- Open Access
Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway
© Perez-Plasencia et al. 2008
Received: 19 February 2008
Accepted: 07 July 2008
Published: 07 July 2008
The Human papillomavirus plays an important role in the initiation and progression of cervical cancer. However, it is a necessary but not sufficient cause to develop invasive carcinoma; hence, other factors are required in the pathogenesis of this malignancy. In this review we explore the hypothesis of the deregulation of wnt/β-catenin signaling pathway as a "second hit" required to develop cervical cancer.
HPV and cervical cancer
Cervical carcinoma (CC) is one of the most common cancers and a leading cause of death among women worldwide. . The number of patients who died from this disease in 2000 was estimated at >200,000 . An important percentage of cases occur in the developing world, where in some countries CC is the main cause of death in reproductive-aged and economically active women with limited access to early diagnosis or effective treatment .
Over 30 years ago, some authors pointed out that CC had sexually transmitted disease behavior , while others hypothesized and analyzed a possible role of the human papillomavirus (HPV) in this neoplasia [4, 5]. But it was until November 1991 that the association between HPV infection and CC was officially established, after considering the epidemiologic and molecular evidence that the DNA of HPV is integrated in more than 99% of cervical carcinoma specimens [6, 7].
At present, more than 100 types of HPV have been identified , 40 of which infect the genital epithelia. Genital HPVs are classified in three groups according to their potential to induce cervical lesions: high-risk, probable high-risk and low-risk types . Between high-risk viral types, 16 and 18 HPV types are the most frequent viral types, with nearly one half of all cervical cancers the former, and 15%, the latter . Fortunately, not all patients infected with oncogenic HPVs will develop CC due to frequent spontaneous clearance of viral sequences. This discrepancy indicates that the majority of HPV infections are sub-clinical; therefore, only a small number of oncogenic HPV infections will produce early epithelial lesions, and only a very small number of these lesions will lead to CC [10, 11]. Hence, infection with high-risk HPV is a necessary – but not sufficient – cause for developing cervical carcinoma; thus, other types of factors such as cellular, immunological, genetic, epigenetic, environmental, etc. can affect the final outcome of the disease. In this context, viral factors have been reasonably explored, producing adequate evidence to postulate the occurrence of three events during HPV course infection as cancer promoters: viral DNA integration to host genome; expression of viral oncoproteins E6 and E7, and finally the complex interactions between E6/E7 and cellular proteins. In this carcinogenesis complex model, identification of viral, host, and environmental factors exerting an influence on the risk of disease progression from early cervical abnormalities to invasive cancer will lead us to better knowledge of the natural history of HPV infection.
An important step during HPV infection corresponds to viral integration into the host genome. The HPV genome is usually replicated as episome or extrachromosomic molecule in benign cervical precursor lesions. Cancer tissues can contain both episomal and integrated HPV DNA . Because the HPV genome is a ring molecule, it requires being open in order to be integrated; this process often breaks the E1–E2 open reading frames. Part of E2 and adjacent regions to E2–E4, E5, and L2 are commonly deleted after integration; therefore, the partial transcriptional repression exerted by E2 is lost and viral oncogenes E6 and E7 are actively expressed in CC tissues . Furthermore, viral integration frequently occurs in chromosomic regions where genes involved in tumorogenesis, such as MYC, NR4A2, hTERT, APM-1, FANCC, and TNFAIP2, etc., are found .
E6 and E7 epithelial expression and its interactions with cellular proteins have been at the center of the HPV biomedical research scenario probably for the past 20 years. The central core of the classic E6/E7 model is the binding and inactivation of tumor suppressor proteins p53 and pRb respectively; which was established between the late 1980s and the early 1990s [20, 21]. Currently, it is well-known that E6 and E7 interact with a plethora of cellular proteins that participate in molecular pathways involved in the activation and establishment of the malignant phenotype.
One of the candidate signaling pathways that has been recently studied in cervical carcinoma model is the Wnt/beta catenin pathway. The role of wnt signaling in cancer was initially described 20 years ago with the seminal discovery of wnt-1 gene as an integration site for mouse mammary tumor virus (MMTV) . Since then a wealth of information has highlighted the role of the wnt pathway in the control of several biological processes, for instance, cell fate specification, proliferation, migration, cell adhesion, cell polarity, tissue architecture, and organogenesis [23, 24]. In an adult body, Wnts regulate hematopoiesis, osteogenesis, angiogenesis, and adipogenesis [25–27]. This wide range of biological effects shows a high pleiotropism of wnt signals, which are also involved in human diseases including cancer. Several reports have demonstrated aberrant activation of the wnt signaling pathway in different human cancers, including colorectal ; gastric  and melanoma . In CC little is known about the wnt signaling pathway, however we and other researchers have recently described alterations on this pathway in cervical neoplasia. The aim of this review therefore, is to analyze current evidence of wnt pathway involvement on CC.
Wnt/beta-catenin signaling pathway
Wnt binds to seven-transmembrane domain proteins denominated Frizzled (FZD). The broad range of cellular processes regulated by the wnt pathway can be explained -at least in part-by the high diversity between wnt proteins and FZD receptors. In the human genome, 19 WNT and 11 FZD genes have been identified. For a complete list of WNT and FZD genes, please visit the World Wide Web Wnt Homepage . Interactions between Wnt proteins and their receptors show an important rate of promiscuity ; therefore, a Wnt protein can bind with different FZD receptors, and vice versa. This interaction requires the cooperation of LRP5 and LRP6, which are long single-pass transmembrane proteins acting as co-receptors . Mutations in both genes can lead to developmental defects similar to inactivating mutations in individual Wnt genes, e.g., defects in dorsal thalamic development, skeletal and neural tube abnormalities, decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization [34–36]. This evidence shows that LRPs proteins perform an important role in Wnt pathway activation and regulation. The interaction between LRP5/6, FZD, and Wnt can be regulated by secreted proteins such as Dikkopf (Dkk), secreted frizzled-related proteins (sFRP), and Cerberus1 (Cer1), which can inhibit wnt signaling through direct binding to wnt or co-receptor molecules. Dkk binds to LRP with other transmembrane proteins, the Kremens (Krm); thus promoting LRP internalization and inactivation [37, 38]
Following the trimerization of Wnt/Fzd/LRPs, the LRP co-receptor is phosphorylated leading to the binding and phosphorylation of Disheveled (Dvl), which transduces the Wnt signal into the cell through direct binding with FZD [42, 43]. Dvl is a central player in the Wnt signal routing and amplification through pathway-specific effectors . Dvl interacts with axin, which performs a scaffolding function in the wnt pathway by its association with key proteins for β-catenin phosphorylation and poly-ubiquitination, including GSK-3β, CK1, APC, and β-catenin itself. The consequence of axin phosphorylation is β-catenin activation through axin sequestration and its inactivation by the proteasome pathway. Some reports indicate that in mammalian cell culture wnt activation precedes axin degradation, however, the exact mechanism remains unclear .
An important hallmark in the canonical Wnt pathway is the stabilization of β-catenin in cytoplasm and its accumulation into the nucleus. This is possible due to the detachment of β-catenin from the degradation complex, a multi-protein assembly activated in the absence of wnt signaling, whose main task is to add ubiquitins to β-catenin resulting in its inactivation by means of the ubiquitin-proteasome pathway . In an unstimulated cell, β-catenin interacts with E-cadherin and α-catenin at epithelial cell adherens junctions, regulating cell adhesion. The excess of β-catenin levels are modulated by means of the degradation complex . A key component of the degradation complex is APC. When β-catenin binds to APC, it displaces the union of axin because the binding affinity of β-catenin increases dramatically upon phosphorylation and because the binding motifs of APC to axin and β-catenin overlap . Most colorectal tumors contain truncating mutations on APC, which leads to an inability to bind Axin or degrade β-catenin .
After the FZ/LRP activation by its ligand, the degradation complex kinase activity is inhibited. Consequently, non-phosphorylated β-catenin is stabilized, and increasing levels tend to accumulate in the cytoplasm. β-catenin accumulation in cytoplasm leads to its nuclear accumulation, where it is associated with lymphoid enhancer-binding factor 1/Tcell-specific transcription factor (LEF/TCF) and transcriptional activator Pygopus (Pygo). Pygo contains a domain (PHD), which is shared by many nuclear proteins with a role in chromatin remodeling and transcriptional co-activation . Mutations in Pygo result in many defects that are very similar to those of wnt loss-of-function .
In the absence of wnt signaling, TCF is bound to Groucho, forming a repressor complex of Wnt target genes. Groucho can repress gene transcription by inhibition of basal transcriptional machinery and recruitment of histone deacetylases (HDACs) [51, 52]. Although Groucho does not interact with DNA, it exerts its repressive function by its interaction with the tails of core histones H3 and H4 and by modifying chromatin structure . Thus, the specificity of the genes that will be repressed by Groucho is provided by LEF/TCF.
When β-catenin enters the nucleus, it converts the repressor LEF/TCF/Groucho into a transcriptional activator complex. This is possible due to Groucho displacement by interaction between β-catenin and LEF/TCF, thereby activating wnt target genes . Several genes activated by the wnt signaling pathway, which are mainly involved in cell proliferation and differentiation processes, have been identified; for a comprehensive list of genes regulated by this signaling pathway, please visit the Wnt homepage.
Wnt pathway and cervical carcinoma
To this point we have reviewed how the wnt/β-catenin pathway turns on complex signaling events leading to the activation of target genes. Mutations in several components of this pathway have been studied and identified in nearly all human cancers. However, in cervical cancer only few studies have shown the involvement of certain wnt/β-catenin genes in their pathogenesis. In this regard, it has been suggested that HPV-immortalized human keratinocyte transformation requires a second hit and could be achieved thanks to the activation of the canonical wnt pathway . This hypothesis is supported by the fact that β-catenin expression is increased in 73% of CC specimens, with cytoplasmic and nuclear positive staining, nevertheless mutations were found in only 20% of the analyzed cases . Thus, evidence suggests the activation of β-catenin at an upstream level, which can be accomplished by the inactivation of negative regulators such as APC and axin. It is well-known that during carcinogenesis, distinct tumor suppressor genes are inactivated by abnormal methylation of CpG islands, probably by means of an increase in DNA methyltransferase (DNMT) activity . HPV16/E7 has the capacity to bind and increase the dna methyl transferase enzyme (DNMT1) activity, the enzyme responsible to add methyl groups on CpG islands ; thus, it is feasible that negative wnt/β catenin-pathway regulators could be inactivated by methylation. In this respect, sFRPs, axin, DICKKOPF (Dkk) and APC genes have enriched CpG islands in their promoters which can be found as hypermethylated in some neoplasias including CC [29, 59–61]; therefore, it is probable that these genes could be inactivated by promoter methylation during cervical carcinogenesis.
Another mechanism involved in the upstream activation of the wnt/β-catenin pathway is over-expression of pathway activators such as wnt ligands, frizzled receptors, and disheveled. There is evidence showing over-expression of WNT10B, -14, FZD10, and DVL-1 in cervical cell lines [62–65]; nonetheless, this has not been explored in pathological specimens by traditional single-gene methodologies such as RT-PCR, immunohistochemistry, or Western and Northern blot.
Interestingly, gene components of the planar cell polarity (PCP) pathway were actively expressed in normal cervices, showing that this branch of wnt signaling is downregulated in CC (Figure 3). In vertebrates, PCP is considered as any process affecting cell polarity within an epithelial plane and involving one or more core PCP genes. PCP has shown to be an important developmental and adult tissue differentiation process. At present, the developmental processes that meet these criteria include convergent extension, neural tube closure, eyelid closure, hair bundle orientation in inner ear sensory cells, and hair follicle orientation in the skin . To our knowledge, there are no previous reports showing active PCP genes in normal cervical epithelia. This result demonstrates that during the carcinogenesis process, infected cervical cells turn off the PCP pathway, activating the canonical pathway with an increase of genes participating in it, e.g., Wnt4, -8A, FZD2, CTNNB1, among others. This turning-on of the canonical pathway leads to the activation of target genes such as MYC, JUN, FOS, and RRAS (for a complete list of altered genes in HPV16CC, please see the additional file 2 in ). A possible mechanism explaining how the canonical pathway is privileged in HPV16CC might be sFRP4 inactivation in normal cells. In an unpublished work, we observe that sFRP4 and DKK are inactivated by promoter methylation in CC; when cells are treated with DNMTs inhibitors we detect a re-expression of these genes (unpublished data). It has been shown that the sFRP gene is frequently inactivated by promoter methylation in gastric and hepatocellular cancer (HCC) [29, 68]. Moreover, sFRP1 restoration attenuated Wnt signaling in HCC cells, decreased abnormal beta-catenin accumulation in nucleus and suppressed cell growth . As previously described, it is common to find cytoplasmic and nuclear β-catenin accumulation in CC accompanied by occasional mutations in the CTNNB gene. With the previous evidence; we could speculate that canonical-pathway activation in CC is accomplished by means of inactivation of wnt negative regulators such as sFRP genes, and particularly SFRP4 and Dkk, as we were able to show [66, 69].
Even though the extensive use of the Papanicolau smear and colposcopy examination have significantly decreased the mortality rates, CC remains as the second cause of death in women worldwide. HPV sequences have been found in more than 99% of CC and HPV infection is the most important etiologic factor in cervical carcinogenesis. Besides, HPV infection is very common among the young sexually active population, but only a small fraction of infected individuals will develop cervical carcinoma later in life. Thus, HPV can be considered as an initial hit in the multistep carcinogenesis that leads to the development of CC. The molecular pathways involved in the progression of HPV-infected cells to CC have not yet been accurately identified. Here, we reviewed the role of Wnt/β-catenin pathway activation and the inactivation of planar cell polarity pathway in CC cells as a second hit to develop CC.
In CC mutations on CTNNB1 gene are uncommon; thus the activation on wnt signalling pathway it seems to be activated upstream of/β-catenin. This fact could be achieved by means of negative regulators inactivation or over-expression of pathway activators.
Other branch in wnt signaling pathway that could be relevant during CC pathogenesis is planar cell polarity (PCP) pathway, which is involved in differentiation processes. PCP is a key differentiation and morphogenetic process involved in development of epithelia. In normal cervical epithelia, cells are polarized and migrate from basal to the luminal space as they differentiate. Interestingly, PCP component genes are down-expressed in CC, indicating that this mechanism could be abated prior the establishment of the neoplasia. From the diagnostic point of view this fact could be important, because if we were able to show as an early process, we could account with potential molecular markers for early detection.
We thank to Itzel PR for her kind help to design the figures in this work. During this work CPP was recipient of postdoctoral fellowship of Universidad Nacional Autonoma de Mexico.
- Parkin DM, Bray F: Chapter 2: the burden of HPV-related cancers. Vaccine 2006, 24:S11-S25.View ArticleGoogle Scholar
- Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001, 94:153–156.View ArticlePubMedGoogle Scholar
- Kessler II: Venereal factors in human cervical cancer: evidence from marital clusters. Cancer 1977, 39:1912–1919.View ArticlePubMedGoogle Scholar
- zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW: Attempts to detect virus-specific DNA sequences in human tumors: I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer 1974, 13:650–656.View ArticlePubMedGoogle Scholar
- zur Hausen H: Condylomata acuminata and human genital cancer. Cancer Res 1974, 36:794.Google Scholar
- Bosch FX, Muñoz N, Shah KV, Meheus A: econd International Workshop on the epidemiology of cervical cancer and human papillomavirus. Int J Cancer 1992, 171–173.Google Scholar
- Walboomers JM, Jacobs MV, Manos MM, FX B, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999, 12–19.Google Scholar
- Bernard HU, Chan SY, Manos MM, Ong CK, Villa LL, Delius H, Peyton CL, Bauer HM, Wheeler CM: Identification and assessment of known and novel human papillomaviruses by polymerase chain reaction amplification, restriction fragment length polymorphisms, nucleotide sequence, and phylogenetic algorithms. J Infect Dis 1994, 170:1077–1085.PubMedGoogle Scholar
- Munoz MN, Bosh FX, de San Jose S, al : Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003, 518–527.Google Scholar
- Molano M, Van den Brule A, Plummer M, Weiderpass E, Posso H, Arslan A, Meijer CJ, Munoz N, Franceschi S: HPV Study Group. Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study. Am J Epidemiol 2003, 158:486–494.View ArticlePubMedGoogle Scholar
- Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD: Natural history of cervicovaginal papillomavirus infectionin young women. N Engl J Med 1998, 338:423–428.View ArticlePubMedGoogle Scholar
- Matsukura T, Koi S, Sugase M: Both episomal and integrated forms of Human Papillomavirus Type 16 are involved in Invasive Cervical cancers. Virology 1989, 172:63–72.View ArticlePubMedGoogle Scholar
- Ward P, Coleman DV, Malcolm DB: Regulatory mechanisms of the papillomaviruses. Trends Genet, 1989, 5:97–98.View ArticleGoogle Scholar
- Stevenson M, Hudson LC, Burns JE, Stewart RL, Wells M, Maitland NJ: Inverse relationship between the expression of the human papillomavirus type 16 transcription factor E2 and virus ADN copy number during the progression of cervical intraepithelial neoplasia. J Gen Virol 2000, 81:1825–1832.PubMedGoogle Scholar
- zur Hausen H: Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92:690–698.View ArticlePubMedGoogle Scholar
- Park TW, Fujiwara H, Wright TC: Molecular biology of cervical cancer and its precursors. Cancer 1995, 76:1902–1913.View ArticlePubMedGoogle Scholar
- Hudelist G, Manavi M, Pischinger KI, Watkins-Riedel T, Singer CF, Kubista E, Czerwenka KF: Physical state and expression of HPV DNA in benign and dysplastic cervical tissue: different levels of viral integration are correlated with lesion grade. Gynecol Oncol 2008,92(3):873–880.View ArticleGoogle Scholar
- Ueda Y, Enomoto T, Miyatake T, Ozaki K, Yoshizaki T, Kanao H, Ueno Y, Nakashima R, Shroyer KR, Murata Y: Monoclonal expansion with integration of high-risk type human papillomavirus is an essential step for cervical carcinogenesis: association of clonal status and human papillomavirus infection with clinical outcome in cervical intraepithelial neoplasia. Lab Invest 2003, 83:1517–1527.View ArticlePubMedGoogle Scholar
- Wentzensen N, Vinokurova S, von Knebel Doeberitz M: Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract. Cancer Res 2004, 64:3878–3884.View ArticlePubMedGoogle Scholar
- Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990, 63:1129–1136.View ArticlePubMedGoogle Scholar
- Dyson N, Howley PM, Munger K, Harlow E: The human papilloma virus-l6 El oncoprotein is able to bind to the retinoblastoma gene product. Science 1989, 243:934–940.View ArticlePubMedGoogle Scholar
- Nusse R, van Ooyen A, Cox D, Fung YK, Varmus H: Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 1984, 307:131–136.View ArticlePubMedGoogle Scholar
- Wodarz A, Nusse R: Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998, 14:59–88.View ArticlePubMedGoogle Scholar
- Peifer M, Polakis P: Wnt signaling in oncogenesis and embryogenesis: a look outside the nucleus. Science 2000, 287:1606–1609.View ArticlePubMedGoogle Scholar
- Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA: Inhibition of Adipogenesis by Wnt Signaling. Science 2000, 289:950–953.View ArticlePubMedGoogle Scholar
- Goodwin AM, D'Amore PA: Wnt signaling in the vasculature. Angiogenesis 2002, 5:1–9.View ArticlePubMedGoogle Scholar
- Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, rslan-Kirchner M, Batch JA, Beighton P, Black GCM, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML: LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development. Cell 2001, 107:513–523.View ArticlePubMedGoogle Scholar
- Segditsas S, Tomlinson I: Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 2006, 25:7531–7537.View ArticlePubMedGoogle Scholar
- Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H: Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene 2007, 26:4699–4713.View ArticlePubMedGoogle Scholar
- Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790–1792.View ArticlePubMedGoogle Scholar
- http://www.stanford.edu/rnusse/wntwindow.html 2008.Google Scholar
- Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R: A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996, 382:225–230.View ArticlePubMedGoogle Scholar
- Wehrli M, Dougan ST, Caldwell K, O'Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: Arrow encodes an LDL-receptor-related protein essential for Wingless signaling. Nature 2000, 407:527–530.View ArticlePubMedGoogle Scholar
- Zhou CJ, Pinson KI, Pleasure SJ: Severe defects in dorsal thalamic development in low-density lipoprotein receptor-related protein-6 mutants. J Neurosci 2004, 24:7632–7639.View ArticlePubMedGoogle Scholar
- Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L: Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 2002, 157:303–314.View ArticlePubMedGoogle Scholar
- Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M, Wahl MB, Galceran J, Grosschedl R, Ozono K, Imai K: Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 2004, 131:5469–5480.View ArticlePubMedGoogle Scholar
- Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C: Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signaling. Nature 2002, 417:664–667.View ArticlePubMedGoogle Scholar
- Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC: An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 2000, 407:535–538.View ArticlePubMedGoogle Scholar
- Polakis P: Wnt signaling and cancer. Genes Dev 2000, 14:1837–1851.PubMedGoogle Scholar
- Qian D, Jones C, Rzadzinska A, Mark S, Zhang X, Steel KP, Dai X, P C: Wnt5a functions in planar cell polarity regulation in mice. Dev Biol 2007, 306:121–133.View ArticlePubMedGoogle Scholar
- Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT: The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000, 16:279–283.View ArticlePubMedGoogle Scholar
- Umbhauer M, Djiane A, Goisset C, Penzo-Mendez A, Riou JF, et : The C- terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/betacatenin signalling. EMBO J 2000, 19:4944–4954.View ArticlePubMedGoogle Scholar
- Wallingford JB, Habas R: The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 2005, 132:4421–4436.View ArticlePubMedGoogle Scholar
- Wharton KA: Runnin' with the Dvl: pr oteins that associate with Dsh/Dvl and their significance to Wnt signal tr ansduction. Dev Biol 2003, 253:1–17.View ArticlePubMedGoogle Scholar
- Yamamoto A, Nagano T, Takehara S, Hibi M, Aizawa S: Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, Wnt and FGF. Cell 2005, 120:223–235.View ArticlePubMedGoogle Scholar
- Aberle H, Bauer A, Stappert J, Kispert A, Kemler R: beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 1997, 16:3797–3804.View ArticlePubMedGoogle Scholar
- Xing Y, Clements WK, Kimelman D, Xu W: Crystal structure of a [beta]-catenin//Axin complex suggests a mechanism for the [beta]-catenin Destruction complex. Genes Dev 2003, 17:2753–2764.View ArticlePubMedGoogle Scholar
- Kinzler KW, Vogelstein B: Lessons from Hereditary Colorectal Cancer. Cell 1996, 87:159–170.View ArticlePubMedGoogle Scholar
- Belenkaya TY, Han C, Standley HJ, Lin X, Houston DW, Heasman J, Lin X: pygopus encodes a nuclear protein essential for Wingless/Wnt signaling. Development 2002, 129:4089–4101.PubMedGoogle Scholar
- Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Zullig S, Basler K: Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 2002, 109:47–60.View ArticlePubMedGoogle Scholar
- Yu X, Li P, Roeder RG, Wang Z: Inhibition of androgen receptor-mediated transcription by amino-terminal enhancer of split. Mol Cell Biol 2001, 21:4614–4625.View ArticlePubMedGoogle Scholar
- Chen G, Fernandez J, Mische S, Courey AJ: A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev 1999, 13:2218–2230.View ArticlePubMedGoogle Scholar
- Sekiya T, Zaret KS: Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Mol Cell 2007, 28:291–303 .View ArticlePubMedGoogle Scholar
- Daniels DL, Weis WI: Neta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol 2005, 12:364–371.View ArticlePubMedGoogle Scholar
- Uren A, Fallen S, Yuan H, Usubutun A, Kucukali T, Schlegel R, Toretsky JA: Activation of the Canonical Wnt Pathway during Genital Keratinocyte Transformation: A Model for Cervical Cancer Progression. Cancer Res 2005, 65:6199–6206.View ArticlePubMedGoogle Scholar
- Shinohara A, Yokoyama Y, Wan X, Takahashi Y, Mori Y, Takami T, Shimokawa K, Tamaya T: Cytoplasmic/nuclear expression without mutation of exon 3 of the beta-catenin gene is frequent in the development of the neoplasm of the uterine cervix. Gynecol Oncol 455 2001, -450.Google Scholar
- Robertson KD: DNA methylation, methyltransferases, and cancer. Oncogene 3155 2001, 20–3139.Google Scholar
- Burgers WA, Blanchon L, Pradhan S, Launoit YD, Kouzarides T, Fuks F: Viral oncoproteins target the DNA methyltransferases. Oncogene 2007, 26:1650–1655.View ArticlePubMedGoogle Scholar
- Oates NA, van Vliet J, Duffy DL, Kroes HY, Martin NG, Boomsma DI, Campbell M, Coulthard MG, Whitelaw E, Chong S: Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly. The American Journal of Human Genetics 2006, 79:155–162.View ArticleGoogle Scholar
- Yang HJ, Liu V, Wang Y, Tsang P, Ngan H: Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. BMC Cancer 2006, 6:212.View ArticlePubMedGoogle Scholar
- Lee J, Yoon YS, Chung JH: Epigenetic silencing of the WNT antagonist DICKKOPF-1 in cervical cancer cell lines. Gynecologic Oncology 2008, 109:270–274.View ArticlePubMedGoogle Scholar
- Kirikoshi H, Katoh M: Expression and regulation of WNT10B in human cancer: up-regulation of WNT10B in MCF-7 cells by beta-estradiol and down-regulation of WNT10B in NT2 cells by retinoic acid. Int J Mol Med 2002, 10:507–511.PubMedGoogle Scholar
- Kirikoshi H, Sekihara H, Katoh M: Expression of WNT14 and WNT14B mRNAs in human cancer, up-regulation of WNT14 by IFNgamma and up-regulation of WNT14B by beta-estradiol. Int J Oncol 2001, 19:1221–1225.PubMedGoogle Scholar
- Koike J, Takagi A, Miwa T, Hirai M, Terada M, Katoh M: Molecular cloning of Frizzled-10, a novel member of the Frizzled gene family. Biochem Biophys Res Commun 1999, 262:39–43.View ArticlePubMedGoogle Scholar
- Okino K, Nagai H, Hatta M, Nagahata T, Yoneyama K, Ohta Y, Jin E, Kawanami O, Araki T, Emi M: Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma. Oncol Rep 2003, 10:1223.Google Scholar
- Perez-Plasencia C, Vazquez-Ortiz G, Lopez-Romero R, Pina-Sanchez P, Moreno J, Salcedo M: Genome wide expression analysis in HPV16 Cervical Cancer: identification of altered metabolic pathways. Infectious Agents and Cancer 2007, 2:16.View ArticlePubMedGoogle Scholar
- Wang Y, Nathans J: Tissue/planar cell polarity in vertebrates: new insights and new questions. Development 2007, 134:647–658.View ArticlePubMedGoogle Scholar
- Shih YL, Hsieh CB, Lai HC, Yan MD, Hsieh TY, Chao YC, Lin YW: SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. Int J Cancer 2007, 121:1028–1035.View ArticlePubMedGoogle Scholar
- Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, de la Cruz-Hernandez E, Herrera LA: Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev 2008, 34:206–222.View ArticlePubMedGoogle Scholar
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