Interaction between Wnt/β-catenin signaling pathway and EMT pathway mediates the mechanism of sunitinib resistance in renal cell carcinoma
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ABSTRACT:
SUBMITTER: Cai F
PROVIDER: S-EPMC10840195 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:In this study, we investigated the role of SERPINH1 in gastric cancer (GC) progression. GC patient tissues show significantly higher SERPINH1 mRNA and protein levels than normal gastric mucosal tissues. GC patients with high SERPINH1 expression are associated with lymph node metastasis and poor prognosis. SERPINH1 mRNA levels negatively correlate with E-cadherin mRNA levels and positively correlate with levels of N-cadherin, MMP2, and MMP9 mRNA levels. This suggests SERPINH1 regulates epithelial to mesenchymal transition (EMT). SERPINH1 expression was significantly higher in the HGC-27, AGS, MGC-803, and SGC-7901 GC cell lines than in the GES-1 normal gastric mucosal cell line. In SERPINH1-silenced SGC-7901 cells, survival, colony formation, migration and invasion were all reduced, whereas they were all enhanced in SERPINH1-overexpressing MGC-803 cells. Levels of WNT/β-catenin signaling pathway proteins, including β-catenin, Wnt2, GSK-3β, p-GSK-3β, NF-κB P65, Snail1, Slug and TWIST, were all reduced in SERPINH1-silenced SGC-7901 cells, and increased in the SERPINH1-overexpressing MGC-803 cells. Inhibition of SERPINH1 protein using Co1003 significantly decreased survival, invasion, and migration of GC cells. SERPINH1 thus appears to regulate EMT and GC progression via the Wnt/β-catenin pathway, making SERPINH1 a potential prognostic biomarker and therapeutic target in GC patients.
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Project description:As renal fibrosis significantly contributes to various kinds of chronic kidney diseases, this study aimed to investigate the renal protective effects of Qingshen Buyang Formula against renal fibrosis on 5/6 nephrectomized rats, and its underlying mechanisms were explored. A total of 24 male Sprague-Dawley rats were randomly divided into sham operation group (Sham group), 5/6 nephrectomy group (5/6Nx group), and Qingshen Buyang Formula treatment group (QBF group). The intervention was intragastric administration for 12 weeks. In the end, the blood samples were collected to test renal functional parameters, urine proteins were measured, and the left kidneys were removed for histological studies, as well as mRNA and protein expression analysis. The results showed that Qingshen Buyang Formula significantly decreased BUN, Scr, and proteinuria in 5/6Nx rats. Meanwhile, it ameliorated the kidney injury and fibrosis, exemplified by the depressed expression of collagen I and fibronectin (FN), which are the main components of ECM. Furthermore, the process of EMT inhibited the Wnt/β-catenin signaling pathway related genes, such as Wnt4, TCF4, β-catenin, and p-GSK3β. Collectively, the Qingshen Buyang Formula can improve renal function and attenuate renal fibrosis, and its underlying mechanisms may be related with inhibiting EMT and Wnt/β-catenin signaling pathway.
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Project description:BackgroundOvarian cancer (OC) is recognized as one of the deadliest forms of gynecological cancer, approximately two-thirds of patients have already developed metastasis when they are diagnosed. The function of transmembrane protein 176B (TMEM176B) in the progression of OC remains elusive. This study aimed to investigate the role and molecular mechanism of TMEM176B on OC proliferation and metastasis.MethodExpression of TMEM176B in OC and normal tissues were determined from the TCGA, GTEx, and CPTAC databases, and verified by patient-derived tissue samples. We analysed the prognostic relevance of TMEM176B in OC via Kaplan‒Meier (K‒M) survival curves and receiver operating characteristic (ROC) curves. Subsequent in vitro assays, including the CCK8 assay, colony formation assay, wound healing assay, and transwell assay, were performed to detect the influence of TMEM176B on cell proliferation and metastasis. Furthermore, a tumorigenesis study in nude mice was conducted to confirm the suppressive impact of TMEM176B on OC. RNA sequencing (RNA-seq) was utilized to uncover the mechanisms of TMEM176B on OC progression. Spearman correlation analysis was used to calculate the correlations between TMEM176B and cell adhesion, DNA replication, and the Wnt/β-catenin pathway. Finally, the role of TMEM176B in regulating the epithelial-mesenchymal transition (EMT) depending on the Wnt/β-catenin pathway was evaluated using LiCl agonist.ResultThe mRNA expression of TMEM176B was significantly downregulated in OC tissues, with lower TMEM176B correlating with a worse prognosis. Moreover, higher tumor stage and tumor grade were associated with a lower TMEM176B protein level. Consistent with these findings, OC tissues exhibited significantly reduced of TMEM176B compared to normal ovarian tissue from patients. In vitro studies indicated that TMEM176B knockdown increased both the proliferation, metastasis and EMT levels of OC cells, while TMEM176B overexpression had the opposite effects. In vivo investigations reinforced that TMEM176B significantly inhibited the progression of OC. RNA-seq analysis demonstrated that TMEM176B enhanced cell adhesion, diminished DNA replication, and suppressed EMT through the regulation of the Wnt/β-catenin signaling pathway, effectively obstructing the proliferation and metastasis of OC cells and impeding the disease's progression.ConclusionsTMEM176B inhibited EMT in OC cells by controlling the activation of the Wnt/β-catenin pathway. This mechanism underscored the diagnostic and prognostic potential of TMEM176B for OC and highlights its tumor-suppressive properties as a promising therapeutic candidate.
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Project description:The von Hippel-Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-alpha transcription factors; additional mechanisms have been proposed. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk. Here we show that Jade-1 binds the oncoprotein beta-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type beta-catenin but not a cancer-causing form of beta-catenin. Whereas the well-established beta-catenin E3 ubiquitin ligase component beta-TrCP ubiquitylates only phosphorylated beta-catenin, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated beta-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of beta-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates beta-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.
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Project description:ObjectiveThis study aimed to establish a prognostic model related to prostate cancer (PCa) recurrence-free survival (RFS) and identify biomarkers.MethodsThe RFS prognostic model and key genes associated with PCa were established using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression from the Cancer Genome Atlas (TCGA)-PRAD and the Gene Expression Omnibus (GEO) GSE46602 datasets. The weighted gene co-expression network (WGCNA) was used to analyze the obtained key modules and genes, and gene set enrichment analysis (GSEA) was performed. The phenotype and mechanism were verified in vitro.ResultsA total of 18 genes were obtained by LASSO regression, and an RFS model was established and verified (TCGA, AUC: 0.774; GSE70768, AUC: 0.759). Three key genes were obtained using multivariate Cox regression. WGCNA analysis obtained the blue module closely related to the Gleason score (cor = -0.22, P = 3.3e - 05) and the unique gene glutathione peroxidase 2 (GPX2). Immunohistochemical analysis showed that the expression of GPX2 was significantly higher in patients with PCa than in patients with benign prostatic hyperplasia (P < 0.05), but there was no significant correlation with the Gleason score (GSE46602 and GSE6919 verified), which was also verified in the GSE46602 and GSE6919 datasets. The GSEA results showed that GPX2 expression was mainly related to the epithelial-mesenchymal transition (EMT) and Wnt pathways. Additionally, GPX2 expression significantly correlated with eight kinds of immune cells. In human PCa cell lines LNCaP and 22RV1, si-GPX2 inhibited proliferation and invasion, and induced apoptosis when compared with si-NC. The protein expression of Wnt3a, glycogen synthase kinase 3β (GSK3β), phosphorylated (p)-GSK3β, β-catenin, p-β-catenin, c-myc, cyclin D1, and vimentin decreased; the expression of E-cadherin increased; and the results for over-GPX2 were opposite to those for over-NC. The protein expression of GPX2 decreased, and β-catenin was unchanged in the si-GPX2+ SKL2001 group compared with the si-NC group.ConclusionWe successfully constructed the PCa RFS prognostic model, obtained RFS-related biomarker GPX2, and found that GPX2 regulated PCa progression and triggered Wnt/β-catenin/EMT pathway molecular changes.
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Project description:BackgroundTransmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive.MethodsWe investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC.ResultsTM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model.ConclusionOur study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.
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Project description:Although estrogen has crucial functions for endometrium growth, the specific dose and underlying molecular mechanism in intrauterine adhesion (IUA) remain unclear. In this study, we aimed to investigate the effects of estrogen on epithelial-mesenchymal transition (EMT) in normal and fibrotic endometrium, and the role of estrogen and Wnt/β-catenin signaling in the formation of endometrial fibrosis. CCK-8 and immunofluorescence assay were performed to access the proliferation of different concentrations of estrogen on normal human endometrial epithelial cells (hEECs). qRT-PCR and western blot assay were utilized to explore the effect of estrogen on EMT in normal and fibrotic endometrium, and main components of Wnt/β-catenin signaling pathway in vitro. Hematoxylin and eosin and Masson staining were used to evaluate the effect of estrogen on endometrial morphology and fibrosis in vivo. Our results indicated that the proliferation of normal hEECs was inhibited by estrogen at a concentration of 30 nM accompanied by upregulation of mesenchymal markers and downregulation of epithelial markers. Interestingly, in the model of transforming growth factor β1 (TGF-β1)-induced endometrial fibrosis, the same concentration of estrogen inhibited the process of EMT, which might be partially mediated by regulation of the Wnt/β-catenin pathway. In addition, relatively high doses of estrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction of EMT in IUA animal models. Taken together, our results demonstrated that an appropriate concentration of estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-β1-induced EMT and activating the Wnt/β-catenin pathway.
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Project description:One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer. Although many studies on BRAF inhibitor resistance in colorectal cancer have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on colorectal cancer resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next-generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant colorectal cancer cell lines through activating the cytoplasmic tyrosine kinase focal adhesion kinase (FAK). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR or ERK1/2 activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant colorectal cancer, including cell line xenograft model and a patient-derived xenograft model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that although complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant colorectal cancer, cotargeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential. Mol Cancer Ther; 17(4); 806-13. ©2017 AACR.
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