the Wnt/β-catenin signaling pathway and its biomolecules in the light of the literature.
Key words: Wnt/β-catenin signaling pathway, cancer, β-catenin, adhesion, cell proliferation
Wnt/β-katenin sinyal yolunun jinekolojik kanserlerle olan ilişkisi
Özet: Wnt/β-katenin sinyal yolu hücre bölünmesi, farklılaşması gibi önemli biyolojik süreçleri kontrol eden ve evrimsel
açıdan oldukça korunmuş bir sinyal yoludur. Ayrıca hem embriyonik hem erişkin dönemde hücre polaritesinin
sağlanması, hücre siklusunun düzenlenmesi ve hücre adezyonu gibi süreçlerde de rol oynar. Ancak bu sinyal yolunda
görev alan çeşitli biyomoleküllerde meydana gelen bazı patolojik değişikliklerin başta kolorektal ve servikal kanserler
olmak üzere çeşitli ciddi hastalıkların oluşumunda rol oynadığı literatürde geniş yer bulmaktadır. Wnt sinyal yolunun üç
+2
tipi vardır: Wnt/β-katenin sinyal yolu, hücre polaritesinin sağlanmasında rol oynayan sinyal yolu ve Wnt/Kalsiyum (Ca )
sinyal yolu. Hastalıklarla olan ilişkisi nedeniyle derlememizde sadece Wnt/β-katenin sinyal yolu üzerinde durulacaktır.
Son yıllarda yapılan çalışmalar Wnt/β-katenin sinyal yolunun mekanizması, bu yolda rol oynayan biyomoleküller ve bu
sinyal yolunun diğer sinyal yolları ile olan ilişkilerinin açıklıkla ortaya konulmasına yöneliktir. Bütün bu çalışmalar yeni
teşhis ve tedavi yöntemlerinin oluşturulmasına çok önemli katkılar sağlamaktadır. Jinekolojik kanserler dişi üreme
sisteminden köken alır ve sevikal, endometrium, over, vulvar ve fallopian kanserlerini içerir. Bu kanserler kadınların
227
Relation of the Wnt/β-catenin signaling pathway with gynecological cancers
yaklaşık % 45’ini etkilediği için oldukça önemlidir. Jinekolojik malignansilerin en yaygın iki tipi servikal ve over
kanserleridir ve ilerleyişleri ölümle sonuçlanabilir dolayısıyla bu kanserlerin oluşum mekanizmalarının aydınlatılması
hedefe yönelik yeni tedavi yöntemlerinin geliştirilebilmesi için çok önemlidir. Bu nedenle, derlememizde, Türkiye’de ve
dünyada mortalitesi meme kanserlerinden sonra en yüksek olan jinekolojik kanserlerin oluşumu ile Wnt/β-katenin sinyal
yolu ve bu yolda rol oynayan biyomoleküller arasındaki ilişkisinin literatür bilgileri ışığında ortaya konulması
hedeflenmiştir.
Anahtar sözcükler: Wnt/β-katenin sinyal yolu, kanser, β-katenin, adezyon, hücre proliferasyonu
Introduction
The Wnt genes and also the Wnt/β-catenin
signaling pathway are evolutionarily conserved and
play a crucial role in numerous biological processes. It
takes part in cell proliferation, differentiation,
regulation of several target genes’ transcription, and
cell adhesion both in the embryonic and adult periods
(1,2). The Wnt genes give the name of the signaling
pathway and were found approximately 25 years ago.
The name “Wnt” is generated by a fusion of the name
of the Drosophila segment polarity gene “wingless”
and the name of the mouse “integrated-1” (int-1)
proto-oncogene.
The Wnt signaling pathway diversifies into 3
branches: the Wnt/β-catenin signal pathway
(canonical pathway), the planar cell polarity pathway
+2
(non-canonical pathway), and the Wnt/Ca pathway.
Inappropriate signaling activity of these pathways
causes several serious diseases, including cancers.
Because the Wnt/β-catenin signaling pathway has a
close relationship with several cancers, it is planned
to focus on the role of the Wnt pathway in the
formation of cancer.
Mechanism of the Wnt/β-catenin signaling
pathway
The Wnt/β-catenin signaling pathway starts on the
cell membrane. When a signal comes to the cell to
generate any of these events, the Wnt/β-catenin
signaling mechanism activates. Wnt proteins, which
have crucial roles in the signaling pathway, are
synthesized by adult stem cells and secreted in the
intercellular spaces by exocytosis. When a signal
comes to the cell to start the signal mechanism, these
Wnt proteins, which are in intercellular spaces, bind to
their receptors on the target cell membrane. One of
these receptors is known as Frizzled (Fz), while the
other one is LRP5/6 (low-density lipoprotein
receptor-related protein). These receptors are integral
228
transmembrane proteins on the membrane. Wnt
proteins bind directly to both of them and Wnt-FzLRP5/6 to form a ternary complex together. This
ternary complex is necessary for starting the Wnt/βcatenin signaling pathway (Figure) (3-5).
Binding of Wnt proteins to their receptors
stimulates 2 significant phosphorylations in the
cytosol. Firstly, the cytosolic part of the LRP5/6
transmembrane protein is phosphorylated by various
kinases and then the cytosolic protein disheveled is
phosphorylated (6). These phosphorylations cause the
disruption of the “cytoplasmic degradation complex”,
which is composed of GSK3β-Axin and APC. βcatenin, which is a key mediator of the Wnt/β-catenin
signaling pathway, is tightly regulated by this large
multi-protein complex. It promotes degradation of βcatenin by phosphorylation (2,5,7). When this ternary
complex detaches, β-catenin does not phosphorylate
and an increasing amount of it accumulates in the
cytosol. Accumulative non-phosphorylated β-catenin
enters the nucleus and activates the transcription
factors (co-activator) for expressing several target
genes, like c-myc, cyclin D1, VEGF, c-jun, and
follistatin (7-9). If the Wnt/β-catenin signaling
pathway continues under control, biologic processes
like proliferation, differentiation, and regulation of
target genes’ transcription occur normally, but these
target genes’ aberrant activation causes cancer and
other serious diseases. In addition, by the activation of
transcription of genes that express the biomolecules
like Fz, LRP and Axin are synthesized for the signaling
pathway (9,10).
The activation of this signaling pathway is
controlled by the inhibitor proteins, like WIF, Dkk1,
sFRP, and cerbeus-1, in the extracellular matrix (11).
These proteins either bind directly to the Wnt and
block binding to its receptors, or bind to Wnt’s
receptors and block its relation with them. In this way,
the activation of the signaling pathway is blocked
H. G. TANIR, Ş. DEMİREZEN, M. S. BEKSAÇ
Figure. The Wnt/β-catenin signaling pathway. Wnt signaling controlled and inactivated by Dkk1, sFRP, and WIF (left). β-catenin is
degraded in proteasomes through interactions of degradation complex members. Wnt protein binds (right) its receptors and
degradation complex is disrupted. Consequently, β-catenin accumulates in the cytosol and enters the nucleus. β-catenin then
interacts with transcription factors (TCF) and activates target genes’ transcription. (This figure is changed from Cong F,
Schweizer L, Varmus H. Development 131: 5103-5115, 2004 and drawn again).
controllably but when it is unchecked it causes cancer
and other serious diseases (10,11).
When Wnt signaling protein does not bind to its
receptor, critical phosphorylations do not occur in the
cytosol, and so the degradation complex remains
active. β-catenin is phosphorylated by this active
complex containing GSK3β. This phosphorylation is
key for degradation of β-catenin by means of the
proteasome pathway. Phosphorylated β-catenin is
recognized by βTrCP enzyme, which carries β-catenin
to the proteasomes and β-catenin is degraded there.
Thereby, because there is not any β-catenin in the
cytosol to enter the nucleus, transcription factors
remain inactive and target genes’ transcription is
repressed. These events show that the Wnt/β-catenin
signaling pathway is inhibited (7,8,12).
Relation of the Wnt/β-catenin signaling pathway
with cancers
A relation of the Wnt/β-catenin signaling pathway
with cancers was found when the proto-oncogenic
properties of Wnts were discovered in the studies of
mouse mammary tumor viruses in 1982 (1,13). After
this finding, the number of studies about the Wnt/βcatenin signaling pathway and the related
biomolecules increased. Crucial roles of the signaling
pathway in cell proliferation, differentiation, cell
migration, planar polarity of cell, and cell adhesion
were shown in various studies (1,14). Besides this
normal events in the cell, it was reported that defects
in the Wnt/β-catenin signaling pathway cause mainly
colorectal cancer, cervical cancer, leukemia, gastric
cancers,
melanoma,
Alzheimer’s
disease,
schizophrenia, retinal angiogenesis defect, tetraamelia, polycystic renal diseases, and osteoporosis
(1,7,10,13,15,16). In addition to all of these diseases, it
was thought that Wnt signaling is important for breast
cancer etiology as well as estrogen, glutathione-Stransferase enzyme, which has crucial roles in the
mutagenic effects of carcinogens, and mammary
tumor viruses (1,2,17). Wnt signaling not only affects
tumorigenesis, but also has roles in infections
diseases. In the literature, the relation of Wnt signaling
with infections can be mentioned via cytokines.
Cytokines are important biomolecules synthesized
from defending cells during the inflammatory process
229
Relation of the Wnt/β-catenin signaling pathway with gynecological cancers
(18). They also studied in terms of diagnostic and
therapeutic aspects. Thus, effects of cytokines on the
activity of Wnt signaling should be examined because
of their importance in inflammation (4,10). In recent
years, related studies about the Wnt signaling and
components have increased. In particular, mutations
of β-catenin, APC, Axin, and negative regulators, like
Dkk, WIF and sFRP have been shown to have a
crucial role in the formation of several cancers
including colon, cervical, lung, liver, ovarian, brain,
skin and prostate cancers (7,19-22). For instance, the
relation of the Wnt/β-catenin signaling pathway with
prostate cancer, which is the most common type seen
in males, has appeared frequently in the literature in
recent years. The prostate gland is affected by
androgen. Androgen enters the prostate cell by
passing through the membrane and binds its receptor,
called androgen receptor (AR), in the cytosol. After
binding, androgen-AR complex is formed and it is
transferred to the nucleus. This complex enters the
nucleus by passing through the nucleolus membrane
and binds DNA to activate the specific genes. If these
events occur abnormally, carcinogenic transformation
can be seen. One of the events that has a critical role
in this carcinogenic transformation is aberrant
activation of the Wnt/β-catenin signaling pathway. It
has been shown that mutations of β-catenin and APC,
which is a member of a degradation complex, have
important roles in prostate cancer. These mutations
cause the accumulation of β-catenin in the cytosol.
Accumulative β-catenin binds AR receptor in the
cytosol, and AR-β-catenin complex is formed. This
complex enters the nucleus and activates target
specific genes that are normally not activated without
androgen. This uncontrolled event has a significant
role in prostate carcinogenesis (7,23,24).
The Wnt/β-catenin signaling pathway also has a
close relationship with colorectal cancer. This
relationship arises from APC protein, which is a
product of “APC tumor suppressor genes”. In
physiologic conditions, degradation complex
containing APC phosphorylates β-catenin and then
β-catenin is degraded. APC mutations result in the
disruption of the degradation complex. Consequently,
β-catenin does not degrade and accumulates in the
cytosol. This accumulative β-catenin enters the
nucleus and drags the cell to the neoplasia by causing
several target genes’ expression (4,19,25,26).
230
In both of these examples, β-catenin accumulates
in the cytosol and causes aberrant activation of target
genes. This uncontrolled activation results in the
formation of cancers. The localization of β-catenin in
various parts of the cell (membrane, cytosol, and
nucleus) is used to show the relationship between the
Wnt/β-catenin signaling pathway and cancers. When
Wnt signaling is inactive, β-catenin localizes only in
the cell membrane for regulating cell adhesion.
However, when the signaling pathway is active, βcatenin accumulates in the cytosol and/or nucleus.
This feature has been used to determine the relation of
the Wnt/β-catenin signaling pathway with cancer,
especially in immunohistochemical studies. After
molecular biological techniques became more
widespread, various biomolecules involved in this
pathway and mutations of these biomolecules have
been found.
Relation of the Wnt/β-catenin signaling pathway
with gynecologic cancers
Cancer is still one of the most important diseases
that result in death. There is unfortunately an increase
in the rate of gynecologic cancers among which
cervical, endometrial, ovarian, vaginal, and tubal
(fallopian) cancers are widely known (27). It is well
known that aberrant Wnt/β-catenin signaling causes
neoplasia. Thus, it is necessary to explain the
relationship between the Wnt/β-catenin signaling
pathway and gynecologic cancers. Recent related
studies focus mainly on cervical and ovarian cancers.
Relation of the Wnt/β-catenin signaling pathway
with cervical cancer
The relation of the human papilloma virus (HPV)
with cervical cancer was first reported by Hausen in
1977 (28). Subsequent research has shown that the
most important risk factor for cervical cancer is HPV.
In recent years, only a few studies have aimed to
understand the role of the aberrant activation of the
Wnt/β-catenin signaling pathway in cervical cancer
formation (13,29-31).
For instance, Shiohara et al. (32) and Uren et al.
(33) showed that Wnt/β-catenin signaling was also
activated in “HPV-effected keratinocyte” by using βcatenin localization in the cell. During the
examination of the localization of β-catenin in the cell,
it was found that β-catenin accumulated in the cytosol
H. G. TANIR, Ş. DEMİREZEN, M. S. BEKSAÇ
and/or nucleus by using immunohistochemical and
molecular biological methods. It has been also
revealed that this is the result of abnormal Wnt/βcatenin signaling because when the signal pathway is
inactive some of β-catenin is degraded, and the
remaining amount localizes only in the cell
membrane to affect the cell-cell adhesion, and so it is
not seen in the cytosol and/or nucleus. However,
when the signaling pathway becomes active or there
are any mutations in the member of the degradation
complex, like APC and Axin, this complex detaches.
Thus, β-catenin is degraded and it accumulates in the
cytosol and/or in the nucleus. In conclusion, it is
reported that the Wnt/β-catenin signaling pathway
has a crucial role in HPV-infected cells’ carcinogenic
transformation (13,32,33).
Wnt signaling pathway is not clear, it was reported
that the level of Dkk3 was decreased in the cervical
cancer cells. This caused the activation of the
important target genes in carcinogenesis like VEGF
and cyclin D1 was increased. It was thought that this
aberrant activation of Wnt/β-catenin signaling has a
critical role in the formation of cervical tumors and
cancer. It was indicated in these studies that mutations
of biomolecules that are negative regulators of Wnt
signaling like sFRP and Dkk3 have a significant role in
the induction of cervical cancer (37). However, the
other studies of Wnt signaling did not only
demonstrate negative regulators’ effect on cancer but
also explored the up-regulation of the positive
regulators, like Wnt, Fz, and Dvl, which have roles in
aberrant activation of signaling (38-40).
In addition to the studies about the relationship
between the Wnt/β-catenin signaling pathway and
cervical cancer, there are increasing studies in which
biomolecules that take part in this way and alterations
that occur are investigated. The relation of sFRP
proteins with cervical cancer has been researched.
Additionally, it has been shown that cervical
cancer is associated with mutational activation of
Wnt/β-catenin signaling in tumorogenesis, based on
studies of the DVL-1 gene and its product Dvl protein,
which is a positive regulator of the Wnt/β-catenin
signaling pathway. When Wnt protein binds its
receptor on the membrane, Dvl protein is
phosphorylated in the cytosol. Phosphorylated Dvl
inhibits GSK3β, which is a member of the degradation
complex. When GSK3β is active, it phosphorylates the
β-catenin, and so inhibited GSK3β causes β-catenin
stabilization in the cytosol. Accumulated β-catenin
enters the nucleus for activating the target genes
transcriptions. It was determined that the level of Dvl
protein was prominently increased in cervical cancer
cells by means of the fact that the DVL gene was
overexpressed. It was claimed that this excessive gene
expression and increased Dvl protein are associated
with the formation of cervical cancer (41).
sFRP proteins are found in the intercellular spaces
of normal cervical epithelia. The Wnt protein is the
initiator molecule of the Wnt/β-catenin signaling
pathway and it competes with these sFRP proteins to
bind the Fz receptor on the target cell membrane. If
sFRP binds Fz, Wnt/β-catenin signaling becomes
inactive. However, if Wnt protein binds, it becomes
active. It was shown that sFRP proteins are inhibited
by means of hypermethylation of the SFRP gene
family promoter region. According to these data, if
sFRP binds to the receptor, the signaling pathway
activates when it must be inactive. In a few studies the
role of aberrant activation of Wnt/β-catenin signaling
in the carcinogenesis of cervical cancer was also
reported (11,13,34-36).
In another related study, the relation of Dkk3
protein with the Wnt/β-catenin signaling pathway and
cervical cancer was investigated by Lee et al. (37). In
that study, it is supposed that Dkk3 is a cytosolic
protein and binds to βTrCP enzyme, which recognizes
β-catenin and carries it to the proteosome to degrade.
With this binding, Dkk3 increases the degradation of
β-catenin or inhibits the transcription of target genes
by blocking the nuclear entry of β-catenin. As regards
these findings, although the function of Dkk3 in the
In many studies, cancer-associated mutations of a
component of the Wnt/β-catenin signaling pathway
were demonstrated in APC. It was proved that
mutations of APC, a tumor suppressor gene, have a
critical role in the initiation of colorectal cancer
formation. Most of the mutations in the APC gene
result in truncated APC protein, which cannot bind
β-catenin, and so as the result of APC mutation, βcatenin does not degrade and the level of β-catenin
increases in the cytosol. By means of this, β-catenin
gets into the nucleus and causes uncontrolled
expression of target genes, and so the cytoplasmic
231
Relation of the Wnt/β-catenin signaling pathway with gynecological cancers
level of β-catenin is controlled tightly by the APC
(19,25,42). The relation of mutations in APC protein
with cervical cancer was investigated in certain
studies. For instance, the methylations of various gene
promoter regions were investigated, and it was found
that the APC gene was methylated quite little (10%) in
cervical cancer cells. Based on these results, it was
claimed that mutations in APC affect the formation
of cervical cancer slightly (43).
In conclusion, in all studies it was suggested that
not only HPV infections but also aberrant activations
of the Wnt/β-catenin signaling pathway may take part
in the carcinogenesis of cervical cancer. It was also
reported that alterations in positive and negative
regulators of Wnt/β-catenin signaling may cause
mainly this aberrant activation.
Relation of the Wnt/β-catenin signaling pathway
with ovarian cancer
Ovarian cancers cause the largest proportion of
deaths from gynecologic cancers because their
diagnosis is very difficult. Little has been determined
about the mechanism of ovarian carcinogenesis.
Methylations in the promoter regions of genes were
often seen as an important factor in the development
of ovarian cancer (42). For instance, methylations in
the genes that encoded biomolecules of Wnt signaling
have a critical role in ovarian cancer formation via
causing abnormal activation of the Wnt/β-catenin
signaling pathway.
Related studies for explaining the relationship
between ovarian endometrioid adenocarcinoma and
the Wnt/β-catenin signaling pathway showed that the
mutations occur mainly in the N-terminal of βcatenin. The critical component in this pathway is βcatenin, and so the key event is the regulation of
β-catenin stability. Because of mutation in the Nterminal, β-catenin is not phosphorylated, and
consequently it does not degrade. This stabilizes βcatenin accumulate in the cytosol and translocates to
the nucleus for activating the aberrant gene
transcription, thus leading to the formation of ovarian
cancer. It was demonstrated that not only mutations
in the N-terminal of β-catenin, but also mutations in
the genes that encode components of degradation
complex, like APC, Axin1, and Axin-2 in the target
cell cytosol affect uncontrolled activation of Wnt
signaling (13,43,44).
232
Methylations in SFRP1 genes promoter region
repressed its expression and this silence resulted in
abnormal activation of Wnt/β-catenin signaling via
truncated sFRP protein, which is an important
antagonist of Wnt/β-catenin signaling. It was also
defined that because of inactivating the signaling
pathway β-catenin accumulates at high levels in the
cytoplasm and translocates into the nucleus. As a
result, unchecked Wnt signaling via methylationassociated silencing of SFRP1 gene is involved in the
induction and progression of ovarian cancer.
Therefore, SFRP1 is expected to be a novel target
biomolecule for ovarian cancer, the diagnosis and
therapy of which are very difficult (45).
In conclusion, it has been explained that
methylations in genes that encode Wnt inhibitors and
mutations in the N-terminal of β-catenin may have a
crucial role in the formation of ovarian cancer by
immunocytochemical and molecular biological
methods. According to these data, the SFRP1 gene is
expected to be a new target (marker) for the diagnosis
and therapy of ovarian cancer.
Conclusion
The Wnt/β-catenin signaling pathway has been
exhibited to be necessary for several biological
processes like proliferation, differentiation, and
regulation of the cell cycle, and also it has critical roles
in the pathogenesis of various diseases, including
cancer. This signaling pathway is tightly regulated by
diverse proteins, which act as agonists or antagonists.
These numerous components have helped to identify
the role of the Wnt/β-catenin signaling pathway in
carcinogenesis. As a consequence, clarifying the effect
of inappropriate signaling in diseases, identifying all
components, and discussing new therapeutic
opportunities are very important.
Corresponding author:
Şayeste DEMİREZEN
Department of General Biology
Faculty of Science, University of Hacettepe,
Ankara- TURKEY
E.mail: [email protected]
H. G. TANIR, Ş. DEMİREZEN, M. S. BEKSAÇ
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