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International Journal of Molecular... Oct 2020Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and... (Review)
Review
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.
Topics: Animals; Biomarkers, Tumor; Cadherins; Catenins; Cell Adhesion; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Signal Transduction
PubMed: 33076339
DOI: 10.3390/ijms21207624 -
Molecular Cancer Jul 2022Increasing studies suggest that circular RNAs (circRNAs) are critical regulators of cancer development and progression. However, the biological roles and mechanisms of...
BACKGROUND
Increasing studies suggest that circular RNAs (circRNAs) are critical regulators of cancer development and progression. However, the biological roles and mechanisms of circRNAs in gastric cancer (GC) remain largely unknown.
METHODS
We identified the differentially expressed circRNAs in GC by analyzing Gene Expression Omnibus (GEO) datasets. We explored the biological roles of circRNAs in GC by in vitro functional assays and in vivo animal studies. We performed tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), mass spectrometry (MS), RNA sequencing, luciferase reporter assays, and rescue experiments to investigate the mechanism of circRNAs in GC.
RESULTS
Downregulated expression of circular RNA EIF4G3 (circEIF4G3; hsa_circ_0007991) was found in GC and was associated with poor clinical outcomes. Overexpression of circEIF4G3 suppressed GC growth and metastasis through the inhibition of β-catenin signaling, whereas knockdown of circEIF4G3 showed the opposite effects. Mechanistic studies revealed that circEIF4G3 bound to δ-catenin protein to promote its TRIM25-mediated ubiquitin degradation and interacted with miR-4449 to upregulate SIK1 expression.
CONCLUSION
Our findings uncovered a tumor suppressor function of circEIF4G3 in GC through the regulation of δ-catenin protein stability and miR-4449/SIK1 axis. CircEIF4G3 may act as a promising prognostic biomarker and therapeutic target for GC.
Topics: Animals; Catenins; Cell Line, Tumor; Cell Proliferation; MicroRNAs; RNA, Circular; Stomach Neoplasms; Ubiquitin; beta Catenin; Delta Catenin
PubMed: 35780119
DOI: 10.1186/s12943-022-01606-9 -
Nature Genetics Oct 2013Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations...
Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
Topics: Brain Neoplasms; Catenins; ErbB Receptors; Gene Expression Regulation, Neoplastic; Genomics; Glioblastoma; Humans; Mutation; Transcription Factors; Delta Catenin
PubMed: 23917401
DOI: 10.1038/ng.2734 -
Cell Death & Disease Jun 2023Hepatocellular carcinoma (HCC) is the most common type of primary hepatic carcinoma, which is a growing public health problem worldwide. One of the main genetic...
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic carcinoma, which is a growing public health problem worldwide. One of the main genetic alterations in HCC is the deregulated Wnt/β-catenin signaling, activation of β-catenin is associated with the progression of HCC. In the present study, we aimed to identify novel modulators in controlling β-catenin ubiquitination and stability. USP8 was overexpressed in HCC tissues and correlated with β-catenin protein level. High expression of USP8 indicated poor prognosis of HCC patients. USP8 depletion significantly decreased β-catenin protein level, β-catenin target genes expression and TOP-luciferase activity in HCC cells. Further mechanistic study revealed that the USP domain of USP8 interacted with the ARM domain of β-catenin. USP8 stabilized β-catenin protein via inhibiting K48-specific poly-ubiquitination process on β-catenin protein. In addition, USP8 depletion inhibited the proliferation, invasion and stemness of HCC cells and conferred ferroptosis resistance, which effects could be further rescued by β-catenin overexpression. In addition, the USP8 inhibitor DUB-IN-3 inhibited the aggressive phenotype and promoted ferroptosis of HCC cells through degradation of β-catenin. Thus, our study demonstrated that USP8 activated the Wnt/beta-catenin signaling through a post-translational mechanism of β-catenin. High expression of USP8 promoted the progression and inhibited ferroptosis of HCC. Targeting the USP8 may serve as a promising strategy for patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; beta Catenin; Ferroptosis; Liver Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Catenins; Endopeptidases; Ubiquitin Thiolesterase; Endosomal Sorting Complexes Required for Transport
PubMed: 37311739
DOI: 10.1038/s41419-023-05747-7 -
Military Medical Research Sep 2022Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the...
BACKGROUND
Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.
METHODS
ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC.
RESULTS
Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.
CONCLUSIONS
Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.
Topics: Animals; Catenins; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Feedback; Histone Deacetylases; Humans; Melatonin; Mice; Mice, Nude; Protein Stability; Proto-Oncogene Proteins c-myc; Ubiquitin Thiolesterase; Ubiquitin-Specific Proteases; beta Catenin
PubMed: 36163081
DOI: 10.1186/s40779-022-00412-0 -
Journal of Gastroenterology Feb 2019Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP)... (Review)
Review
Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP) patients have mild disease, and about 20% have severe disease, which causes multiple organ failure and has a high mortality rate. Chronic pancreatitis (CP) is characterized by chronic inflammation and destruction of normal pancreatic parenchyma, which leads to loss of exocrine and endocrine tissues. Patients with CP also have a higher incidence of pancreatic ductal adenocarcinoma. Although a number of factors are associated with the development and progression of AP and CP, the underlying mechanism is unclear. Adhesion molecules play important roles in cell migration, proliferation, and signal transduction, as well as in development and tissue repair. Loosening of cell-cell adhesion between pancreatic acinar cells and/or endothelial cells increases solute permeability, resulting in interstitial edema, which promotes inflammatory cell migration and disrupts tissue structure. Oxidative stress, which is one of the important pathogenesis of pancreatitis, leads to upregulation of adhesion molecules. Soluble adhesion molecules are reportedly involved in AP. In this review, we focus on the roles of tight junctions (occludin, tricellulin, claudin, junctional adhesion molecule, and zonula occludin), adherens junctions (E-cadherin and p120-, α-, and β-catenin), and other adhesion molecules (selectin and intercellular adhesion molecules) in the progression of AP and CP. Maintaining the normal function of adhesion molecules and preventing their abnormal activation maintain the structure of the pancreas and prevent the development of pancreatitis.
Topics: Adherens Junctions; Animals; Cadherins; Catenins; Cell Adhesion Molecules; Humans; Intercellular Adhesion Molecule-1; Pancreatitis; Tight Junction Proteins; Tight Junctions
PubMed: 30140950
DOI: 10.1007/s00535-018-1500-0 -
Protein Expression and Purification May 2022The dynamic regulation of epithelial adherens junctions relies on all components of the E-cadherin-catenin complex. Previously, the complexes have been partially...
The dynamic regulation of epithelial adherens junctions relies on all components of the E-cadherin-catenin complex. Previously, the complexes have been partially reconstituted and composed only of α-catenin, β-catenin, and the E-cadherin cytoplasmic domain. However, p120-catenin and the full-length E-cadherin including the extracellular, transmembrane, and intra-cellular domains are vital to the understanding of the relationship between extracellular adhesion and intracellular signaling. Here, we reconstitute the complete and full-length cadherin-catenin complex, including full-length E-cadherin, α-catenin, β-catenin, and p120-catenin, into nanodiscs. We are able to observe the cadherin in nanodiscs by cryo-EM. We also reconstitute α-catenin, β-catenin, and p120-catenin with the E-cadherin cytoplasmic tail alone in order to analyze the affinities of their binding interactions. We find that p120-catenin does not associate strongly with α- or β-catenin and binds much more transiently to the cadherin cytoplasmic tail than does β-catenin. Overall, this work creates many new possibilities for biochemical studies understanding transmembrane signaling of cadherins and the role of p120-catenin in adhesion activation.
Topics: Cadherins; Catenins; Cell Adhesion; Cell Membrane; Phosphoproteins; Signal Transduction; beta Catenin
PubMed: 35063654
DOI: 10.1016/j.pep.2022.106056 -
Current Opinion in Insect Science Apr 2022Mechanisms and evolution of primary axis specification in insects are discussed in the context of the roles of ß-catenin and TCF in polarizing metazoan embryos. Three... (Review)
Review
Mechanisms and evolution of primary axis specification in insects are discussed in the context of the roles of ß-catenin and TCF in polarizing metazoan embryos. Three hypotheses are presented. First, insects with sequential segmentation and posterior growth use cell-autonomous mechanisms for establishing embryo polarity via the nuclear ratio of ß-catenin and TCF. Second, TCF homologs establish competence for anterior specification. Third, the evolution of simultaneous segmentation mechanisms, also known as long-germ development, resulted in primary axis specification mechanisms that are independent of ß-catenin but reliant on TCF, a condition that preceded the frequent replacement of anterior determinants in long germ insects.
Topics: Animals; Body Patterning; Catenins; Gene Expression Regulation, Developmental; Insecta; beta Catenin
PubMed: 35104659
DOI: 10.1016/j.cois.2022.100877 -
Hepatology (Baltimore, Md.) Jun 2018The duality of β- and γ–catenin during liver injury has not been defined. It’s well known that loss of β-catenin plays a critical role in overall liver health and...
The duality of β- and γ–catenin during liver injury has not been defined. It’s well known that loss of β-catenin plays a critical role in overall liver health and is a major component of adherens junctions (AJ). Further, γ-catenin has been shown to regulate β-catenin and vice-versa. In this excellent manuscript, the authors investigated the effects of knocking out both β- and γ–catenin creating a β-;γ-catenin-double knockout (DKO). The result of this interbreeding revealed a model that is reminiscent of early childhood cholestatic liver diseases (CLD) like Progressive Familial Intrahepatic Cholestasis (PFIC). The authors provide both and data to demonstrate the important role of these catenin genes in the regulation of hepatocyte-junctions. The experiments show partially redundant function of catenin’s at hepatocyte AJ in regulating tight junctions (TJ) and contributing to a disrupted blood-bile barrier. Further, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Overall, these studies shed important light on junctional protein dysregulation during CLD.
Topics: Adherens Junctions; Cadherins; beta Catenin; gamma Catenin
PubMed: 29272046
DOI: 10.1002/hep.29761 -
ELife Aug 2020The β-catenin transcriptional coregulator is involved in various biological and pathological processes; however, its requirements in hematopoietic cells remain...
The β-catenin transcriptional coregulator is involved in various biological and pathological processes; however, its requirements in hematopoietic cells remain controversial. We re-targeted the gene locus to generate a true β-catenin-null mutant mouse strain. Ablation of β-catenin alone, or in combination with its homologue γ-catenin, did not affect thymocyte maturation, survival or proliferation. Deficiency in β/γ-catenin did not detectably affect differentiation of CD4T follicular helper cells or that of effector and memory CD8 cytotoxic cells in response to acute viral infection. In an MLL-AF9 AML mouse model, genetic deletion of β-catenin, or even all four Tcf/Lef family transcription factors that interact with β-catenin, did not affect AML onset in primary recipients, or the ability of leukemic stem cells (LSCs) in propagating AML in secondary recipients. Our data thus clarify on a long-standing controversy and indicate that β-catenin is dispensable for T cells and AML LSCs.
Topics: Leukemia; Neoplastic Stem Cells; T-Lymphocytes; beta Catenin; gamma Catenin
PubMed: 32820720
DOI: 10.7554/eLife.55360