Добірка наукової літератури з теми "Wnt/b-Catenin pathway"
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Статті в журналах з теми "Wnt/b-Catenin pathway":
1
Yu, Fujun, Yong Guo, Bicheng Chen, Liang Shi, Peihong Dong, Mengtao Zhou та Jianjian Zheng. "LincRNA-p21 Inhibits the Wnt/β-Catenin Pathway in Activated Hepatic Stellate Cells via Sponging MicroRNA-17-5p". Cellular Physiology and Biochemistry 41, № 5 (2017): 1970–80. http://dx.doi.org/10.1159/000472410.
Анотація:
Background/Aims: It is known that the activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Aberrant activated Wnt/β-catenin pathway is known to accelerate the development of liver fibrosis. microRNAs (miRNAs)-mediated Wnt/β-catenin pathway has been reported to be involved in HSC activation during liver fibrosis. However, whether long noncoding RNAs (lncRNAs) regulate Wnt/β-catenin pathway during HSC activation still remains unclear. Methods: Long intergenic noncoding RNA-p21 (lincRNA-p21) expression was detected in Salvianolic acid B (Sal B)-treated cells. Effects of lincRNA-p21 knockdown on HSC activation and Wnt/β-catenin pathway activity were analyzed in Sal B-treated cells. In lincRNA-p21-overexpressing cells, effects of miR-17-5p on HSC activation and Wnt/β-catenin pathway activity were examined. Results: LincRNA-p21 expression was up-regulated in HSCs after Sal B treatment. In primary HSCs, lincRNA-p21 expression was down-regulated at Day 5 relative to Day 2. Sal B-inhibited HSC activation including the reduction of cell proliferation, α-smooth muscle actin (α-SMA) and type I collagen was inhibited by lincRNA-p21 knockdown. Sal B-induced Wnt/β-catenin pathway inactivation was blocked down by loss of lincRNA-p21. Notably, lincRNA-p21, confirmed as a target of miR-17-5p, suppresses miR-17-5p level. Lack of the miR-17-5p binding site in lincRNA-p21 prevents the suppression of miR-17-5p expression. In addition, the suppression of HSC activation and Wnt/β-catenin pathway induced by lincRNA-p21 overexpression was almost inhibited by miR-17-5p. Conclusion: We demonstrate that lincRNA-p21-inhibited Wnt/β-catenin pathway is involved in the effects of Sal B on HSC activation and lincRNA-p21 suppresses HSC activation, at least in part, via miR-17-5p-mediated-Wnt/β-catenin pathway.
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Adjei-Fremah, Sarah, Emmanuel Kwaku Asiamah, Kingsley Ekwemalor, Louis Jackai, Keith Schimmel, and Mulumebet Worku. "Modulation of Bovine Wnt Signaling Pathway Genes by Cowpea Phenolic Extract." Journal of Agricultural Science 8, no. 3 (February 16, 2016): 21. http://dx.doi.org/10.5539/jas.v8n3p21.
Анотація:
<p class="ANMmaintext">The Wingless (Wnt) signaling pathway is a conserved pathway with essential roles in cellular and biological processes in mammals. Wnt signal transduction has been implicated in inflammation, innate immunity and homeostasis via Toll-like receptor and NF-kB pathways. Plant bioactive compounds are capable of modulating the Wnt signalling pathway, which can be either a canonical (B-Catenin dependent) or non-canonical (B-Catenin independent) mechanism. This study evaluated the effect of cowpea phenolic extract (CPE) on the expression and modulation of genes of the Wnt signaling pathway in cow blood. Whole blood collected from six Holstein-Friesian cows was treated with 10 ug/ml of the extract, and evaluated for packed cell volume (PCV), total count and viability of cells, and white blood cell differential count before and after treatment. Cowpea phenolic extract agonist activity in blood was measured using a Bovine toll-like receptor (TLR) 2, and TLR 4 ELISA kit. Total RNA was isolated from the blood cell pellet, reverse transcribed and used for real-time PCR to detect expression of 84 genes on the Cow Wnt signaling pathway array. The total cell-associated B-Catenin level was measured using a commercial ELISA kit. There was no treatment effect on PCV, total cell and viability (P > 0.05). The percentage of mononuclear cells were influenced by treatment, % monocytes (P = 0.0136) decreased and % lymphocytes (P = 0.0114) increased. Treatment with CPE activated cow blood cells, increased TLR2 release and total B-Catenin levels (6 ng/ml, P < 0.05), but TLR4 was not detected. Polyphenols from cowpea modulated the expression of Wnt signalling genes, especially canonical B-Catenin mediated pathway genes. Modulation of Wingless gene expression may be an important mechanism by which polyphenols in cowpea feed impact cellular immune response and homeostasis. Thus, further studies are needed to determine the association of CPE-mediated Wnt gene modulation on blood leucocytes subpopulations and animal health.</p>
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Li, Xinyu, Lingyu Geng, Xiangxiang Zhou, Kang Lu, Peipei Li, and Xin Wang. "5-Aza-2-Deoxycytidine Regulates Wnt Beta-Catenin Pathway in B Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 4810. http://dx.doi.org/10.1182/blood.v126.23.4810.4810.
Анотація:
Abstract Introduction: The Wnt/beta-catenin pathway is aberrantly activated in B cell lymphomas, unphosphorylated beta-catenin accumulates and translocates into the nucleus, regulates the expression of c-myc, cyclinD1 and many other target genes which govern fundamental cell functions, such as proliferation, cell cycle regulation and apoptosis. Methylation is a highlight of epigenetic regulation research which also occurred in lymphoma, but the concrete mechanism of how the demethylation drug 5-aza-2-deoxycytidine affect Wnt/beta-catenin pathway is still unknown. This study was designed to illuminate the implications on Wnt/beta-catenin pathway via demethylation 5-aza in B cell lymphoma. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from samples of 30 primary CLL patients. The PBMCs contained more than 90% of CD19+ B lymphocytes, which were detected by flow cytometry and were referred to as primary CLL cells. The activation of Wnt/beta-catenin pathway and DNMT-1 of B cell lymphoma cells lines (MEC-1, LY8, Jeko-1, Grant519, mino and sp53) and the 30 patients were detected by qPCR and western blot. The expressions of beta-catenin in 20 cases of B cell lymphoma tissues were measured by IHC. The B cell lines and PBMCs from 10 primary CLL patients were given 5-aza-2-deoxycytidine in different concentrations, the effects in the pathway and apoptosis were observed by WB and flow cytometry. Results: The expressions of beta-catenin, c-myc, cyclinD1 and DNMT-1 were aberrantly higher in all cell lines we used ( MEC-1,LY8, Jeko-1, Grant519, mino and sp53 Fig.1-A,B), most primary CLL patients (Fig.1-C), and B cell lymphoma tissues (Fig.1-D). The protein expressions of beta-catenin in MEC-1 were higer than primary CLL patients. 0, 0.5, 1.0, 2.0¦ÌM 5-aza-2-deoxycytidine were given to the B cells lines and PBMCs from primary CLL patients for 48h, beta-catenin were found accumulated, but c-myc and cyclinD1 in the downstream were reduced (Fig.2-A,B,C,D). For further understanding of aberrant accumulation ofbeta-catenin, we extracted the nuclear protein of MEC-1, nuclear beta-catenin protein expressions were found decreased and cytoplasmic were increased (Fig.2-E). After 5-aza treatment, the apoptosis rate increased and caspase pathway were activated (Fig.2-A,F). Conclusions: The enhanced expressions of beta-catenin, c-myc, cyclinD1 in the B cell lines and the B cell lymphoma samples indicated the Wnt/beta-catenin was aberrantly activated. After 5-aza treatment with the cell lines (MEC-1, Jeko-1, LY8) and primary CLL cells, the abnormal accumulation of beta-catenin protein was observed which was discrepancy with previous reports, but the decrease of c-myc and cyclinD1 suggested the pathway was inhibited, apoptosis also occurred. The increase of totalbeta-catenin protein was supposed to be an stress reaction of the 5-aza treatment, however, the redundant beta-catenin protein in B cell lymphoma was speculated to be combined with demethylated genes and resulted in dormancy of this pathway. Our results indicated that 5-aza played a demethylation role through Wnt/beta-catenin pathway in B cell lymphoma. The data are of interest in the context of epigenetic-based therapy in B cell lymphoma. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Langhammer, Tina-Susann, Catrin Roolf, Saskia Krohn, Christin Kretzschmar, Rayk Huebner, Arndt Rolfs, Mathias Freund та Christian Junghanss. "PI3K/Akt Signaling Interacts With Wnt/β-Catenin Signaling But Does Not Induce An Accumulation Of β-Catenin In The Nucleus Of Acute Lymphoblastic Leukemia Cell Lines". Blood 122, № 21 (15 листопада 2013): 4886. http://dx.doi.org/10.1182/blood.v122.21.4886.4886.
Анотація:
Abstract Signaling pathways play essential roles in biological processes as development, cell proliferation and homeostasis. The accurate modulation of signaling pathways, their adapted interaction and their time- and tissue-specific adjusted regulation are required for normal cell development. PI3K/Akt and Wnt/β-Catenin signaling pathways act as key regulators in cell proliferation, differentiation and growth. Both signaling pathways include GSK3β as a common protein, which may mediate an interaction and cross-talk between the pathways. Aberrant activation of PI3K/Akt signaling has been linked to different types of leukemia while Wnt/β-Catenin signaling is known to be deregulated in some solid tumors. However, a potential role of Wnt/β-Catenin signaling for pathogenesis of acute lymphoblastic leukemia (ALL) has not yet been analyzed. In our study we analyzed both signaling pathways in different B- and T-ALL cell lines (RS4;11, SEM, REH, CEM, Jurkat, MOLT-4), thereby focusing mainly on their potential interaction via the protein GSK3β. Western Blot experiments were performed to evaluate the expression of specific PI3K/Akt and Wnt/β-Catenin key proteins. To evaluate the activation status of Wnt signaling immunofluorescence and protein fractionation experiments were performed, analyzing the activation linked nucleic localization of β-Catenin. The effect of pathway activation and inhibition on cell proliferation via chemical compounds was analyzed by WST-1 test. High pAkt levels were detected in B-ALL cell line SEM and T-ALL cell line CEM, indicating a hyperactive PI3K/Akt signaling, whereas other analyzed cell lines diplayed lower pAkt status. Among all cell lines analyzed SEM and CEM also showed the highest cytoplasmic β-Catenin levels, indicating a direct interaction of both signaling pathways. However, immunofluorescence and fractionation experiments revealed that a translocation of β-Catenin into the nucleus did not occur. To further investigate the role and interaction of PI3K/Akt and Wnt/β-Catenin signaling, pathway inhibiting and stimulating experiments were performed. Treatment of cells with Wnt3a led to activation of the Wnt/β-Catenin signaling cascade, characterized by nuclear β-Catenin accumulation. Inhibition of cell proliferation was detected after treatment with high concentrations Wnt3a (≥ 500 ng/ml). PI3K inhibition by LY294002 led to decreased phosphorylation of GSK3β at Ser9 and an increased decay of β-Catenin. Stimulation of PI3K/Akt signaling using activating ligand FLT3L induced GSK3β phosphorylation at Ser9 and accumulation of cytoplasmic β-Catenin. However a translocation of β-Catenin into the nucleus seems not to occur. In summary our results indicate that PI3K/Akt and Wnt/β-Catenin signaling can interact through their common protein GSK3β, but stimulation of the PI3K/Akt signaling pathway by addition of PI3K/Akt specific activators does not fully activate Wnt/β-Catenin signaling in ALL cells. Complete activation of the Wnt cascade characterized by translocation of β-Catenin into the nucleus can only be induced by use of specific Wnt effectors. Disclosures: No relevant conflicts of interest to declare.
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Fachel, Angela A., Ashlesha Shrikant Muley, Cem Meydan, Xabier Agirre, Leandro Cerchietti, Ari Melnick, and Kristy L. Richards. "Targeting ß-Catenin Signaling in DLBCL with ICG-001 and PAM-1 Suppresses Cell Proliferation and Induces Apoptosis." Blood 128, no. 22 (December 2, 2016): 5382. http://dx.doi.org/10.1182/blood.v128.22.5382.5382.
Анотація:
Abstract Introduction: DLBCL is a fast-growing, aggressive form of NHL and ~30% of the patients are not cured with the current treatment regimens. Recently Wnt/ ß-catenin signaling has been identified as a new target pathway for lymphoma. To specifically target B-catenin we picked two drugs that act downstream of the Wnt/B-catenin pathway. ICG-001 inhibits TCF/β-catenin mediated transcription by competing specifically with β-catenin for CREB binding protein (CBP), but not for p300. PAM-1 is a p21-activated kinase 4 (PAK4) allosteric modulator acting as a nucleo-cytoplasmic shuttling protein. PAK4 interacts with and phosphorylates β-catenin on Ser675, promoting TCF/B-catenin transcriptional activity and stabilizing β-catenin through inhibition of its degradation. We conducted a pre-clinical study with ICG-001 and PAM-1 ß-catenin inhibitors on 16 ABC and GCB DLBCL cell lines and provided a molecular rationale for Wnt/ß-catenin directed therapy. Material & Methods: RNAseq data from DLBCL cell lines, patient and normal B-cell samples were used to profile transcript abundance of the Wnt pathway in DLBCL. Western blotting was used to measure ß-catenin expression in 16 ABC and GCB DLBCL cell lines. Pharmacological inhibition of ß-catenin-signaling was tested using ICG-001 and PAM-1 compounds. A metabolically active cellular assay (CellTiter Glo) and flow cytometry with annexin V staining were used to determine cell viability and apoptosis. To address the specificity of the drug response, DLBCL cells were transduced with a ß-catenin/TCF pathway reporter, knocked down for ß-catenin, and canonical Wnt target expression was assessed using quantitative real-time (qRT-PCR) and Western blot. Results: ß-catenin is expressed on all DLBCL cell lines at different levels that do not correlate with the ABC/GCB classification. The ß-catenin inhibitors ICG-001 and PAM-1 significantly reduced viability in all ABC and GCB DLBCL cell lines, regardless of DLBCL subtype. The EC50 after 48h of treatment ranged from 1.4 μM to 6.3 μM for ICG001 and from 80 nM to 870 nM for PAM-1. Both compounds suppressed cell proliferation, induced apoptosis, and reduced Wnt/ß-catenin transcriptional activity. Conclusions: Our data indicate that targeting ß-catenin pathway with ICG-001 and PAM-1 could be therapeutically beneficial to DLBCL patients. Disclosures Melnick: Janssen: Research Funding.
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Tran, Bang Manh, Dustin James Flanagan, Gregor Ebert, Nadia Warner, Hoanh Tran, Theodora Fifis, Georgios Kastrappis, et al. "The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling." Cancers 12, no. 6 (May 31, 2020): 1435. http://dx.doi.org/10.3390/cancers12061435.
Анотація:
An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer.
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Rogaczewski, Patryk, Michał Janiak, Kamil Borysewicz, Tadeusz Głos, Navid Ahmadi, and Łukasz Szylberg. "Clinical significancy of WNT pathway inhibition in various cancers." Journal of Education, Health and Sport 12, no. 11 (November 3, 2022): 183–91. http://dx.doi.org/10.12775/jehs.2022.12.11.024.
Анотація:
The tumor microenvironment (TME) plays an important role in the cell cycle. There is a correlation between the Wnt/B–catenin signaling pathway and TME. This article reviews methods of inhibiting Wnt Pathway, a useful process in the treatment of various cancers. Compounds of Wnt/β–Catenin Signaling Pathway, such as TCF–1, have an impact on the differentiation and migration of CD8+ T cells. CCL4 expression is regulated by the beta–catenin protein to recruit CD103+ dendritic cells, which enables CD8+ T cell activation. Inhibition of the Wnt/β–catenin pathway has an impact on ovarian cancer patients’ prognosis, reducing the development of ovarian cancer. Research shows that inhibition of the pathway with the use of the LGK974 inhibitor may boost immunity, especially when applied with a Paclitaxel mix. After treatment, expression of the inhibitory receptors CTLA–4, TIM3, PD–1 on CD8+ T cells decreased. The combination of LGK974 and Paclitaxel can cause the death of tumor cells and significantly inhibit their proliferation. The application of dose–dense Paclitaxel avoids toxicity related to the maximum dose needed to protect the patient's immune system by increasing CD8+ TILs. There are concerns regarding toxicity of the LGK 974, especially for cells dependent on the Wnt/β–catenin pathway to maintain homeostasis. Many Wnt/β–catenin pathway inhibitors are tested against colorectal cancer (CRC) with successful results. These include NSAIDs, porcupine inhibitors, tankyrase inhibitors, Wnt5A inhibitors, and disheveled protein inhibitors.The Wnt/β–catenin pathway, when expressed in Triple Negative Breast Cancer (TNBC), leads to the transition of epithelial to mesenchymal cells. In early clinical development, there are multiple inhibitors (ex. KYA1797K) targeting the Wnt/β–catenin pathway in TNBC cells, which could become a viable anticancer strategy.
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Thanendrarajan, S., Y. Kim та I. G. H. Schmidt-Wolf. "Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia". Leukemia Research and Treatment 2011 (4 грудня 2011): 1–7. http://dx.doi.org/10.4061/2011/329572.
Анотація:
It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.
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Shi, Chong-Shan, Ning-Na Huang, Kathleen Harrison, Sang-Bae Han, and John H. Kehrl. "The Mitogen-Activated Protein Kinase Kinase Kinase Kinase GCKR Positively Regulates Canonical and Noncanonical Wnt Signaling in B Lymphocytes." Molecular and Cellular Biology 26, no. 17 (September 1, 2006): 6511–21. http://dx.doi.org/10.1128/mcb.00209-06.
Анотація:
ABSTRACT Wnt ligands bind receptors of the Frizzled (Fz) family to control cell fate, proliferation, and polarity. Canonical Wnt/Fz signaling stabilizes β-catenin by inactivating GSK3β, leading to the translocation of β-catenin to the nucleus and the activation of Wnt target genes. Noncanonical Wnt/Fz signaling activates RhoA and Rac, and the latter triggers the activation of c-Jun N-terminal kinase (JNK). Here, we show that exposure of B-lymphocytes to Wnt3a-conditioned media activates JNK and raises cytosolic β-catenin levels. Both the Rac guanine nucleotide exchange factor Asef and the mitogen-activated protein kinase kinase kinase kinase germinal center kinase-related enzyme (GCKR) are required for Wnt-mediated JNK activation in B cells. In addition, we show that GCKR positively affects the β-catenin pathway in B cells. Reduction of GCKR expression inhibits Wnt3a-induced phosphorylation of GSK3β at serine 9 and decreases the accumulation of cytosolic β-catenin. Furthermore, Wnt signaling induces an interaction between GCKR and GSK3β. Our findings demonstrate that GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes.
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Qiang, Ya-Wei, Bo Hu, Yu Chen, Wei Qiang, Christoph Heuck, Bart Barlogie, and John D. Shaughnessy. "Bortezomib Induces Activation of b-Catenin/TCF Signaling Pathway in Multiple Myeloma." Blood 118, no. 21 (November 18, 2011): 1851. http://dx.doi.org/10.1182/blood.v118.21.1851.1851.
Анотація:
Abstract Abstract 1851 Background: The proteasome inhibitor Bortezomib (Bz) shows significant activity in Multiple Myeloma (MM) by acting on MM cell directly as well as by augmenting bone formation in vitro and in vivo. Its effect on the bone could be traced to promoting differentiation of mesenchymal stem cells into osteoblast cells by regulating BMP2 and canonical Wnt signaling. However, the molecular mechanism mediating the direct anti-MM activity of Bz remains to be fully understood. Initially the rationale for the use of Bz in MM was inhibition of NF-kB signaling, yet subsequent studies showed that Bz actually induces activation of this pathway. In this study, we examined whether Bz regulates the activity of canonical Wnt signaling pathway in MM and whether the growth-inhibition effect of Bz was associated with activation of this pathway by using multiple MM cell lines including EJM, H929, INA6, KMS28BM, JJN3, L363, OPM1, OPM2, RPMI8226, UTMC, XG2 and XG6 as well as primary plasma cells (PC) from six patients with newly diagnosed MM. Methods/Results: Immunoblotting demonstrated that Bz induces stabilization of b-catenin protein in three MM cell lines (H929, OPM2 and UTMC) in a time- and dose-dependent manner. These changes were not seen when the same cell lysate were immunoblotted for other catenin family members, a-catenin and g-catenin. Increased levels of b-catenin protein response to Bz treatment were observed in other 9 MM cell lines (EJM, INA6, KMS28BM, JJN3, L363, OPM1, RPMI8226, XG2 and XG6) and in the 6 CD138+ sorted bone marrow PC from patients with MM. To determine if Bz regulation of b-catenin level is a specific effect of the inhibition of 26S proteasome subunit we treated the same MM cell lines with another proteasome inhibitor, MG132. Similar results were observed in response to MG132 for all four MM cell lines, suggesting the effect of Bz on b-catenin protein is 26S proteosome inhibitor specific. Increases in b-catenin protein levels in MM cells were not due to increased Ctnnb1/CTNNB (b-catenin) gene transcription as b-catenin mRNA did not change in these cells treated with Bz. These results indicate that proteasome inhibition increases b-catenin is independent of transcriptional upregulation. To determine whether Bz induces the nuclear localization and transcriptional activity of b-catenin, cells were incubated with Bz for 6 hours and then fractionated to separate the nuclear and cytoplasmic fractions. Treatment with Bz resulted an increase in nuclear b-catenin as well as b-catenin in cytoplasm in four cell lines including H929, INA6, OPM1 and MM144. Increase in cytoplasmic and nuclear b-catenin was further confirmed by immunofluorescence with antibodies specific for active form of b-catenin. To determine whether Bz affects b-catenin-mediated transcriptional activity, we used a TCF/LEF luciferase reporter construct cloned in lentiviral vector. OPM2 cells were infected with lentiviral particle containing the TCF reporter or containing empty vector and were then treated with serial concentrations of Bz. The luciferase activity exhibited a dose-dependent response to Bz analogous to the stabilization of b-catenin. Similar results were observed in 7 out of 8 MM cell lines compared with untreated control. Stimulation of TCF transcriptional activity by Bz was independent of modifiers of extracellular Wnt ligands, such as Frizzled receptors, LRP5/6 co-receptors and sFRPs or the activation of intracellular GSK3b. Conclusion: These results indicate that Bz augments activation of canonical Wnt signaling by preventing b-catenin protein from proteosome-mediated degradation in MM cells. Concentrations of Bz for stimulating TCF transcriptional activity are comparable to those being used to induce inhibition of MM proliferation. Experiments modulating cytoplasmic as well as the nuclear players and interactions of the Wnt-pathway are ongoing to determine if Bz mediated activation of b-catenin signaling is responsible for its direct anti-MM effect. Disclosures: Barlogie: Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties. Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.
Дисертації з теми "Wnt/b-Catenin pathway":
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Ferreira, Catarina Domingues. "WNT/ß-catenin and Hedgehog signaling pathways as therapeutic targets in B cell neoplasms." Master's thesis, Universidade de Aveiro, 2018. http://hdl.handle.net/10773/22676.
Анотація:
Mestrado em Bioquímica - Métodos BiomolecularesAs neoplasias de células B são caracterizadas por um grupo heterogéneo de doenças que incluem linfomas de células B e doenças de células plasmáticas, entre outras. O mieloma múltiplo (MM) é uma neoplasia maligna originada pela proliferação de células plasmáticas monoclonais que permanece incurável. Esta proliferação de células plasmáticas malignas no microambiente da medula óssea produz proteína monoclonal no sangue ou na urina e está associada a sinais malignos. Representa aproximadamente 1% das doenças neoplásicas e 10% a 15% das neoplasias hematológicas. O linfoma difuso de grandes células B (DLBCL) é a forma mais comum de linfoma não-Hodgkin, representando 31% dos linfomas não-Hodgkin, e sendo fatal se não for tratado. DLBCL é um linfoma agressivo e de crescimento rápido que pode surgir nos gânglios linfáticos ou fora do sistema linfático, no trato gastrointestinal, testículos, tiroide, pele, mama, osso ou cérebro. A ativação inadequada de vias de sinalização embrionárias, como WNT/β-catenina e Hedgehog, vias críticas de autorrenovação das células estaminais e diferenciação das células hematopoiéticas, tem sido implicada nestas neoplasias de células B. Neste sentido, essas vias podem constituir potenciais novos alvos terapêuticos para tratar o MM e o DLBCL. O objetivo principal deste estudo foi avaliar o potencial terapêutico de inibidores das vias WNT/β-catenina e Hedgehog, respetivamente IWR-1 e vismodegib, isolados e em combinação um com o outro, usando linhas celulares de MM e DLBCL. Para avaliar o efeito dos inibidores IWR-1 e vismodegib no MM e no DLBCL foram utilizadas linhas celulares H929 (MM) e FARAGE (DLBCL), submetidas a diferentes concentrações dos inibidores. A atividade metabólica foi avaliada utilizando o ensaio de resazurina, a morte celular por microscopia ótica (coloração de May-Grunwald) e citometria de fluxo (FC) (marcação com anexina V/7-AAD e quantificação de BCL-2 e caspases, proteínas relacionadas com a apoptose). A análise do ciclo celular foi avaliada por FC, utilizando a solução PI/RNAse. Também por FC, foi avaliada a expressão de β-catenina e ERK fosforilado, moléculas relacionadas com as vias de sinalização WNT/β-catenina e HH. Os resultados mostraram que IWR-1 e vismodegib reduziram a atividade metabólica celular de modo dependente do tempo, da linha celular e da concentração, em monoterapia ou em combinação. O IC50 do IWR-1 nas células H929 e Farage foi de 40 μM e 75 μM, respetivamente, enquanto que o IC50 do vismodegib foi de 70 μM para as células H929 e 57 μM para as células Farage, após 24 horas de tratamento. Estes resultados mostram que as células H929 são mais sensíveis ao IWR-1 e, contrariamente, as células Farage são mais sensíveis ao vismodegib. Estes compostos induzem a morte celular predominantemente por apoptose e induzem bloqueio do ciclo celular em G1. Em conclusão, os resultados sugerem que IWR-1 e vismodegib são potenciais novas terapias direcionadas que poderão ser eficientes no tratamento de MM e DLBCL. No entanto, IWR-1 é mais indicado para a terapêutica do MM e o vismodegib para a terapêutica do DLBCL.
B-cell neoplasms are characterized by a heterogeneous group of diseases that include, B-cell lymphomas and plasma cell disorders, among others. Multiple myeloma (MM) is a malignant neoplasm originated by proliferation of monoclonal plasma cells that remains incurable. This clonal proliferation of malignant plasma cells occurs in the bone marrow microenvironment, leads to the production of monoclonal protein in the blood or urine and is associated with malignant signals. It accounts for approximately 1% of neoplastic diseases and 10% to 15% of hematologic neoplasms. Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, representing 31% of the non-Hodgkins lymphomas, being fatal if untreated. DLBCL is an aggressive, fast-growing lymphoma, that can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testicles, thyroid, skin, breast, bone, or brain. Inappropriate activation of conserved embryonic signaling pathways, such as WNT/β-catenin and Hedgehog (HH), critical for stem cell self-renewal and differentiation of hematopoietic cells, has been implicated in these B-cell neoplasms. In this sense, these pathways may constitute new potential therapeutic targets to treat MM and DLBCL. The main goal of this study was to evaluate the therapeutic potential of a WNT/ β-catenin and a Hedgehog inhibitor, respectively, the IWR-1 and vismodegib, alone and in combination, using MM and DLBCL cell lines. To evaluate the effect of IWR-1 and vismodegib in MM and in DLBCL, H929 (MM) and FARAGE (DLBCL) cell lines were submitted to different concentrations of the inhibitors. Metabolic activity was evaluated using resazurin assay and cell death was evaluated by optical microscopy (May-Grunwald staining) and flow cytometry (FC) (Annexin V/7-AAD staining and by quantification of BCL-2 and caspases expression, apoptosis-related proteins). Cell cycle analysis was evaluated by FC, using a PI/RNAse solution. Also by FC the expression of β-catenin and phosphorylated ERK, molecules related to the WNT/β-catenin and HH signaling pathways, were tested. Results showed that IWR-1 and vismodegib reduced cell metabolic activity in a time-, cell line- and dose-dependent manner, when administrated in monotherapy or in combination. The IC50 of IWR-1 in H929 and Farage cells was 40 μM and 75 μM, respectively, and the IC50 of vismodegib was 70 μM for H929 cells and 57 μM in Farage cells, after 24h of treatment. These results show that H929 cells are more sensitive to IWR-1 and, contrarily, Farage cells are more sensitive to vismodegib. These compounds induce cell death mainly by apoptosis and showed an arrest in cell cycle at G1. In conclusion, results suggest that IWR-1 and vismodegib are potential new targeted therapies that could be efficient in MM and DLBCL treatment in the future. However, IWR-1 is more indicated for MM therapy and vismodegib for DLBCL therapy
2
Dias, Neto Domingos Pedro Manuel. "The wnt/b-catenin signalling pathway and anterior posterior patterning in the vertebrate central nervous system." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368691.
3
Fiore, Donatella. "In vitro and in vivo study of cannabinoids as modulators of Wnt/β-catenin pathway in human colorectal cancer". Doctoral thesis, Universita degli studi di Salerno, 2017. http://hdl.handle.net/10556/2485.
Анотація:
2014 - 2015Colorectal cancer (CRC) is the second most common cause of cancer death. Molecular events in CRC has been extensively studied and several data suggest that Wnt/β-catenin signaling deregulation play a pivotal role in colorectal carcinogenesis. Majority of both familial syndromes (FAP) and sporadic colon cancers, arise from APC or β-catenin genes alterations, leading to Wnt signaling hyperactivation. According to the cancer stem cells (CSCs) theory, some cancer-initiating cells, harboring stem-cell like properties, evade standard chemotherapies, resulting in recurrent and metastatic tumors. Wnt/β-catenin signaling and its deregulation is involved in the recurrence and maintenance of CSCs. In recent years, understanding of molecular mechanisms underlying CSCs biology, led to development of novel strategies to completely eradicate colorectal cancer. Some evidences suggest a potential crosstalk between the endocannabinoid system and the Wnt pathway, also in cancer stem cells, in several tumor types. This could represent a key mechanism in the control of the anti-cancer activity of cannabinoids, as well as a novel putative site for pharmacological intervention. Results from this work led to identification of Rimonabant, originally an inverse agonist of CB1 cannabinoids receptor, as modulator of Wnt/β-catenin pathway in CRC, able to control colon cancer stemness, without toxicity toward cells from healty tissue. Moreover, for the first time, we proposed a novel epigenetic mechanism Rimonabant-mediated. [edited by author]
XIV n.s.
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Vadnais, Charles. "Transcriptional regulation by CUX1 and its implication in the DNA damage response and Wnt/b-Catenin pathway activation." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116915.
Анотація:
The objective of my research project was to study and characterize the transcriptional role of the CUX1 transcription factor both on a global scale and with regards to specific cellular processes. I have carried out genome-wide location analysis experiments to identify large numbers of potential direct targets of CUX1 and investigated their regulation by CUX1 using expression profiling experiments following both overexpression of the active p110 CUX1 isoform and following its knockdown using shRNA. This study demonstrated that CUX1 can both activate and repress its targets even when binding at a distance from their promoters and that its consensus binding sequence does play a role in its binding but is not required forit in many cases. Analysis of the putative targets of CUX1 identified by genome-wide location analysis strongly suggested a role for the factor in the cellular response of cells to DNA damage. I used molecular biology methods to investigate this and demonstrated that CUX1's transcriptional activity is required for the maintenance of adequate levels of several key proteins constituting the machinery necessary for an effective response to DNA damage. Cells lacking CUX1 expression have defective cell cycle arrest and DNA damage repair capacities, reduced survival following DNA damage and show a phenotype of increased genomic instability. Previous studies of a mouse model of mammary gland tumours showed that a subset of tumours from p110 and p75 CUX1 over-expressing mice display activation of the Wnt/β-Catenin pathway. However, the mechanism by which only some of these tumours displayed this phenotype were not fully understood. I used expression profiling on microdissected material from these tumours to characterize the transcriptional effect of p110 and p75 CUX1 expression in these tumours and to identify collaborating events in Wnt/β-Catenin pathway activation. I identified members of the GLI family of transcription factors as being required for activation of the Wnt/β-Catenin pathway in these tumours. I also showed that these tumours display features of epithelial to mesenchymal transition, which may have implications for the invasiveness and severity of these tumours. The cooperation between CUX1 and GLI genes was confirmed by meta-analysis of human tumour datasets as well as cell based assays testing the ability of each factor to activate the Wnt/β-Catenin pathway on their own and in combination.L'objectif global de ma thèse était d'étudier et de caractériser l'activité transcriptionelle du facteur de transcription CUX1, autant de façon globale que dans le contexte de processus cellulaires spécifiques. J'ai effectué des expériences de localisation génomiques à grande échelle afin d'identifier un grand nombre de cibles potentielles directes de transcription de CUX1 et j'ai analysé leur régulation par CUX1 en effectuant des expériences de profilage d'expression génétique à la suite de la surexpression de l'isoform p110CUX1 ainsi qu'à la suite de la répression de CUX1 par shRNA. Cette étude a démontré que CUX1 peut activer ou réprimer l'expression de ces cibles, même lorsqu'il se lie à une distance considérable du promoteur de ces gènes, et que la séquence consensus de liaison de CUX1 joue un rôle dans sa liaison à l'ADN mais n'est pas nécessaire pour celle-ci dans plusieurs cas. L'analyse de cibles potentielles de CUX1 identifiées par des expériences de localisation génomique a grande échelle ont fortement suggéré l'implication de CUX1 dans la réponse des cellules au dommage à l'ADN. J'ai utilisé diverses techniques de biologie moléculaire pour étudier ce phénomène et j'ai démontré que l'activité transcriptionelle de CUX1 est nécessaire au maintien de niveaux suffisants de nombreuses protéines constituant la machinerie essentielle à la réponse des cellules au dommage à l'ADN. Les cellules n'exprimant pas ou peu de CUX1 sont déficientes dans leur capacité d'arrêt du cycle cellulaire et de réparation du dommage à l'ADN, sont plus sensibles au dommage et montrent un phénotype d'instabilité génomique accrue. Des études précédentes de tumeurs des glandes mammaires dans un modèle de souris ont montré qu'une partie des tumeurs provenant de souris surexprimant p110 ou p75 CUX1 montraient une activation du processus de signalement Wnt/β-Catenin. Cependant, le mécanisme par lequel seule une partie des tumeurs montrait ce phénotype n'était pas connu. J'ai donc effectué du profilage d'expression génétique sur ces tumeurs afin de caractériser l'effet transcriptionel de CUX1 dans celles-ci et d'identifier d'autres facteurs qui collaborent dans l'activation de Wnt/β-Catenin. J'ai ainsi identifié des membres de la famille de facteurs de transcription GLI comme étant requis pour l'activation de Wnt/β-Catenin dans ces tumeurs. J'ai aussi observé des caractéristiques de transition épithélio-mésenchymateuse dans ces tumeurs, ce qui pourrait avoir des implications sur la capacité d'invasion et la sévérité de celles-ci. La coopération entre CUX1 et les gènes GLI a été confirmée par une méta-analyse de données de profilage d'expression de tumeurs humaines ainsi qu'avec des expériences cellulaires testant la capacité de chacun de ces deux facteurs à activer Wnt/β-Catenin, individuellement et en combinaison.
5
Berenguier, Camille. "Exploration de la fonction du canal potassique KCNQ1 dans l'homéostasie de la crypte colique." Electronic Thesis or Diss., Université Côte d'Azur, 2023. http://www.theses.fr/2023COAZ6025.
Анотація:
Le rôle des canaux ioniques dans les processus cancéreux a émergé ces dernières années et constitue un domaine en plein essor. Il a notamment été montré, d'une part que l'expression de certains canaux ioniques était dérégulée dans les cancers et d'autre part que les canaux ioniques pouvaient réguler diverses voies de signalisation cellulaire. L'équilibre des voies de signalisation est essentiel en physiologie. Dans l'épithélium du colon, cet équilibre est d'autant plus crucial que les cellules sont soumises à un renouvèlement rapide, régit par l'action conjointe de plusieurs voies de signalisation. L'activation dérégulée de la voie de signalisation Wnt/β-caténine, favorisant la prolifération cellulaire, est un moteur majeur du développement tumoral dans le colon. Il a été montré que la plupart des patients atteints de cancer colorectal étaient porteurs de mutations sur des composants de cette voie, participant ainsi à sa suractivation. Le canal potassique KCNQ1 a diverses fonctions notamment dans l'épithélium du colon où il participe à la sécrétion d'eau mais également au maintien de l'intégrité épithéliale par son action de suppresseur de tumeur en réprimant la voie de signalisation Wnt/β-caténine. Malgré l'impact des mutations somatiques dans les cancers, il n'existe à ce jour aucune étude explorant les mutations portées par des canaux ioniques dans ce contexte. Nous avons donc émis l'hypothèse que des patients atteints de cancer colorectal pourraient être porteurs de mutations pathogènes sur KCNQ1. Grâce aux bases de données publiques, nous avons identifié 36 mutations portées par KCNQ1 dans divers cancers. Les mutations les plus fréquentes se sont avérées être perte de fonction. Dans les cellules de cancer colorectal, cette perte de fonction est associée à une activité accrue de la voie Wnt/β-caténine indépendamment des récepteurs canoniques de la voie. Nous avons identifié une activation de plusieurs récepteurs tyrosine kinases qui pourraient médier directement l'activation de la β-caténine. Dans le modèle des colonoïdes murins, plus physiologique, les mutations pertes de fonctions de KCNQ1 semblent également augmenter l'activité de la voie Wnt/β-caténine. De plus, ces mutations ont un impact sur l'expression de régulateurs de la voie Wnt/β-caténine, favorisant ainsi un état permissif à une suractivation pathogénique de la voie. Le canal potassique KCNQ1 restreindrait ainsi la voie de signalisation à plusieurs niveaux : un direct en séquestrant la β-caténine aux jonctions adhérentes, empêchant son activité de facteur de transcription, et un niveau indirect en permettant l'expression de protéines régulatrices inhibant la voie Wnt/β-caténine. Nos résultats mettent en évidence pour la première fois que les canaux ioniques peuvent être porteurs de mutations somatiques dans les cancers et que ces mutations peuvent altérer la fonction du canal. Nos résultats sont également les premiers à démontrer que ces mutations exercent une influence directe sur l'activité de voies de signalisation impliquées dans les processus cancéreux. De plus, les niveaux d'expression de KCNQ1 pouvant servir à la classification des cancers colorectaux, ces mutations pourraient également aider au pronostic et la stratification des patients. Ensemble, ces données ouvrent donc une nouvelle voie d'investigation permettant de mieux comprendre la diversité des mécanismes mis en place dans les processus cancéreux. De nombreux autres canaux ioniques ou leurs sous-unités associées pourraient porter des mutations somatiques dans les cancers dérégulant leur activité et les processus qui en découlentIn recent years, the role of ion channels in cancer processes has emerged and the field continues to expand. It has been shown that 1) the expression of certain ion channels is deregulated in cancers, and 2) ion channels can regulate various signalling pathways. In physiology, the balance of signalling pathways must be maintained. In the epithelium of the colon, maintaining this balance is particularly crucial as cells undergo rapid renewal which relies on the combined action of multiple signalling pathways. Dysregulated activation of the Wnt/β-catenin signalling pathway, promoting cell proliferation, is a major driver of tumour development in the colon. In most cases of colorectal cancer, patients harbour mutations on the component of this pathway, contributing to its overactivation. The potassium channel KCNQ1 has diverse functions. In the colonic epithelium, it enables water secretion and maintains epithelial integrity by exerting its tumour suppressor activity through the repression of the Wnt/β-catenin pathway. Despite the impact of somatic mutations in cancers, there are no studies, to this day, exploring mutations of ion channels in this context. Therefore, we hypothesized that colorectal cancer patients carry pathogenic mutations on KCNQ1. By analysing publicly available databases, we identified 36 different mutations harboured by KCNQ1 in various cancers. We found that the most common mutations were loss-of-function. In colorectal cancer cells, the loss-of-function mutations were associated with increased Wnt/β-catenin pathway activity, independently of the canonical pathway receptors. We also observed an activation of several tyrosine kinase receptors that could directly mediate β-catenin activation. In the more physiological model of murine colonoids, loss-of-function mutations in KCNQ1 also seem to increase Wnt/β-catenin pathway activity. Furthermore, these mutations had an impact on the expression of Wnt/β-catenin pathway regulators, favouring a permissive state for the pathway overactivation. KCNQ1 thus appears to restrict the signalling pathway at multiple levels: directly by sequestering β-catenin at adherens junctions, preventing its activity as a transcription factor, and indirectly by allowing the expression of regulatory proteins that inhibit the Wnt/β-catenin pathway. Our results highlight, for the first time, that ion channels can carry somatic mutations in cancers, altering channel function. Moreover, our findings demonstrate that these mutations directly influence the activity of signaling pathways involved in cancer processes. Additionally, given that KCNQ1 expression levels can be used for classifying colorectal cancers, these mutations could potentially aid in the prognosis and stratification of patients. Altogether, these findings open a new avenue of investigations to better understand the diversity of mechanisms involved in cancer processes. Numerous other ion channels or their associated subunits may carry somatic mutations in cancers, deregulating their activity and the processes they govern
6
Armstrong, Victoria Janetta. "Involvement of the WNT/b-catenin signalling pathway and the estrogen receptor in bone cells' adaptive responses to mechanical strains." Thesis, Royal Veterinary College (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500028.
Анотація:
Osteoporosts is a disease characterised by low bone mass and microarchitectural deterioration. of bone tissue leading to enhanced fragility and a consequent increase in fracture risk. In western society, the lifetime risk of a fragility fracture in a 50 year old Caucasian woman is 45% and in a man is 13%. A major question in osteoporosis research is why estrogen withdrawal at the menopause is associated with a decreased effectiveness of the mechanically adaptive response which matches bones' strength to their load-bearing. In both men and women the severity of bone loss is related to levels of bio-available estrogen. The mechanism underlying this association is not known since estrogen levels do not directly control bone mass. In contrast, mechanical loading substantially influences bone mass. Previous work from this laboratory has demonstrated that bone cells' early response to loading involves the estrogen receptor (ER) alpha. Recently, Wnt/b-catenin signalling has also been implicated in the regulation of bone mass through its involvement in bone cells' response to their mechanical environment. The aim of the study in this thesis was to determine whether the Wnt/b-catenin pathway was involved in bone cells' early responses to strain and if so whether the mechanisms of this response also involved the ER. Western blot and immunocytochemical analysis showed that in cells of the ROS 17/2.8 osteoblastic cell line a short period dynamic strain in vitro or lithium chloride (LlCl) treatment, an inhibitor of glycogen synthase kinase-Jf (GSK-3(3)), increased the expression of activated catenin and stimulated nuclear accumulation within 3 hours. Strain and LiCl also induced a significant increase in TCF/LEF mediated transcriptional activity. Estrogen treatment had no influence on the level or distribution of activated b-catenin at the time points studies, or any effect on TCF/LEF mediated activation.
7
Usongo, Macalister. "Characterization of the WNT/B-catenin signaling pathway in the development of mouse ovarian surface epithelium (MOSE) and follicular ovulatory capability." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116973.
Анотація:
Wnts are secreted extracellular signaling molecules that act locally to control diverse developmental processes such as cell fate specification, cell proliferation, and cell differentiation. Three WNT signaling pathways have been identified. The best characterized is the canonical or WNT/β-catenin signaling pathway. Recently, the WNT signaling pathway has been implicated in ovarian development and differentiation. However, little is known about the expression or role of β-catenin/Tcf-signaling activity within ovarian compartments. In order to aid in the ongoing pursuit of elucidating the mechanisms that govern ovarian differentiation and development, I explored the possible roles of the canonical WNT signaling pathway in the development of the ovarian surface epithelium (OSE) and follicular ovulatory capability. To examine canonical Wnt-signaling within the ovary, I utilized the Tcf-lacZ-reporter mice. In Manuscript I, I present a detailed spatio-temporal pattern of β-catenin/Tcf mediated expression in the OSE throughout development. Cells covering the indifferent gonad at E11.5 were β-catenin/Tcf signaling (lacZ-positive). With further development and sexual differentiation, lacZ staining was lost over the testis but maintained on embryonic ovaries. This staining became dispersed and the proportion of lacZ-positive OSE cells decreased to relative constancy when female mice reached maturity. FACS analyses revealed the lacZ-positive cell population exhibits cytoprotective mechanisms as indicated by enrichment within a side population. The results indicate that the mouse OSE is heterogeneous and may contain a population of progenitor cells. In Manuscript II, I investigated the molecular connection between β-catenin and Tcf-mediated lacZ activity and assessed whether β-catenin stabilization regulates β-catenin/Tcf-mediated gene expression and OSE proliferation. β-catenin was detected on the lateral membranes of ovarian epithelium. I demonstrated that treatment of OSE cells with Wnt agonist stabilized β-catenin but failed to induce β-catenin/Tcf-lacZ expression. Furthermore, E-cadherin expression was down-regulated and the proliferative potency of OSE cells increased. Of four ovarian cancers cell lines screened, only the HEY cell line demonstrated induction of luciferase reporter expression upon canonical WNT stimulation. These studies indicate that nuclear localization of β-catenin is insufficient for β-catenin/Tcf mediated gene expression in OSE cells, suggesting GSK-3β inhibition as a result of altered WNT signaling is of major importance in the control of epithelial-mesenchymal transition and cell proliferation leading to tumorigenesis. In Manuscript III, I investigated the role of the canonical WNT signaling pathway in the development of follicular ovulatory capability. Oocytes in primordial and primary follicles did not show active WNT signaling. β-catenin/Tcf-signaling was activated at the secondary follicle stage and the proportion of β-catenin/Tcf-signaling (lacZ-positive) follicles increased with follicular maturation. In contrast, the majority (>90%) of oocytes recovered from the oviducts at estrus and following hormone stimulation were lacZ-negative. The results indicate that the canonical WNT signaling pathway is active in growing oocytes and suggest that canonical WNT signaling may be involved in the development of follicular ovulatory capability and identifies non-ovulatory follicles.Les Wnts sont des molécules de signalisation sécrétées dans l'espace extracellulaire pour réagir localement et contrôler divers processus du développement comme la spécification, la prolifération et la différenciation des cellules. Trois voies de signalisation WNTS ont été identifiées. La plus connue est la voie canonique appelée aussi la voie WNT/β-catenin. Récemment des études ont montré que la voie de signalisation WNT serait impliquée dans le développement et la différenciation ovarienne. Malgré ces études, peu est connu sur l'expression et la fonction de l'activité β-catenin/Tcf dans les différents compartiments d'ovaire. Pour clarifier les mécanismes moléculaires responsables dans le développement d'ovaire, j'ai étudié le rôle de la signalisation WNT/β-catenin durant la formation d'épithélium superficiel ovarien et dans la capacité ovulatoire des follicules. Pour visualiser l'implication de la voie canonique dans l'activation ovarienne, nous avons utilisé des souris transgéniques qui expriment la protéine β-galactosidase (lacZ) en réponse des protéines β-catenin/Tcf.Le premier article que je présente (Manuscrit I) décrit l'activation spatiotemporal de β-catenin/Tcf dans l'épithélium superficiel ovarien au cours du développement de la souris. Au jour E11.5, la gonade non-différenciée est marquée positivement pour LacZ indiquant que β-catenin/Tcf est activée. Au cours de la différenciation sexuelle de la souris, l'expression de LacZ disparait dans les testicules. Par contre, dans l'ovaire embryonnaire l'expression de LacZ est maintenue. À la maturation sexuelle de la souris femelle, l'expression de LacZ est devenue plus diffuse et la quantité de cellules qui expriment LacZ a diminué. Une analyse de cytométrie en flux a indiqué que la population de cellules positive pour LacZ démontre des mécanismes cytoprotecteurs. En conclusion, les résultats suggèrent que l'épithélium superficiel ovarien est constitué d'une population de cellules hétérogène et mais aussi de cellules progénitrices. Le deuxième article que je présente (Manuscrit II) étudie la stabilisation de β-catenin, les gènes induit par le complexe de β-catenin/Tcf et la prolifération d'épithélium superficiel ovarien. β-catenin est localisée dans les membranes latérales d'épithélium ovarien. J'ai démontré que la stimulation des cellules d'épithélium superficiel ovarien avec une agoniste Wnt stabilise β-catenin mais n'induit pas l'expression de lacZ dans les souris transgéniques. En plus, le niveau d'expression du gène E-cadherin a baissé et la prolifération des cellules d'épithélium superficiel ovarien a augmenté. Des quatre lignées cellulaires de cellules ovariennes cancéreuses qu'on a examinées, seulement la lignée HEY avait une réponse transcriptionelle à la stimulation de protéines WNT canoniques. Nos études révèlent que la localisation nucléaire de β-catenin n'est pas suffisante pour induire l'expression de ces gènes cibles dans l'épithélium superficiel ovarien. Dans les cellules cancereuses la voie de signalisation WNT est altèrée de sorte que l'inhibition de GSK-3β est augmentée et β-catenin est activée ce que contrôle la prolifération et la transition d'éptihelium à mésenchyme durant la tumorigenèse.Le troisième article que je présente (Manuscrit III) examine le rôle de la voie canonique durant le développement folliculaire. Les ovocytes des follicules primordiaux et primaires ne montraient aucune activation de la signalisation WNT. L'activation de β-catenin/Tcf était présente dans les follicules secondaires et la proportion de follicules positifs pour l'expression de lacZ a augmenté durant la maturation des follicules. Au contraire, la majorité (>90%) d'ovocytes retrouvés dans les oviductes durant l'oestrus et aprés un traitement hormonal n'exprimait pas le gène lacZ. Nos résultats indiquent que la voie de signalisation canonique de WNT est activée durant la croissance des ovocytes et peut identifier les follicules non-ovulatoires.
8
Spadoni, I. "IDENTIFICATION AND CHARACTERIZATION OF THE 'GUT VASCULAR BARRIER'." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/234155.
Анотація:
In order to protect the body from a wide range of harmful environmental agents, the intestine has developed a number of barrier mechanisms to limit the entry of potential hazards. These include the physical barrier formed by the epithelial layer and the intestinal immune system that is important to induce either tolerance against food antigens and intestinal flora or inflammatory responses against dangerous microorganisms.
It has been demonstrated that tolerance against commensal bacteria is strictly compartmentalized, in the sense that the systemic immune system is completely unprimed by these bacteria. It was demonstrated that the mLNs function as a “firewall” confining induction of tolerance to the mucosa while the systemic immune system remains ignorant to these bacteria.
However, in these studies how the bacterial flora is excluded from the entrance in the bloodstream via the intestinal blood vessels has not been analyzed.
Here, we describe a new barrier that we called the GVB (gut vascular barrier) that plays a fundamental role in controlling the spreading of molecules and bacteria to systemic sites. We found that intestinal endothelial cells (ECs) express the main components of TJs (occludin, JAM-A, CLDN-12, ZO-1 and cingulin) and AJs (VE-cadherin and junctional β-catenin), indicating the presence of a barrier that excludes bacteria from passing through the paracellular route. In addition, we observed the existence of a “gut vascular unit” (GVU) whereby ECs were associated with enteric glial cells and pericytes, whose role in the establishment of the endothelial barrier phenotype remains to be analyzed.
Moreover, we show that GVB integrity could be modified by Salmonella typhimurium infection. Indeed, upon infection ECs up-regulated the expression of PLVAP, that has been previously used as a marker of immature/damaged vascular barrier in the brain, and up-regulated caveolin-1, the major component of caveolae. These changes correlated with a higher permeability of the endothelium to small molecules and to bacteria.
One way by which S. typhimurium could modify the barrier properties of the intestinal blood vessels could be through the negative regulation of the Wnt/β-catenin signaling pathway. Indeed, we found that the activation of β-catenin was reduced upon Salmonella infection in vitro. Consistently, we found that Salmonella was incapable to modify ECs permeability and to spread systemically in mice where β-catenin was constitutively activated by genetic means only in vascular ECs. Furthermore, it appeared that the TTSS encoded by Salmonella pathogenicity island-2 was involved in the regulation of Wnt/β-catenin signaling pathway in ECs.
Finally, preliminary results show that the microbiota could induce GVB maturation and maintenance. However, the mechanisms involved in these processes as well as the bacterial species responsible for this process have not been investigated yet.
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Sammarco, Alessandro. "Study on normal and tumoral cell subpopulations and their interactions in the mammary gland cancer of humans and animals." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3425737.
Анотація:
Human breast cancer (HBC), canine (CMT), and feline mammary tumors (FMT) are extremely common and are characterized by a remarkable both inter- and intra-tumor heterogeneity. Intra-tumor heterogeneity is due to the coexistence of cancer cells that differ between each other in terms of phenotypic, genetic, behavioral characteristics, and metastatic potential. Cancer stem cells (CSCs) are thought to be responsible for such heterogeneity, resistance to therapy, and metastasis development. Several pathways are altered in CSCs, such as the oncogenic Wnt/-catenin and Hippo pathways, and CSCs are associated to the epithelial-to-mesenchymal transition (EMT) process.
The aims of this study were to i) isolate and characterized mammary CSCs; ii) investigate EMT process and Wnt/-catenin and Hippo pathways in mammary cancer of the three species; iii) establish a metastatic mouse model of breast cancer seeking for genes responsible of metastatic dissemination; iv) isolate and characterize extracellular vesicles (EVs), which is one of the main forms of intercellular communication, from canine and feline mammary tumors as well as study the role that EVs play during tumor development.
CSC-like cells were isolated from established canine and feline mammary tumor cell lines (CYPp and FMCp, respectively) and phenotypically and molecularly characterized for common CSC markers: CD44, CD24, CD133, SOX2, OCT4. Moreover, gene (qPCR) and protein (IHC and WB) expression of Wnt/-catenin and Hippo pathways-related molecules (-catenin, CCND1, YAP, TAZ, CTGF, ANKRD1) as well as protein expression (IHC) of EMT-related molecules (E-cadherin, SNAIL, TWIST, ZEB) were evaluated in a subset of human, canine, and feline mammary cancer tissues, that were also phenotypically characterized for the following markers: CK8/18, CK5/6, CK14, CD44, and vimentin. Additionally, triple negative breast cancer (TNBC) cell line MDA-MB-231 was used to establish a clinically relevant in vivo metastatic model. Finally, EVs were isolated and characterized from CYPp and FMCp and human glioblastoma-derived EVs were used to study tumor angiogenesis.
We found that CD44, CD133, SOX2, and OCT4 expression increase in CSC-like cells (mammospheres) compared to parental adherent cells, therefore they could be used as useful markers in CMTs and FMTs. Wnt/-catenin and Hippo pathways seem to be deregulated at a post-transcriptional level in HBCs, CMTs, and FMTs. Interesting similarities were confirmed between TNBCs and FMTs, as well as between ER+ HBC and CMTs. In our metastatic model, mice developed distant metastases and we found a few genes that might play a role during metastatic dissemination. Among these, caspase 3 seems to be involved in brain metastases. Additionally, EVs were isolated from CYPp and FMCp, visualized by transmissible electron microscopy, counted using nanoparticle tracking analysis, and characterized by immunogold and WB (Alix, CD63, TSG101). Finally, using a human glioblastoma cell line (GBM8) we demonstrated that EVs are directly involved in tumor angiogenesis.
Overall, this study confirms the use of dogs and cats as spontaneous models of mammary cancer development due to highly interesting biological similarities among the three species. Also, identification of EVs in CMTs and FMTs opens an interesting unexplored field in veterinary medicine.Human breast cancer (HBC), canine (CMT), and feline mammary tumors (FMT) are extremely common and are characterized by a remarkable both inter- and intra-tumor heterogeneity. Intra-tumor heterogeneity is due to the coexistence of cancer cells that differ between each other in terms of phenotypic, genetic, behavioral characteristics, and metastatic potential. Cancer stem cells (CSCs) are thought to be responsible for such heterogeneity, resistance to therapy, and metastasis development. Several pathways are altered in CSCs, such as the oncogenic Wnt/-catenin and Hippo pathways, and CSCs are associated to the epithelial-to-mesenchymal transition (EMT) process. The aims of this study were to i) isolate and characterized mammary CSCs; ii) investigate EMT process and Wnt/-catenin and Hippo pathways in mammary cancer of the three species; iii) establish a metastatic mouse model of breast cancer seeking for genes responsible of metastatic dissemination; iv) isolate and characterize extracellular vesicles (EVs), which is one of the main forms of intercellular communication, from canine and feline mammary tumors as well as study the role that EVs play during tumor development. CSC-like cells were isolated from established canine and feline mammary tumor cell lines (CYPp and FMCp, respectively) and phenotypically and molecularly characterized for common CSC markers: CD44, CD24, CD133, SOX2, OCT4. Moreover, gene (qPCR) and protein (IHC and WB) expression of Wnt/-catenin and Hippo pathways-related molecules (-catenin, CCND1, YAP, TAZ, CTGF, ANKRD1) as well as protein expression (IHC) of EMT-related molecules (E-cadherin, SNAIL, TWIST, ZEB) were evaluated in a subset of human, canine, and feline mammary cancer tissues, that were also phenotypically characterized for the following markers: CK8/18, CK5/6, CK14, CD44, and vimentin. Additionally, triple negative breast cancer (TNBC) cell line MDA-MB-231 was used to establish a clinically relevant in vivo metastatic model. Finally, EVs were isolated and characterized from CYPp and FMCp and human glioblastoma-derived EVs were used to study tumor angiogenesis. We found that CD44, CD133, SOX2, and OCT4 expression increase in CSC-like cells (mammospheres) compared to parental adherent cells, therefore they could be used as useful markers in CMTs and FMTs. Wnt/-catenin and Hippo pathways seem to be deregulated at a post-transcriptional level in HBCs, CMTs, and FMTs. Interesting similarities were confirmed between TNBCs and FMTs, as well as between ER+ HBC and CMTs. In our metastatic model, mice developed distant metastases and we found a few genes that might play a role during metastatic dissemination. Among these, caspase 3 seems to be involved in brain metastases. Additionally, EVs were isolated from CYPp and FMCp, visualized by transmissible electron microscopy, counted using nanoparticle tracking analysis, and characterized by immunogold and WB (Alix, CD63, TSG101). Finally, using a human glioblastoma cell line (GBM8) we demonstrated that EVs are directly involved in tumor angiogenesis. Overall, this study confirms the use of dogs and cats as spontaneous models of mammary cancer development due to highly interesting biological similarities among the three species. Also, identification of EVs in CMTs and FMTs opens an interesting unexplored field in veterinary medicine.
10
Lima, Ana Paula Calheiros de. "Efeitos in vitro de soro de pacientes com nefrite lúpica ativa em células de linhagem osteoblástica humana hFOB 1.19." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-20032019-084434/.
Анотація:
INTRODUÇÃO: Perda óssea é um achado comum em pacientes com Nefrite Lúpica (NL), mesmo naqueles com diagnóstico recente. Algumas evidências indicam um aumento na osteoclastogênese como um dos distúrbios principais no processo de remodelamento ósseo. O objetivo deste estudo foi investigar algumas vias de sinalização (RANKL/OPG, Wnt/Beta-catenin and Th17/IL-17) possivelmente envolvidas na osteoclastogênese anormal detectada em mulheres jovens ao diagnóstico de nefrite lúpica ativa, assim como avaliar a ação da vitamina D (VitD) nesse cenário e sua correlação com fatores inflamatórios. MÉTODOS: Realizamos culturas com a linhagem de células osteoblásticas humanas hFOB 1.19 (ATCC) e as dividimos em um grupo suplementado com soro de pacientes lúpicas (NL) (n=15) e em um grupo com soro de controles saudáveis (CS) (n=15) em vez de soro fetal bovino (SFB). Em seguida, adicionamos 1,25-dihidroxivitamina D3 (1,25(OH)2D3) em dois subgrupos nas concentrações 10-9M e 10-7M, resultando em 6 grupos: CS, CS+vitD 10-9M, CS+vitD 10-7M, NL, NL+vitD 10-9M, NL+vitD 10-7M). Após 48h da adição de 1,25(OH)2D3 ao meio de cultura, células hFOB foram tripsinizadas e separado o lisato celular de cada grupo. Ensaios de citometria de fluxo e multiplex foram realizados para quantificação das seguintes proteínas do lisato cellular: CD166, CD54, fosfatase alcalina, RANKL, OPG, CD14, TLR4, NF-KappaB, SOST, DKK-1, Beta-catenina, IL-1-beta, IL-2, IL-6, TNF-alfa, IL-17A, IL-17F, IL-21 and IL-22. RT-PCR foi empregado para quantificação de mRNA dos genes RANKL, SOST, OPG e Beta-catenina. RESULTADOS: Pacientes com NL evidenciaram maiores níveis séricos de DKK-1 (2802,04 ± 1380,06 x 696,30 ± 421,22pg/ml, p < 0,001), OPG (560,12 ± 333,56 x 340,24 ± 102,08pg/ml, p=0,0212), TNF-alfa (9,63 ± 14,49 x 1,27 ± 0,35pg/ml, p=0,0337), IL-6 (15,58±39,08 x 8,02±3,49, p= 0,0053) and IL-2 (3,36 ± 3,06 x 1,54 ± 0,9pg/ml, p=0,0353) do que CS. Após exposição ao meio enriquecido com soro de pacientes com NL, células hFOB 1.19 apresentaram maior nível de mRNA de RANKL (p=0,045)) e menor nível de proteína OPG (178,81 ± 66,40 x 298,76 ± 114,94pg/mg, p=0,0016). Suplementação com 1,25(OH)2D3 aumentou a diferença da expressão das proteínas DKK-1 (673,03 ± 171,93 x 456,69 ± 234,53pg/mg, p=0,0215), IL-6 (0,80 ± 0,25pg/mg x 0,66 ± 0,18, p=0,0417) and IL-2 (4,97 ± 2,2 x 3,90 ± 1,66pg/mg, p=0,042) entre hFOB NL comparados com hFOB CS, enquanto diminuiu o nível de mRNA de Beta-catenina em células do grupo NL. DISCUSSÃO: Dentro das limitações deste estudo, os resultados sugerem que os maiores níveis séricos de citocinas pró-inflamatórias, como TNF-alfa, IL-6 e talvez IL-2, detectadas em pacientes com NL pode ter induzido a maior expressão osteoblástica de RANKL, representada pelo maior nível de mRNA RANKL em células do grupo NL, e suprimido OPG, conforme a diminuição observada na quantificação proteica de OPG nos lisatos celulares, o que pode ter contribuído para a aumentada osteoclastogênese evidenciada pela biópsia óssea dessas pacientes. A adição de 1,25(OH)2D3 não preveniu os efeitos inflamatórios do soro de pacientes com NL ativa em células hFOB 1.19 neste estudoINTRODUCTION: Bone loss is a common finding in Lupus Nephritis (LN) patients even in those recently diagnosed. Some evidences indicate an increased osteoclastogenesis as the main disturb of the bone remodeling process. The aim of this study was to investigate some pathways (RANK-L/OPG, Wnt/?-catenin and Th17/IL-17) possibly involved in the abnormal osteoclastogenesis detected in women at the diagnosis of proliferative LN as well as evaluating the action of vitamin D (vitD) in this scenario and their correlation with inflammatory factors. METHODS: We cultured the human osteoblastic cell line hFOB 1.19 (ATCC), and divided cultures into those supplemented with serum from healthy controls (HC) (n=15) and LN patients (n=15) instead of fetal bovine serum (FBS). Then 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was added in two subgroups at the concentrations of 10-9M e 10-7M while vitD was absent in one subgroup in both HC and LN cultures (HC, HC+vitD 10-9M, HC+vitD 10-7M, LN, LN+vitD 10-9M, LN+vitD 10-7M) . After 48h of vitD addition, hFOB cultures were trypsinized. Flow cytometry and multiplex assays were performed to test CD166, CD54, alkaline phosphatase, RANKL, OPG, CD14, TLR4, NF-KappaB, SOST, DKK-1, ?-catenin, IL-1Beta, IL-2, IL-6, TNF-alfa, IL-17A, IL-17F, IL-21 and IL-22 concentrations in the cell lysates. Polymerase reaction chain (RT-PCR) assays analyzed the expression of RANKL, SOST, OPG and Beta-catenin mRNA. RESULTS: LN patients showed higher serum levels of DKK-1 (2802.04 ± 1380.06 x 696.3 ± 421.22pg/ml, p < 0.001), OPG (560.12 ± 333.56 x 340.24 ± 102.08pg/ml, p=0.0212), TNF-alfa (9.63 ± 14.49 x 1.27 ± 0.35pg/ml, p=0.0337), IL-6 (15.58±39.08 x 8.02±3.49, 0.0053) and IL-2 (3.36 ± 3.06 x 1.54 ± 0.9pg/ml, p=0.0353) than HCs. After exposure to medium enriched with LN serum, osteoblasts expressed higher RANKL mRNA (fold change 1.573, p=0.045) and lower OPG protein (178.81 ± 66.40 x 298.76 ± 114.94pg/mg, p=0.0016). 1,25(OH)2D3 supplementation increased the difference between LN and HC expression of DKK-1 (673.03 ± 171.93 x 456.69 ± 234.53pg/mg, p=0.0215), IL-6 (0.80 ± 0.25pg/mg x 0.66 ± 0.18, p=0.0417) and IL-2 (4.97 ± 2.2 x 3.90 ± 1,66pg/mg, p=0.042) proteins and diminished Beta-catenin mRNA in LN cells. DISCUSSION: Within the limitations of this study, the results suggest that the higher serum levels of proinflammatory cytokines, such as TNF-alfa, IL-6 and perhaps IL-2, detected in LN patients would possibly have induced RANKL genes, as demonstrated by an enhanced RANKL mRNA expression in LN osteoblasts, and suppressed OPG protein in cell lysates, which would have contributed to the increased osteoclastogenesis detected in bone biopsies of women with new onset of LN. 1,25(OH)2D3 addition to osteoblast cultures did not prevent the effects of inflammatory LN serum in vitro
Частини книг з теми "Wnt/b-Catenin pathway":
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Thakkar, Roshni D., Ruimin Wang, Gangadhara R. Sareddy, Ratna K. Vadlamudi, and Darrell W. Brann. "Estrogen Neuroprotection and Anti-Inflammation Actions in the Hippocampus." In Estrogens and Memory, 401–15. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780190645908.003.0024.
Анотація:
The steroid hormone 17β-estradiol (E2) is neuroprotective in several neurodegenerative conditions, including cerebral ischemia, traumatic brain injury, and Alzheimer’s disease (AD). This chapter focuses on the evidence supporting a neuroprotective role of E2 in the hippocampus in cerebral ischemia and AD and reviews various mechanisms thought to underlie E2-induced neuroprotection. Specifically, the chapter discusses the mechanistic role of (a) the various estrogen receptor subtypes, (b) genomic versus nongenomic signaling, (c) regulation of the prosurvival Wnt/β−catenin pathway, and (d) anti-inflammatory effects of E2 in the hippocampus. Finally, we also discuss the role of a novel estrogen receptor co-activator protein, proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) in mediating E2 genomic and non-genomic signaling, as well as the neuroprotective and cognitive-enhancing effects of E2 in the hippocampus.
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Nazir, Aqsa, Muhammad Aqib, and Muhammad Usman. "Liver Cancer-Genesis, Progression and Metastasis." In Liver Cancer - Genesis, Progression and Metastasis [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106020.
Анотація:
Liver cancer or hepatocellular carcinoma (HCC) is a malignant tumor in liver tissue and worldwide it is fourth leading death cause among all cancers. The most common causes of liver cancer are hepatitis B or C virus infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), smoking and obesity. The development and metastasis of liver cancer is a multistage and branched process of morphological and genetic traits. Various corresponding signaling pathways such as Yes-Associated Protein-Hippo Pathway (YAP-HIPPO), Wnt/β-catenin and inflammation by interleukin-6 (IL-6), tumor necrosis factor (TNF), nuclear factor-Κb (NF-κB), biological pathways including epithelial–mesenchymal transition (EMT), tumor microenvironment, tumor-stromal interactions and cancer stem cells and gut microbial dysbiosis are allied to both origination, progression and metastasis of liver cancer. Numerous therapeutic approaches are classified into different categories such as pharmacological therapy including sorafenib, lenvatinib and ramuciruma, surgery of HCC patients includes surgical resection, adjuvant therapy after surgical resection and liver transplantation. Loco-regional ablative therapy includes cryotherapy, ethanol injection and radiofrequency ablation, cytotoxic chemotherapy, natural compounds such as piperine, as curcumin and oleocanthal, oncolytic virus therapy, immunotherapies and nanotechnology.
Тези доповідей конференцій з теми "Wnt/b-Catenin pathway":
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Vaira, Sergio, R. Ellen Friday, Keith Scott, Steven Conrad, Glenn Mills, and Francesco Turturro. "Abstract 3141: Hyperglycemia modulates the Wnt /b-catenin signaling pathway in breast cancer." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3141.
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Kanwar, Shailender S., Yingjie Yu, Jyoti Nautiyal, Bhaumik Patel, and Adhip P. N. Majumdar. "Abstract 4254: The Wnt/ B-catenin pathway regulates colon cancer stem cells proliferation." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4254.
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Shomali, Maysoun, Patrick McGlynn, Dmitri Wiederchain, Paul August, Francisco Adrian, Carlos Garcia-Echeverria, Joachim Theilhaber, and Monsif Bouaboula. "Abstract B158: Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-b158.
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Khan, Shahanshah, and Hasan Zaki. "Abstract 2732: NLRP12 suppresses colorectal cancer progression and invasion via downregulation of the Wnt/b-catenin pathway." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-2732.
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Barrueco, R. Rodriguez, EA Nekritz, J. Yu, D. Llobet Navas, and JM Silva. "PO-085 MiR-424(322)/503 regulates Wnt/b-catenin pathway and resistance to treatment in breast cancer." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.128.
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Ro, Eun Ji, Jeong-Ha Hwang, Yong-Hee Cho, and Kang-Yell Choi. "Abstract 4181: Simultaneous inhibition of the Wnt/B-catenin and Ras pathways by KY1022 effectively suppresses tumor initiation and progression of colorectal cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-4181.
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Radhakrishnan, Sridhar, Lavanya Reddivari, and Jairam Vanamala. "Abstract 1882: Resveratrol and grape seed extract synergistically elevate human colon cancer cell apoptosis and suppress cell proliferation via upregulation of p53 and suppression of Wnt/b-catenin signaling pathways." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1882.
Звіти організацій з теми "Wnt/b-Catenin pathway":
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Williams, Bart O. Analysis of the Role of the Wnt/B-Catenin Pathway in Prostate Development and Tumorigenesis. Fort Belvoir, VA: Defense Technical Information Center, April 2005. http://dx.doi.org/10.21236/ada437150.