VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling
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PROVIDER: S-EPMC10915959 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:N-myc downstream-regulated gene 1 (NDRG1) has been implicated in tumorigenesis and metastasis in different cancers. However, its role in nasopharyngeal carcinoma remains unknown. We found that NDRG1 expression level was high in nasopharyngeal cancer 5-8F cells but low in 5-8F-LN cells with lymphatic metastasis potential. Knockdown of NDRG1 by shRNA promoted 5-8F cell proliferation, migration, and invasion in vitro and its tumorigenesis in vivo. Moreover, NDRG1 deficiency induced an epithelial-mesenchymal transition (EMT) of 5-8F cells as shown by an attenuation of E-cadherin and an induction of N-cadherin and vimentin expression. NDRG1 knockdown also enhanced Smad2 expression and phosphorylation. Smad2 signaling was attenuated in 5-8F cells but was significantly activated in 5-8F-LN cells. Knockdown of Smad2 restored E-cadherin but attenuated N-cadherin expression in NDRG1-deficient 5-8F cells, suggesting a reduction of EMT. Consistently, blockade of Smad2 in 5-8F-LN cells increased E-cadherin while diminishing N-cadherin and vimentin expression. These data indicate that Smad2 mediates the NDRG1 deficiency-induced EMT of 5-8F cells. In tumors derived from NDRG1-deficient 5-8F cells, E-cadherin expression was inhibited while vimentin and Smad2 were increased in a large number of cancer cells. Most importantly, NDRG1 expression was attenuated in human nasopharyngeal carcinoma tissues, resulted in a lower survival rate in patients. The NDRG1 was further decreased in the detached nasopharyngeal cancer cells, which was associated with a further reduced survival rate in patients with lymphatic metastasis. Taken together, these results demonstrated that NDRG1 prevents nasopharyngeal tumorigenesis and metastasis via inhibiting Smad2-mediated EMT of nasopharyngeal cells.
| S-EPMC4561576 | biostudies-literature
Project description:BackgroundExposure to nicotine has been observed associated with tumor progression, metastasis, and therapy resistance of many cancers. Hepatocellular carcinoma (HCC) is one major cancer related to the liver and the most difficult to treat malignancies worldwide. The underlying mechanism of nicotine in the stimulation of HCC tumorigenesis is still not studied well.MethodsClassically, nicotine binds to nicotinic acetylcholine receptors (nAChRs) and induces many downstream cancer-associated signaling pathways. Big data analysis is used to explore the importance of a7nAChR-Jak2 axis in the progression of hepatocellular carcinoma. Bioinformatic analysis was performed to determine gene associated with a7nAChR-Jak2 axis of HCC patients. Biological importance of a7nAChR-Jak2 axis was investigated in vitro (Hun7 and HepG2 cell lines), and athymic nude mouse models bearing HepG2-HCC cells xenografts were established in vivo.ResultWe found that nicotine exposure stimulated the HCC tumorigenicity by inducing the expression of one of the key nAChRs subunit that is α7nAChR as well as the expression of Janus kinase (JAK)-2. In both the in vitro and in vivo studies, the reduced overexpression of α7nAChR and increased sensitization of HCC towards treatment is observed with dehydrocrenatidine (DHCT), a novel and potent JAK family kinase inhibitor. Interestingly, DHCT treatment results in the reduction of the epithelial-mesenchymal transition process which leads to a significant reduction of clonogenicity, migratory, and invasive ability of HCC cells. Moreover, DHCT treatment also inhibits the cancer stem cell phenotype by inhibiting the tumor-sphere formation and reducing the number of ALDH1+ cells population in nicotine-stimulated HCC cells.ConclusionsTaken together, the presented results indicate the positive effect of inhibition of nicotine induced overexpression of α7nAChR and JAK2, unique to HCC. Thus, these findings suggest the nicotine effect on HCC progression via α7nAChR-mediated JAK2 signaling pathways, and DHCT treatment enhances the therapeutic potential of HCC patients via overcoming/reversing the effect of nicotine in HCC patients.
| S-EPMC8803439 | biostudies-literature
Project description:Bladder cancer (BC) is a prevalent and deadly disease. circCD2AP was suggested to be highly expressed in BC. However, the exact mechanism needs further investigation. In this study, circCD2AP was observed to be upregulated in BC and linked to poor prognosis in individuals. Functionally, circCD2AP or USP21 knockdown inhibited BC cell EMT and stemness both in vitro and in vivo. Mechanistically, circCD2AP interacted with ELAVL1 to enhance the stability of USP21 mRNA, which, in turn, inhibited the ubiquitination degradation of FOXQ1. Through rescue assay, USP21 or FOXQ1 knockdown was found to abolish the promoting effects of circCD2AP or USP21 overexpression on BC cell EMT and stemness. Overall, this study has unveiled the role of circCD2AP/ELAVL1/USP21/FOXQ1 axis in BC EMT and stemness regulation, offering insights into the mechanisms underlying BC progression, with potential implications for therapeutic strategies.
| S-EPMC10827552 | biostudies-literature
Project description:BackgroundEpithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.MethodsType 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4'-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.ResultsDN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).ConclusionFGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.
| S-EPMC7043973 | biostudies-literature
Project description:In a number of cancers, deregulated MET pathway leads to aberrantly activated proliferative and invasive signaling programs that promote malignant transformation, cell motility and migration, angiogenesis, survival in hypoxia, and invasion. A better understanding of oncogenic MET signaling will help us to discover effective therapeutic approaches and to identify which tumors are likely to respond to MET-targeted cancer therapy. In this review, we will summarize the roles of MET signaling in cancer, with particular focus on epithelial-mesenchymal transition (EMT) and cancer stemness. Then, we will provide update on MET targeting agents and discuss the challenges that should be overcome for the development of an effective therapy.
| S-EPMC5253283 | biostudies-literature
Project description:Human amniotic epithelial cells (hAECs), which are a type of placental stem cell, express stem cell marker genes and are capable of differentiating into all three germ layers under appropriate culture conditions. hAECs are known to undergo TGF-β-dependent epithelial-mesenchymal transition (EMT); however, the impact of EMT on the stemness or differentiation of hAECs has not yet been determined. Here, we first confirmed that hAECs undergo EMT immediately after starting primary culture. Comprehensive transcriptome analysis using RNA-seq revealed that inhibition of TGF-β-dependent EMT maintained the expression of stemness-related genes, including NANOG and POU5F1, in hAECs. Moreover, the maintenance of stemness did not affect the nontumorigenic characteristics of hAECs. We showed for the first time that TGF-β-dependent EMT negatively affected the stemness of hAECs, providing novel insight into cellular processes of placental stem cells.
| S-EPMC9622541 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, fibrosis, and cancer metastasis. During cancer progression, the activation of EMT permits cancer cells to acquire migratory, invasive, and stem-like properties. A growing body of evidence supports the critical link between EMT and cancer stemness. However, contradictory results have indicated that the inhibition of EMT also promotes cancer stemness, and that mesenchymal-epithelial transition, the reverse process of EMT, is associated with the tumor-initiating ability required for metastatic colonization. The concept of 'intermediate-state EMT' provides a possible explanation for this conflicting evidence. In addition, recent studies have indicated that the appearance of 'hybrid' epithelial-mesenchymal cells is favorable for the establishment of metastasis. In summary, dynamic changes or plasticity between the epithelial and the mesenchymal states rather than a fixed phenotype is more likely to occur in tumors in the clinical setting. Further studies aimed at validating and consolidating the concept of intermediate-state EMT and hybrid tumors are needed for the establishment of a comprehensive profile of cancer metastasis.
| S-EPMC5496497 | biostudies-other
Project description:BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible. Cigarette smoking is one of the most commonly and important risk factors for COPD, which contributes to airway remodeling, the outstanding pathological changes in COPD. One potential mechanism which might be important for airway remodeling is the process called epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms of EMT in CS-induced COPD are still poorly understood.MethodsTwo Gene Expression Omnibus (GEO) datasets (GSE108134 and GSE5058) were combined to identify the key genes involved in COPD. Then, single-gene analysis of Lyn was performed. Lyn expression was confirmed in patients with COPD. 16HBE cells were treated with cigarette smoking extracts (CSE). Wild type (WT) C57BL/6 J mice and Lyn+/+ transgenic mice were exposed to CSE to establish CS-exposed model. Pathological changes were observed by hematoxylin-eosin staining. The expression levels of EMT markers were examined by using western blot and immunofluorescence. The expression and phosphorylation levels of Lyn and Smad2/3 were detected as well.ResultsThe gain of mesenchymal markers vimentin and α-SMA with a concomitant loss of E-cadherin was observed in both in vivo and in vitro studies. Meanwhile, cigarette smoking extracts (CSE) induced EMT in 16HBE cells in a time- and dose- dependent manner. Furthermore, by analyzing GEO datasets and using molecular methods, we explored a kinase, Lyn, its expression correlated with the expression of E-cadherin, vimentin and α-SMA in CS-exposed model. Moreover, we found that EMT induced by CSE was regulated by activated Lyn through phosphorylation of Smad2/3.ConclusionsIn summary, we found that Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling. As a kinase, Lyn is "druggable", and might provide a therapeutic opportunity for targeting EMT. Therefore, our research might provide a new method to treat COPD by targeting Lyn kinase specifically.
| S-EPMC6720409 | biostudies-literature
Project description:Although there is increasing evidence that human bone marrow mesenchymal stem cells (hBM-MSCs) play an important role in cancer progression, the underlying mechanisms are poorly understood. Transforming growth factor β (TGF-β) is an important pro-metastatic cytokine. We have previously shown that CD109, a glycosylphosphatidylinositol-anchored protein, is a TGF-β co-receptor and a strong inhibitor of TGF-β signalling. Moreover, CD109 can be released from the cell surface. In the current study, we examined whether hBM-MSCs regulate the malignant properties of squamous cell carcinoma cells, and whether CD109 plays a role in mediating the effect of hBM-MSCs on cancer cells. Here we show that hBM-MSC-conditioned medium decreases proliferation and induces apoptosis in human squamous carcinoma cell lines, A431 and FaDu. Importantly, hBM-MSC-conditioned medium markedly suppresses markers of epithelial-to-mesenchymal transition and stemness, and concomitantly decreases cell migration, invasion, and spheroid formation in A431 and FaDu cells. In addition, knockdown of CD109 in hBM-MSCs abrogates the anti-malignant activity of hBM-MSC-conditioned medium on A431 and FaDu cells. Furthermore, overexpression of CD109 in A431 cells decreases their malignant traits. Together, our findings suggest that hBM-MSCs inhibit the malignant traits of squamous cell carcinoma cells by a paracrine effect via released factors and that CD109 released from hBM-MSCs, at least partially, mediates these effects.
| S-EPMC5707049 | biostudies-literature
Project description:BackgroundDAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown.MethodsWe analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models.ResultsDAXX was downregulated in advanced gastric cancer samples. The expression of DAXX inversely correlates with that of cancer stem cell markers CD44 and Oct4 in gastric cancer lines. DAXX overexpression in gastric cancer cells inhibited migration, invasion and epithelial- mesenchymal transition (EMT). The inhibition of EMT was achieved through the repression of SNAI3, a key inducer of EMT, by recruiting HDAC-1 into the nucleus. Using a xenograft mouse model, we demonstrated that the MKN45 cells formed smaller tumours when DAXX was overexpressed. Wild-type AGS cells were not able to form tumours in nude mice, but in contrast, formed visible tumours when DAXX was silenced in the cells.ConclusionWe for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.
| S-EPMC7217831 | biostudies-literature