scholarly journals VIP36 preferentially binds to core-fucosylated N-glycans: a molecular docking study

2016 ◽  
Author(s):  
Klaus Fiedler
Keyword(s):  
Epithelial Cells ◽  
Large Scale ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Nonsmall Cell Lung Cancer ◽  
Cellular Transformation ◽  
Molecular Docking Study ◽  
Mesenchymal Transition ◽  
Cargo Receptor ◽  
High Mannose

AbstractAlpha 1-6 fucosyltransferase (Fut8) is known for its properties as an enhancer of nonsmall cell lung cancer metastasis and as a suppressor in hepatocellular carcinoma cells (Hep3B). Promising candidates of affected molecules include E-cadherin. In its absence, during epithelial-mesenchymal transition, the pathway triggers signaling to the nucleus via β-catenin-TCF/LEF. Contrarily, in less metastatic tumors, Fut8 stimulates cell-cell adhesion. Regulated classes of molecules could also include the sorting machinery of polarized epithelial cells, sorted ligands or both, that may be altered in cellular transformation. I have analyzed here the cargo receptor VIP36 (Vesicular-integral membrane protein of 36 kD) for carbohydrate interaction. It has been described as a lectin in the ERGIC (endoplasmic reticulum-Golgi intermediate compartment), Golgi apparatus and plasma membrane. The docking reveals top-interacting carbohydrates of the N-glycan and O-glycan class that encompass N-linked glycans of high mannose and equally complex type which likely function as sorted ligands in epithelial cells. O-glycans score lower and include core 2 residue binding. I show that fucose core modifications by Fut8 stimulate binding of N-linked glycans to VIP36, which is known to be different from binding of galectins 3 and 9. This suggests that Fut8-upregulation may directly alter the affinity of sorted cargo and may enhance the sorting to the apical pathway as exemplified in hepatocytes and traffic to bile. High affinity binding of the ganglioside GM1 carbohydrate headgroup to VIP36 suggests a linkage with protein and glycosphingolipid apical transfer in epithelial cells. Thus, this fundamental approach with large scale docking of 165 carbohydrates including 19 N-glycan high mannose, 17 Nglycan hybrid, 9 N-glycan complex, 17 O-glycan core, 27 Sialoside, 25 Fucoside and 51 other glycan residues suggests, that linked cargo-receptor apical transport may provide a path to epithelial polarization that may be modulated by core fucosylation.

scholarly journals MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway

2017 ◽  
Vol 24 (8) ◽  
pp. 1431-1442 ◽  
Author(s):  
Xiaoyun Chen ◽  
Wei Xiao ◽  
Weirong Chen ◽  
Xialin Liu ◽  
Mingxing Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Lens Epithelial Cells ◽  
Mesenchymal Transition ◽  
Fibrotic Diseases

Abstract Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

scholarly journals Identification and validation of putative target genes regulated by miR-34 in cervical cancer

2021 ◽  
Author(s):  
Nalini Venkatesan ◽  
Ashley Xavier ◽  
Sindhu K.J. ◽  
Himanshu Sinha ◽  
Karunagaran Devarajan
Keyword(s):  
Cervical Cancer ◽  
Candidate Genes ◽  
Large Scale ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Target Prediction ◽  
Functional Enrichment ◽  
Mesenchymal Transition ◽  
Putative Target

The emergence of large-scale transcriptomic data provides the opportunity for identifying novel putative targets of microRNAs (miRNAs). In this study, we followed a computational pipeline to predict the candidate gene targets of the miR-34 family. This approach integrates the expressions of miR-34 with genes of heterogeneous primary cervical epithelial squamous cell carcinomas (CESC). Integration of miR-34b and epithelial-mesenchymal transition (EMT) regulated genes has also been focussed, EMT being a reversible process that fuels cancer metastasis. An in-silico approach involving three processes was carried out with CESC datasets of the cancer atlas genome (TCGA), which includes correlation analysis, target prediction database lookup, functional enrichment, network analysis, survival analysis, and EMT score derivation. The results indicate that the miR-34 family may regulate the candidate genes of the mTOR pathway, cell cycle (CCND2) and cell adhesion functions (FZD4). Further, the study reveals the possible regulation of EMT signature genes, namely BMP7, CAV1 and ID2by miR-34b. Further, these transcriptomic signatures were validated in a subset of CESC from the South Asian Indian population (n = 10) and in non-cancerous cervical tissues (n = 5). Upon stably expressing miR-34b in cervical cancer cells (C33A and HeLa), we found repression of these candidate genes and a low negative correlation (r2 = 0.07) between miR-34b and EMT score indicating FN1 as its putative target. Together, these studies revealed the potential targets of the miR-34 family, especially miR-34b, with the hope that they would emerge as potential biomarkers and/or promising therapeutic targets in CESC.

scholarly journals Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition

Oncogenesis ◽  
2021 ◽  
Vol 10 (6) ◽  
Author(s):  
Yoshiaki Maru ◽  
Naotake Tanaka ◽  
Yasutoshi Tatsumi ◽  
Yuki Nakamura ◽  
Makiko Itami ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Cellular Transformation ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Immunodeficient Mice ◽  
Organ Type

AbstractKRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.

scholarly journals Quantitative Proteomic Analysis in Alveolar Type II Cells Reveals the Different Capacities of RAS and TGF-β to Induce Epithelial–Mesenchymal Transition

2021 ◽  
Vol 8 ◽  
Author(s):  
Yilu Zhou ◽  
Charlotte Hill ◽  
Liudi Yao ◽  
Juanjuan Li ◽  
David Hancock ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Proteomic Analysis ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Acute Injury ◽  
Alveolar Type ◽  
Type Ii ◽  
Label Free ◽  
Mesenchymal Transition

Alveolar type II (ATII) epithelial cells function as stem cells, contributing to alveolar renewal, repair and cancer. Therefore, they are a highly relevant model for studying a number of lung diseases, including acute injury, fibrosis and cancer, in which signals transduced by RAS and transforming growth factor (TGF)-β play critical roles. To identify downstream molecular events following RAS and/or TGF-β activation, we performed proteomic analysis using a quantitative label-free approach (LC-HDMSE) to provide in-depth proteome coverage and estimates of protein concentration in absolute amounts. Data are available via ProteomeXchange with identifier PXD023720. We chose ATIIER:KRASV12as an experimental cell line in which RAS is activated by adding 4-hydroxytamoxifen (4-OHT). Proteomic analysis of ATII cells treated with 4-OHT or TGF-β demonstrated that RAS activation induces an epithelial–mesenchymal transition (EMT) signature. In contrast, under the same conditions, activation of TGF-β signaling alone only induces a partial EMT. EMT is a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell–cell adhesion to gain migratory properties, and is involved in embryonic development, wound healing, fibrosis and cancer metastasis. Thus, these results could help to focus research on the identification of processes that are potentially driving EMT-related human disease.

scholarly journals Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1882
Author(s):  
Arpita Datta ◽  
Shuo Deng ◽  
Vennila Gopal ◽  
Kenneth Chun-Hong Yap ◽  
Clarissa Esmeralda Halim ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Actin Cytoskeleton ◽  
Cancer Cells ◽  
Intermediate Filaments ◽  
Actin Polymerization ◽  
Cancer Metastasis ◽  
Cellular Transformation ◽  
Actin Binding ◽  
Migration And Invasion ◽  
Mesenchymal Transition

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton.

scholarly journals Different macrophages equally induce EMT in endometria of adenomyosis and normal

Reproduction ◽  
2017 ◽  
Vol 154 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Min An ◽  
Dong Li ◽  
Ming Yuan ◽  
Qiuju Li ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Quantitative Polymerase Chain Reaction ◽  
Immunohistochemical Analysis ◽  
Secretory Phase ◽  
Normal Endometrium ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Endometrial Cells

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial–mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-β1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of CD163, IL10 and MMP12 using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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