Overexpression of the LEF-1 and TCF4 Transcription Factors in B-CLL: Further Evidence for a Role of the Wnt Signaling Pathway in B-CLL Biology and Leukemogenesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 544-544 ◽  
Author(s):  
Albert Gutierrez ◽  
Renee Tschumper ◽  
Jeanette Eckel-Passow ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Wnt Signaling ◽  
B Cell ◽  
Wnt Pathway ◽  
Perfect Match ◽  
Wnt Signaling Pathway ◽  
Healthy Adults ◽  
P Value ◽  
Expression Levels

Abstract Background: B-chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world but its pathogenesis remains largely unknown. Our strategy was to employ gene expression profiling (GEP) to discover genetic differences between CLL B cells and blood B cells from healthy adults. Previously, we and others identified the transcription factor (TF) lymphocyte enhancer factor-1 (LEF-1) as one of several genes significantly over expressed in CLL B cells suggesting a role for the oncogenic Wnt signaling pathway. LEF-1 acts as a central mediator of Wnt signaling and is crucial for the proliferation and survival of pro-B cells during development. Recently, deregulated LEF-1 activation has been directly linked with leukemogenesis. Methodology: The goals of our study were to: validate LEF-1 over expression in CLL B cells in a new cohort of B-CLL patients and normal controls; study CLL B cell LEF-1 protein expression; and investigate CLL B cell expression levels of other genes linked to Wnt signaling. To accomplish these goals, Affymetrix U133 GEP was performed on B cells from 41 B-CLL patients who were enrolled on a trial of combined pentostatin, cyclophosphamide, and rituximab and 11 healthy adults over age 60. Only the perfect match data were utilized for all analyses; the non-background corrected perfect match data were normalized using an intensity-dependent procedure and analyses were done using the base-2 logarithm transformed normalized values. Results: GEP analysis confirmed CLL B cells expressed the LEF-1 gene at ~28-fold higher levels than normal B cells (p<.0001). These results were validated by quantitative PCR and all CLL B cells studied expressed LEF-1 mRNA. By contrast, LEF-1 mRNA expression was undetectable in blood B cells from healthy adults both before and after in vitro mitogenic stimulation suggesting aberrant LEF-1 expression in B-CLL. Moreover, LEF-1 protein was readily detected by flow cytometry in CLL B cell samples and all clonal B cells expressed a uniform level of LEF-1. Full length LEF-1 is more oncogenic and predominates in certain cancers, while a dominant negative short isoform is found at greater levels in normal lymphocytes. Of interest, western blot analysis revealed that CLL B cells predominantly expressed full length oncogenic LEF-1. Ongoing studies are focused on silencing LEF-1 expression to determine LEF-1 target genes. In this regard, IGFBP4 (IGF binding protein 4) mRNA expression levels are 19-fold higher in CLL vs control B cells (p<0.0001) and the IGFBP4 protein was recently shown to antagonize Wnt signaling. A scan of the IGFBP4 promoter element identified 3 possible LEF/TCF consensus sites. Thus, there is a possible negative feedback loop in CLL, with activation of the Wnt pathway leading to expression of a negative Wnt regulator. Finally, we queried the GEP data for evidence of differential expression of 63 other Wnt-related genes. Surprisingly, in addition to LEF1, only five genes met our selection threshold of ≥1.5 fold change in expression between CLL and control B cells and p value <.001. These genes were CSNK1D (casein kinase, delta 1; 1.9-fold higher in control vs CLL; p<0.0001); CCND2 (cyclin D2; 2.4-fold higher in CLL vs control; p<0.0001); JUN (3.2-fold higher in control vs CLL); WNT3 (6.4-fold higher in CLL vs control; p<0.0001); and TCF4 (transcription factor 4, alias ITF-2; 4-fold higher in CLL vs control; p<0.0001). To our knowledge, we are the first to report that the TCF4 (ITF-2) gene is over expressed in B-CLL. This TF is of great interest because it is a known downstream target of the Wnt/TCF pathway, is activated in human cancers with b-catenin defects, and it promotes neoplastic transformation. Using Spearman correlation analysis to explore the relationship between LEF1, TCF4, and WNT3 expression levels, we observed a marginal correlation between WNT3 expression and LEF1 (ρ=0.31; p value=0.05) and TCF4 (ρ=0.29; p value=0.07). Summary: These studies add new support for a critical role of the Wnt pathway in CLL. The WNT3 results are consistent with the literature; however, it is notable that we failed to corroborate other reports demonstrating that other Wnts and Fzd genes are differentially expressed in CLL B cells vs normal B cells. It is striking that CLL B cells over express two TFs in this pathway that have been linked with neoplastic transformation. Ongoing studies are aimed at further elucidating the roles of these genes in B-CLL.

Different Activation of WNT Signaling Pathway in B-Cell and T-Cell Acute Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4317-4317
Author(s):  
Muge Sayitoglu ◽  
Ozden Hatirnaz ◽  
Yucel Erbilgin ◽  
Fatmahan Atalar ◽  
Ugur Ozbek
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Wnt Signaling ◽  
B Cell ◽  
Signaling Pathway ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Wnt Signaling Pathway ◽  
Hematopoietic Cells ◽  
Expression Levels

Abstract WNT signaling pathway proteins function as hematopoietic growth factors and regulate proliferation in normal T-cell and B-cell development. Recent experimental evidence demonstrated that oncogenic transformation in leukemias of both lymphoid and myeloid lineages is dependent on WNT signaling. Not much is known about activation of WNT signaling pathway, its ligands and receptors in hematopoiesis and leukemia pathogenesis. To define its role in leukemia, we aimed to determine mRNA levels of the critical members of WNT pathway (WNT5A, WNT10B, FZ5, β catenin, APC, TCF-1 and LEF-1) by using quantitative real time PCR in acute lymphoblastic leukemia (ALL) patients (T-cell n=42, B-cell n=46 and pre B-cell n=30) and normal hematopoietic cells (bone marrow n=6, peripheral blood n=10, and CD19+ cells from peripheral blood). These genes expressed varying levels in B-cells, preB-cells and T-cells. In the B-cell leukemia patients, WNT5A was expressed notably (OR=58.05 CI 95% 1.63–1219.55, p>0,001). WNT5A directs Ca++ dependent signaling by PKC and a G protein dependent manner which is an alternative pathway for beta-catenin mediated signaling. Also LEF-1 levels were higher in B-ALL patients and APC expression was down regulated when compared to normal tissue (OR=18.81 CI 95% 0.34–5703, p>0.001 and OR=0.212 CI 95% 0.006–8.816, p=0.001, respectively). It is known that LEF-1 blocks APC mediated β catenin nuclear export and activates transcription of various transforming genes, including cyclin, D1, c-myc, MMP7, and LEF-1 itself. WNT5A or WNT10B proteins were not found to be up regulated in preB-ALL whereas APC and LEF-1 gene expressions were increased compared to normal hematopoietic cells (OR=32.97 CI 95% 0.27–1281, 38 p>0.001 and OR=5.57 CI 95% 0.28–89.51, p=0.01, respectively). We found increased TCF-1 expression (7.4 fold) without any β catenin accumulation in T-ALL patients. It is known that TCF-1 in absence of β catenin functions as a tumor suppressor gene. WNT5A, APC and LEF-1 gene expression levels were also different between T-cell, B-cell and preB cell ALL cases. WNT5A expression had the highest levels in B-ALL compared to T-ALL cases, whereas the highest APC expression levels were observed in preB and T-ALL patients. Also LEF-1 expression levels were significantly different between preB and T-cell ALL patients. Taken together these results indicate that WNT signaling genes have abnormal expression and are active in acute lymphoblastic leukemia. This data suggests different WNT activation mechanisms exist in the leukemic transformation in different hematopoietic cells.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals WNT and β-Catenin in Cancer: Genes and Therapy

2020 ◽  
Vol 4 (1) ◽  
pp. 177-196 ◽  
Author(s):  
Rene Jackstadt ◽  
Michael Charles Hodder ◽  
Owen James Sansom
Keyword(s):  
Tumor Microenvironment ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Pathway ◽  
Therapeutic Strategy ◽  
Wnt Signaling Pathway ◽  
Therapeutic Strategies ◽  
Tissue Homeostasis ◽  
Cancer Genes

The WNT pathway is a pleiotropic signaling pathway that controls developmental processes, tissue homeostasis, and cancer. The WNT pathway is commonly mutated in many cancers, leading to widespread research into the role of WNT signaling in carcinogenesis. Understanding which cancers are reliant upon WNT activation and which components of the WNT signaling pathway are mutated is paramount to advancing therapeutic strategies. In addition, building holistic insights into the role of WNT signaling in not only tumor cells but also the tumor microenvironment is a vital area of research and may be a promising therapeutic strategy in multiple immunologically inert cancers. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Here, we review how the WNT pathway is activated in multiple cancers and discuss current strategies to target aberrant WNT signaling.

scholarly journals Evaluating the Expression of Wnt Pathway Related Genes in Mouse Vitrified Preantral Follicles: An Experimental Study

2021 ◽  
Author(s):  
Shahla Babaki ◽  
Saeed Zavareh ◽  
Parisa Farrokh ◽  
Meysam Nasiri
Keyword(s):  
Wnt Pathway ◽  
Ovarian Follicle ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Culture Period ◽  
Control Group ◽  
P Value ◽  
Mrna Levels ◽  
Preantral Follicles ◽  
Expression Levels

Background: Wnt signaling pathway plays critical role in ovarian follicle development. Therefore, the aim of this study was to evaluate the effects of vitrification on the expression of Wnt pathway related genes in preantral follicles (PFs). Methods: Isolated PFs (n=982) of 14-16 day old female mice (n=45: 15 for each group) were divided into fresh (n=265), toxicity (n=272), and vitrified (n=265). The mRNA levels of Wnt2, Wnt4, Lrp5 and Fzd3 were evaluated by real-time PCR on the 2nd and 6th days of culture period. One-way ANOVA was conducted to analyze the data. Post hoc Tukey's HSD was used for multiple comparisons and p-value less than 0.05 was considered statistically significant. Results: The developmental parameters of fresh PFs were significantly higher than those of vitrified (p<0.001). There were no differences between fresh and vitrified PFs on the 2nd day of culture (p<0.001). Wnt4 expression levels decreased significantly in vitrified groups compared with fresh ones (p<0.001). Fzd3 and Lrp expression levels increased significantly in vitrified groups compared with those in the fresh group on the 2nd day (p<0.001). On the 6th day of culture period, the expression levels of Wnt2 and Fzd3 increased significantly in vitrified group compared to those of fresh group (p<0.001). Moreover, the expression levels of Wnt4 and Lrp increased significantly in toxicity groups compared to those of the control group (p<0.001). Conclusion: Vitrification increase the expression levels of Wnt2, Lrp and Fzd3 genes of PFs during in vitro culture

scholarly journals LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 2975-2983 ◽  
Author(s):  
Albert Gutierrez ◽  
Renee C. Tschumper ◽  
Xiaosheng Wu ◽  
Tait D. Shanafelt ◽  
Jeanette Eckel-Passow ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Wnt Signaling ◽  
B Cell ◽  
Signaling Pathway ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Lymphocytic Leukemia ◽  
Luciferase Reporter ◽  
Aberrant Expression

Abstract The canonical Wnt signaling pathway is pathogenic in a variety of cancers. We previously identified aberrant expression of the Wnt pathway transcription factor and target gene lymphoid enhancer binding factor-1 (LEF1) in chronic lymphocytic leukemia (CLL). This suggested that the Wnt signaling pathway has a role in the biology of CLL. In this study, we performed a Wnt pathway analysis using gene expression profiling and identified aberrant regulation of Wnt pathway target genes, ligands, and signaling members in CLL cells. Furthermore, we identified aberrant protein expression of LEF-1 specifically in CLL but not in normal mature B-cell subsets or after B-cell activation. Using the T cell–specific transcription factor/LEF (TCF/LEF) dual luciferase reporter assay, we demonstrated constitutive Wnt pathway activation in CLL, although the pathway was inactive in normal peripheral B cells. Importantly, LEF-1 knockdown decreased CLL B-cell survival. We also identified LEF-1 expression in CD19+/CD5+ cells obtained from patients with monoclonal B-cell lymphocytosis, suggesting a role for LEF-1 early in CLL leukemogenesis. This study has identified the constitutive activation and prosurvival function of LEF-1 and the Wnt pathway in CLL and uncovered a possible role for these factors in the preleukemic state of monoclonal B-cell lymphocytosis.

scholarly journals Islet Specific Wnt Activation in Human Type II Diabetes

2008 ◽  
Vol 2008 ◽  
pp. 1-13 ◽  
Author(s):  
Seung-Hee Lee ◽  
Carla Demeterco ◽  
Ifat Geron ◽  
Annelie Abrahamsson ◽  
Fred Levine ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Type Ii Diabetes ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Pancreatic Tissue ◽  
Diabetic Patients ◽  
Type Ii ◽  
Diabetes Therapy ◽  
Normal Individuals

The Wnt pathway effector gene TCF7L2 has been linked to type II diabetes, making it important to study the role of Wnt signaling in diabetes pathogenesis. We examined the expression of multiple Wnt pathway components in pancreases from normal individuals and type II diabetic individuals. Multiple members of the Wnt signaling pathway, including TCF7L2, Wnt2b,β-catenin, pGSK3β, TCF3, cyclinD1, and c-myc, were undetectable or expressed at low levels in islets from nondiabetic individuals, but were also upregulated specifically in islets of type II diabetic patients. Culture of pancreatic tissue and islet isolation led to Wnt activation that was reversed by the Wnt antagonist sFRP, demonstrating that Wnt activation in that setting was due to soluble Wnt factors. These data support a model in which the Wnt pathway plays a dynamic role in the pathogenesis of type II diabetes and suggest manipulation of Wnt signaling as a new approach toβ-cell-directed diabetes therapy.

scholarly journals BCL6 Enables RAS-Mediated Pre-B Cell Transformation in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3570-3570
Author(s):  
Christian Hurtz ◽  
Huimin Geng ◽  
Gang Xiao ◽  
Mignon L. Loh ◽  
B. Hilda Ye ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Erk Pathway ◽  
Childhood All ◽  
Expression Levels ◽  
Bcl6 Expression

Abstract Background & Hypothesis: The transcriptional repressor and proto-oncogene BCL6 has recently been identified as a therapeutic target in subtypes of diffuse large B cell lymphoma (DLBCL) and as mediator of a novel for of drug-resistance in Ph+ acute lymphoblastic leukemia (ALL; Duy et al., Nature 2011). A previous senescence rescue screen identified BCL6 as a key factor that bypassed senescence and thereby enabled RAS-mediated transformation of mouse embryonic fibroblasts (Shvarts et al., Genes Dev 2002). Since ~50% of pediatric cases of ALL carry genetic lesions that result in hyperactivation of the Ras-Erk pathway (Zhang et al., Blood 2012), we tested the role of Bcl6 in this large subgroup of childhood leukemia. Results: Mutations leading to hyperactivation of the Ras-Erk pathway are found in about 50% of childhood ALL cases (Zhang et al., 2012). Among 26 ALL xenografts, we found 9 cases with constitutive Erk-T202/Y204 phosphorylation, which was paralleled by elevated expression levels of BCL6 in these cases. Studying mouse pre-B cells that were engineered with a doxycycline-inducible NRASG12D mutant, we were able to directly measure the consequences of acute activation of the Ras-Erk pathway on BCL6 expression levels. First we incubated the cells with doxycycline to induce the expression of NRASG12D and then harvested the cells at different times point to test for BCL6 protein and mRNA expression levels. Interestingly, after 24h NRASG12D-TetO pre-B cells cells showed strong upregulation of BCL6 at the mRNA (352-fold) and protein level (15-fold). Upregulation of BCL6 in response to NRASG12D-activation was sensitive to treatment with the MEK kinase inhibitor PD325901, upstream of Erk, suggesting that BCL6 expression is a consequence of Erk activation in pre-B cells. Likewise, treatment of patient-derived pre-B ALL cells with the MEK inhibitor PD325901 reversed BCL6 expression, as demonstrated by quantitative RT-PCR and Western blot. From one patient, a diagnostic (KRAS wildtype) and a relapse sample with an acquired KRASG12V mutation were available. Consistent with specific expression of BCL6 in the KRASG12V relapse ALL sample, only KRASG12V ALL cells from the relapse but not wildtype cells from the diagnostic sample were sensitive to a retro inversoBCL6 peptide inhibitor (RI-BPI; Cerchietti et al., 2009). Development of a genetic mouse model for inducible ablation of Bcl6. These findings suggest an important role of BCL6 as a cofactor of RAS-driven pre-B cell transformation, comparable to previous findings in mouse embryonic fibroblasts. To directly test a mechanistic role of Bcl6 in RAS-mediated pre-B cell transformation, we generated a novel mouse model for inducible Cre-mediated deletion of Bcl6 exons 5-10, flanked by loxP sites. For lineage-specific deletion in vivo, we crossed these mice with an Mb1-Cre deleter strain, in which Bcl6 was deleted in pro-B cells, resulting in a differentiation block at the pre-B cell stage. Interestingly, Mb1-Cre x Bcl6fl/fl B cell lineage cells could be transduced with NRASG12D retroviral vectors, however these cells did not give rise to leukemia when injected into congenic recipients, whereas NRASG12D-transduced Bcl6fl/fl pro-B cells that retained Bcl6 function developed B cell lineage leukemia in all transplant recipients. In a second experiment, we transformed Bcl6fl/fl pro-B cells with NRASG12D and induced Cre with a second, tamoxifen-inducible vector in full-blown leukemia cells. Acute ablation of Bcl6 in NRASG12D ALL cells completely abrogated the ability of NRASG12DALL cells to form colonies in methylcellulose and resulted in rapid apoptosis and depletion from the cell culture. We conclude that BCL6 is not only required for the initiation of RAS-driven ALL in vivo but also for the maintenance of fully established RAS-driven leukemia. Conclusion: These findings provide genetic evidence for BCL6 function as a critical cofactor of RAS-mediated transformation in childhood ALL. Inhibition of BCL6 in RAS-driven ALL may be useful to prevent leukemia relapse after initial remission (Bcl6-dependent leukemia-initiation) and also to achieve profound remission by combining conventional cytotoxic therapies with BCL6 inhibition (e.g. RI-BPI). Disclosures No relevant conflicts of interest to declare.

scholarly journals A Review of the Role of Wnt in Cancer Immunomodulation

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 771 ◽  
Author(s):  
Whitney N. Goldsberry ◽  
Angelina Londoño ◽  
Troy D. Randall ◽  
Lyse A. Norian ◽  
Rebecca C. Arend
Keyword(s):  
Tumor Microenvironment ◽  
Wnt Signaling ◽  
Immune Suppression ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Cancer Therapeutics ◽  
Multiple Cancer ◽  
Pathway Activation ◽  
Tumor Types

Alterations in the Wnt signaling pathway are associated with the advancement of cancers; however, the exact mechanisms responsible remain largely unknown. It has recently been established that heightened intratumoral Wnt signaling correlates with tumor immunomodulation and immune suppression, which likely contribute to the decreased efficacy of multiple cancer therapeutics. Here, we review available literature pertaining to connections between Wnt pathway activation in the tumor microenvironment and local immunomodulation. We focus specifically on preclinical and clinical data supporting the hypothesis that strategies targeting Wnt signaling could act as adjuncts for cancer therapy, either in combination with chemotherapy or immunotherapy, in a variety of tumor types.

scholarly journals Mechanism of Wnt Pathway on Cartilage Differentiation of Adipose-Derived Stem cells

2020 ◽  
Author(s):  
Wanwu Dai ◽  
Bo Zhang ◽  
Zuquan Huang ◽  
Guili Sun ◽  
Yejing Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Chondrogenic Differentiation ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Adipose Derived Stem Cells ◽  
Expression Levels ◽  
Cartilage Differentiation ◽  
Late Stages

Abstract Background: Adipose-derived stem cells ( ADSCs ) therapy is considered as a promising alternative to treat osteoarthritis (OA).Considerable evidence has shown that the Wnt signaling pathway is involved in chondrogenic differentiation in various stem cells.In the present study, we explored in detail the mechanism of of Wnt signaling pathway in the regulation of adipose-derived stem cell chondrogenic differentiation.Methohs: Adipose-derived stem cells were extracted from Sprague-Dawley groin area, isolated, cultured and verified. Then LiCl and DKK-1 used to induce ADSCs cartilage differentiation to detect indicators of cartilage at different stages, such as collagen type II (Collagen2a), aggrecan (Aggrecan) and Wnt pathway key proteins Sox9, β-catenin, Glycogen synthase kinase-3β (GSK-3β) expression.Subsequently, lentivirus was used as the vector, the full-length Sox9 gene was transfected into ADSCs and the expression levels of relevant indicators were detected again after stable expression.Results: In the process of inducing differentiation, the Wnt pathway promoted the rapid proliferation of ADSCs in the early, middle and late stages, and up-regulates Sox9 expression.Cartilage indicators Collagen 2a and Aggrecan expression levels were not significantly increased in the early stage, but significantly increased in the middle and late stages (P <0.05). At the later stage, however, the Wnt pathway down-regulated Sox9 expression, weakened the mature cartilage phenotype, promoted cartilage hypertrophy and early cartilage ossification. Finally, the overexpression of Sox9 feedback inhibits the Wnt pathway activity, down-regulates β-catenin expression, maintains cartilage phenotype, delays cartilage hypertrophy and early osteogenesis.Conclusion:The Wnt pathway regulates chondrogenic differentiation of ADSCs by regulating Sox9, but its regulatory mechanism is significantly different at different stages of induced differentiation.

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