scholarly journals Wnt2 Contributes to the Development of Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jinyu Zhang ◽  
Samuel Rojas ◽  
Sanjay Singh ◽  
Phillip R. Musich ◽  
Matthew Gutierrez ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Chronic Inflammatory Disease ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Atherosclerotic Lesions ◽  
Endothelial To Mesenchymal Transition

Atherosclerosis, is a chronic inflammatory disease, characterized by the narrowing of the arteries resulting from the formation of intimal plaques in the wall of arteries. Yet the molecular mechanisms responsible for maintaining the development and progression of atherosclerotic lesions have not been fully defined. In this study, we show that TGF-β activates the endothelial-to-mesenchymal transition (EndMT) in cultured human aortic endothelial cells (HAECs) and this transition is dependent on the key executor of the Wnt signaling pathway in vitro. This study presents the first evidence describing the mechanistic details of the TGF-β-induced EndMT signaling pathway in HAECs by documenting the cellular transition to the mesenchymal phenotype including the expression of mesenchymal markers α-SMA and PDGFRα, and the loss of endothelial markers including VE-cadherin and CD31. Furthermore, a short hairpin RNA (shRNA) screening revealed that Wnt2 signaling is required for TGF-β-mediated EndMT of HAECs. Also, we found that LDLR−/− mice fed on a high-fat western-type diet (21% fat, 0.2% cholesterol) expressed high levels of Wnt2 protein in atherosclerotic lesions, confirming that this signaling pathway is involved in atherosclerosis in vivo. These findings suggest that Wnt2 may contribute to atherosclerotic plaque development and this study will render Wnt2 as a potential target for therapeutic intervention aiming at controlling atherosclerosis.

scholarly journals Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

2019 ◽  
Vol 20 (21) ◽  
pp. 5391 ◽  
Author(s):  
Wörthmüller ◽  
Salicio ◽  
Oberson ◽  
Blum ◽  
Schwaller
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Expression System ◽  
Single Agent ◽  
Wnt Signaling Pathway ◽  
Tumor Formation ◽  
Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

scholarly journals MicroRNA-375: Potential cancer suppressor and therapeutic drug

2021 ◽  
Author(s):  
Jiahui Wei ◽  
Yiran Lu ◽  
Ruiqing Wang ◽  
Xiangzhu Xu ◽  
Qing Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Wnt Signaling Pathway ◽  
Human Tumor ◽  
Therapeutic Drug ◽  
Mesenchymal Transition

MiR-375 is a conserved noncoding RNA that is known to be involved in tumor cell proliferation, migration, and drug resistance. Previous studies have shown that miR-375 affects the epithelial-mesenchymal transition (EMT) of human tumor cells via some key transcription factors, such as Yes-associated protein 1 (YAP1), Specificity protein 1 (SP1) -and signaling pathways (Wnt signaling pathway, nuclear factor kappa B (NF-kB) pathway and transforming growth factor β (TGF-β) signaling pathway) and is vital for the development of cancer. Additionally, recent studies have identified miRNA delivery system carriers for improved in vivo transportation of miR-375 to specific sites. Here, we discussed the role of miR-375 in different types of cancers, as well as molecular mechanisms, and analyzed the potential of miR-375 as a molecular biomarker and therapeutic target to improve the efficiency of clinical diagnosis of cancer.

scholarly journals RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis

2020 ◽  
Vol 318 (2) ◽  
pp. G352-G360 ◽  
Author(s):  
Yongan Fu ◽  
Yilin Chen ◽  
Jinghua Huang ◽  
Zongda Cai ◽  
Yangqiang Wang
Keyword(s):  
Gastric Cancer ◽  
Liver Metastasis ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model ◽  
Highly Correlated

Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC. NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.

scholarly journals P4HA2 is associated with prognosis, promotes proliferation, invasion, migration and EMT in glioma

2020 ◽  
Author(s):  
Jing Lin ◽  
Xiao-Jun Wu ◽  
Wen-Xin Wei ◽  
Xing-Chun Gao ◽  
Ming-Zhu Jin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Akt Signaling ◽  
Tumor Xenograft ◽  
Receptor Interaction ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition

AbstractProlyl-4-hydroxylase subunit 2 (P4HA2), as a member of collagen modification enzymes, is induced under hypoxic conditions with essential roles in the collagen maturation, deposition as well as the remodeling of extracellular matrix(ECM). Mounting evidence has suggested that deregulation of P4HA2 is common in cancer. However, the expression pattern and molecular mechanisms of P4HA2 in glioma remain unknown. Here, we demonstrate that P4HA2 is overexpressed in glioma and inversely correlates with patient survival. Knockdown of P4HA2 inhibits proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT)-like phenotype of glioma cells in vitro and suppressed tumor xenograft growth in vivo. Mechanistically, bioinformatics analysis shows that ECM-receptor interaction and PI3K/AKT pathway are the most enriched pathways of the co-expressed genes with P4HA2. Furthermore, P4HA2 mRNA was positively correlated with mRNA expressions of a series of collagen genes, but not mRNA of PI3K or AKT1/2. Conversely, both the protein expressions of collagens and phosphorylated PI3K/AKT could be downregulated either by silencing of P4HA2 expression or inhibition of its prolyl hydroxylase. Moreover, the inhibitory effects on the migration, invasion and the EMT-related molecules by P4HA2 knockdown can be recapitulated by the Akt phosphorylation activator. Taken together, our findings for the first time reveal an oncogenic role of P4HA2 in the glioma malignancy. By regulating the expression of fibrillar collagens and the downstream PI3K/AKT signaling pathway, it may serve as a potential anti-cancer target for the treatment of glioma.HighlightsP4HA2 is overexpressed and correlated with poor prognosis in glioma.P4HA2 depletion inhibits glioma proliferation, migration, invasion and EMT-like phenotype in vitro and tumorigenesis in vivo.P4HA2 depletion attenuates the PI3K/AKT signaling pathway in a collagen-dependent manner.

scholarly journals FER Regulated by miR-206 Promotes Hepatocellular Carcinoma Progression via NF-κB Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenzhou Ding ◽  
Ye Fan ◽  
Wenbo Jia ◽  
Xiongxiong Pan ◽  
Guoyong Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Metastatic Progression ◽  
Loss Of Function ◽  
Mesenchymal Transition ◽  
Hcc Cells

ObjectivesFeline sarcoma-related protein (FER) is known to play a critical regulatory role in several carcinomas. However, the exact biological function of FER in hepatocellular carcinoma (HCC) still needs to be investigated. The primary objective of this research was to investigate the unknown function and molecular mechanisms of FER in HCC.Materials and MethodsThe expression level of FER in HCC tissue samples and cells was examined by RT-qPCR, immunohistochemistry and western blot. Cellular and animal experiments were used to explore the effect of FER on the proliferative and metastatic capacities of HCC cells. The crosstalk between FER and NF-κB signaling was explored by western blot. The upstream factors that regulate FER were evaluated through dual-luciferase experiments and western blot assays.ResultsFER was overexpressed in HCC specimens and HCC cell lines. FER expression levels were positively associated with unfavorable clinicopathological characteristics. The higher the expression of FER was, the worse the overall survival of HCC patients was. The results of loss-of-function and gain-of-function experiments indicated that knockdown of FER decreased, while overexpression of FER increased, the proliferation, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, we found that FER activated the NF-κB signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT). We also found that FER was directly regulated by miR-206, and the downregulation of miR-206 was associated with proliferation and metastatic progression in HCC.ConclusionsThe present research was the first to reveal that a decrease in miR-206 levels results in an increase in FER expression in HCC, leading to enhanced cell growth and metastatic abilities via activation of the NF-κB signaling pathway.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals DNA methylation mediated RSPO2 to promote follicular development in mammals

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiaofeng Zhou ◽  
Yingting He ◽  
Nian Li ◽  
Guofeng Bai ◽  
Xiangchun Pan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Wnt Signaling Pathway ◽  
Follicular Development ◽  
Expression Level

AbstractIn female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction

2019 ◽  
Vol 39 (10) ◽  
pp. 2168-2191 ◽  
Author(s):  
Bronson A. Haynes ◽  
Li Fang Yang ◽  
Ryan W. Huyck ◽  
Eric J. Lehrer ◽  
Joshua M. Turner ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Smooth Muscle Actin ◽  
Phenotypic Change ◽  
Alpha Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Endothelial To Mesenchymal Transition

Objective: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. Conclusions: We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.

scholarly journals Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma

2018 ◽  
Vol 51 (5) ◽  
pp. 2065-2072 ◽  
Author(s):  
Wei Bian ◽  
Hongfei Zhang ◽  
Miao Tang ◽  
Shaojun Zhang ◽  
Lichao Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Reporter Assays

Background/Aims: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. Methods: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. Results: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3’-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. Conclusion: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

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