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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. 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