O-glycan recognition and function in mice and human cancers

2020 ◽  
Vol 477 (8) ◽  
pp. 1541-1564 ◽  
Author(s):  
Gabrielle E. Cervoni ◽  
Jane J. Cheng ◽  
Kathryn A. Stackhouse ◽  
Jamie Heimburg-Molinaro ◽  
Richard D. Cummings
Keyword(s):  
Tumor Cells ◽  
Tumor Development ◽  
Cell Types ◽  
Protein Glycosylation ◽  
Ca 125 ◽  
Post Translational Modification ◽  
Tn Antigen ◽  
Altered Expression ◽  
Sialyl Tn Antigen ◽  
And Function

Protein glycosylation represents a nearly ubiquitous post-translational modification, and altered glycosylation can result in clinically significant pathological consequences. Here we focus on O-glycosylation in tumor cells of mice and humans. O-glycans are those linked to serine and threonine (Ser/Thr) residues via N-acetylgalactosamine (GalNAc), which are oligosaccharides that occur widely in glycoproteins, such as those expressed on the surfaces and in secretions of all cell types. The structure and expression of O-glycans are dependent on the cell type and disease state of the cells. There is a great interest in O-glycosylation of tumor cells, as they typically express many altered types of O-glycans compared with untransformed cells. Such altered expression of glycans, quantitatively and/or qualitatively on different glycoproteins, is used as circulating tumor biomarkers, such as CA19-9 and CA-125. Other tumor-associated carbohydrate antigens (TACAs), such as the Tn antigen and sialyl-Tn antigen (STn), are truncated O-glycans commonly expressed by carcinomas on multiple glycoproteins; they contribute to tumor development and serve as potential biomarkers for tumor presence and stage, both in immunohistochemistry and in serum diagnostics. Here we discuss O-glycosylation in murine and human cells with a focus on colorectal, breast, and pancreatic cancers, centering on the structure, function and recognition of O-glycans. There are enormous opportunities to exploit our knowledge of O-glycosylation in tumor cells to develop new diagnostics and therapeutics.

Impact of protein glycosylation on lipoprotein metabolism and atherosclerosis

2020 ◽  
Author(s):  
Angela Pirillo ◽  
Monika Svecla ◽  
Alberico Luigi Catapano ◽  
Adriaan G Holleboom ◽  
Giuseppe Danilo Norata
Keyword(s):  
Genetic Diseases ◽  
Clinical Manifestations ◽  
Lipoprotein Metabolism ◽  
Protein Glycosylation ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Lipoprotein Receptors ◽  
Additional Information ◽  
Rare Genetic Diseases ◽  
And Function

Abstract Protein glycosylation is a post-translational modification consisting in the enzymatic attachment of carbohydrate chains to specific residues of the protein sequence. Several types of glycosylation have been described, with N-glycosylation and O-glycosylation being the most common types impacting on crucial biological processes, such as protein synthesis, trafficking, localization, and function. Genetic defects in genes involved in protein glycosylation may result in altered production and activity of several proteins, with a broad range of clinical manifestations, including dyslipidaemia and atherosclerosis. A large number of apolipoproteins, lipoprotein receptors, and other proteins involved in lipoprotein metabolism are glycosylated, and alterations in their glycosylation profile are associated with changes in their expression and/or function. Rare genetic diseases and population genetics have provided additional information linking protein glycosylation to the regulation of lipoprotein metabolism.

scholarly journals PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Miguel Hernandez-Quiles ◽  
Marjoleine F. Broekema ◽  
Eric Kalkhoven
Keyword(s):  
Regulatory Networks ◽  
Target Gene ◽  
Critical Role ◽  
Tumor Development ◽  
Cell Types ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Treatment Of Obesity ◽  
And Function ◽  
Cancer And Inflammation

The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation—where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα—is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression—where PPARγ alters gene expression independent of DNA binding—is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ’s target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.

scholarly journals Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability

2004 ◽  
Vol 24 (4) ◽  
pp. 1680-1690 ◽  
Author(s):  
Niall O'Donnell ◽  
Natasha E. Zachara ◽  
Gerald W. Hart ◽  
Jamey D. Marth
Keyword(s):  
Somatic Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Embryonic Stem ◽  
Cell Types ◽  
Protein Glycosylation ◽  
Embryo Viability ◽  
Altered Expression ◽  
T Cell Apoptosis

ABSTRACT The Ogt gene encodes a glycosyltransferase that links N-acetylglucosamine to serine and threonine residues (O-GlcNAc) on nuclear and cytosolic proteins. Efforts to study a mammalian model of Ogt deficiency have been hindered by the requirement for this X-linked gene in embryonic stem cell viability, necessitating the use of conditional mutagenesis in vivo. We have extended these observations by segregating Ogt mutation to distinct somatic cell types, including neurons, thymocytes, and fibroblasts, the latter by an approach developed for inducible Ogt mutagenesis. We show that Ogt mutation results in the loss of O-GlcNAc and causes T-cell apoptosis, neuronal tau hyperphosphorylation, and fibroblast growth arrest with altered expression of c-Fos, c-Jun, c-Myc, Sp1, and p27. We further segregated the mutant Ogt allele to parental gametes by oocyte- and spermatid-specific Cre-loxP mutagenesis. By this we established an in vivo genetic approach that supports the ontogeny of female heterozygotes bearing mutant X-linked genes required during embryogenesis. Successful production and characterization of such female heterozygotes further indicates that mammalian cells commonly require a functional Ogt allele. We find that O-GlcNAc modulates protein phosphorylation and expression among essential and conserved cell signaling pathways.

scholarly journals Single‐cell RNA sequencing in cancer research

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yijie Zhang ◽  
Dan Wang ◽  
Miao Peng ◽  
Le Tang ◽  
Jiawei Ouyang ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Escape ◽  
Tumor Development ◽  
Cell Types ◽  
Resistance Mechanisms ◽  
Single Cell Rna Sequencing ◽  
Tumor Research

AbstractSingle-cell RNA sequencing (scRNA-seq), a technology that analyzes transcriptomes of complex tissues at single-cell levels, can identify differential gene expression and epigenetic factors caused by mutations in unicellular genomes, as well as new cell-specific markers and cell types. scRNA-seq plays an important role in various aspects of tumor research. It reveals the heterogeneity of tumor cells and monitors the progress of tumor development, thereby preventing further cellular deterioration. Furthermore, the transcriptome analysis of immune cells in tumor tissue can be used to classify immune cells, their immune escape mechanisms and drug resistance mechanisms, and to develop effective clinical targeted therapies combined with immunotherapy. Moreover, this method enables the study of intercellular communication and the interaction of tumor cells and non-malignant cells to reveal their role in carcinogenesis. scRNA-seq provides new technical means for further development of tumor research and is expected to make significant breakthroughs in this field. This review focuses on the principles of scRNA-seq, with an emphasis on the application of scRNA-seq in tumor heterogeneity, pathogenesis, and treatment.

Exosome-based Tumor Therapy: Opportunities and Challenges

2020 ◽  
Vol 21 (5) ◽  
pp. 339-351 ◽  
Author(s):  
Chunmei Li ◽  
Xiaoming Hou ◽  
Peng Zhang ◽  
Juan Li ◽  
Xiaoguang Liu ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Tumor Development ◽  
Cell Types ◽  
Target Cells ◽  
Biological Origin ◽  
Major Health Problem ◽  
Therapeutic Drugs ◽  
Multiple Processes ◽  
And Function ◽  
Different Cell Types

Background: Exosomes play an important role in transferring information among different cell types, as they transport materials from the cell membrane to the cytoplasm. They are involved not only in normal physiological functions, but also in the occurrence and development of a variety of diseases. Cancer is a major health problem affecting humans. Currently, exosomes are considered novel stars in tumor therapy. Objective: To present a review focusing on the role of exosomes in tumorigenesis and development and the possibility of treating tumors with exosome-targeted therapies or using exosomes as carriers. Methods: We reviewed literature related to the biological origin and function of exosomes and exosome-tumor relationship. Results: Exosomes are closely related to tumor immunity, angiogenesis, pre-metastasis microenvironment, chemoresistance, energy metabolism, etc. Tumor therapy involving the targeting of exosomes involves block the generation, secretion, uptake of exosomes, and elimination of circulating exosomes, and develop antitumor vaccines. Exosome as delivery vehicles can be loaded with chemotherapeutic drugs, therapeutic genes, and other therapeutic drugs to target cells. Prospects and challenges of exosome-based tumor therapy are also discussed. Conclusion: Exosomes are involved in multiple processes during tumor development and should be further studied as novel targets for cancer therapy.

scholarly journals Investigation of Human Endogenous Retrovirus-K (ERVK) Expression and Function in Normal Placentation and Preterm Pregnancy

2021 ◽  
Author(s):  
Jimi L Rosenkrantz ◽  
Michael Martinez ◽  
Adithi Mahankali ◽  
Lucia Carbone ◽  
Shawn L Chavez
Keyword(s):  
Human Placenta ◽  
Cell Types ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Innate Immune Responses ◽  
Altered Expression ◽  
Early Human Development ◽  
Specific Analysis ◽  
Choriocarcinoma Cells ◽  
And Function

Background: There is a growing body of evidence indicating the importance of endogenous retrovirus (ERV) derived proteins during early development and reproduction in mammals. Recently, a protein derived from the youngest ERV in humans, ERVK (HML2), was shown to be expressed during human placentation. Since a number of highly similar ERVK proviral loci exist across the human genome, locus-specific analysis of ERVK transcription and identification of the coding sequence expressed in the human placenta is difficult. Thus, despite its activity in early human development, the native expression and function of ERVK in the human placenta remains largely uncharacterized. Results: In this study, we comprehensively examined locus-specific ERVK transcription across several human placental tissues and cell types. Through a combination of RNA-seq and siRNA knock-down analyses, we identified the expression of a single ERVK locus, ERVK11q23.3, as (1) being significantly upregulated in preterm compared to term placenta, (2) predominantly expressed by mononuclear trophoblasts, (3) capable of encoding a truncated viral-like envelope protein, and (4) contributing to the expression cytokines involved in both antiviral and anti-inflammatory innate immune responses in human placental trophoblasts and BeWo choriocarcinoma cells, respectively. Conclusions: Collectively, the results of this study highlight the utility of studying locus-specific ERVK expression, provide a thorough characterization of locus-specific ERVK transcription from human placental tissues, and indicate that altered expression of placental ERVK11q23.3 influences interferon antiviral response, which may contribute to preterm birth and other pregnancy complications.

scholarly journals Bidirectional and Opposite Effects of Naïve Mesenchymal Stem Cells Ontumor Growth and Progression

2019 ◽  
Vol 9 (4) ◽  
pp. 539-558 ◽  
Author(s):  
Faramarz Rahmatizadeh ◽  
Shiva Gholizadeh-Ghaleh Aziz ◽  
Khodadad Khodadadi ◽  
Maryam Lale Ataei ◽  
Esmaeil Ebrahimie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Tumor Stroma ◽  
Cell Types ◽  
Great Promise ◽  
Tumor Tissues ◽  
Essential Components

Cancer has long been considered as a heterogeneous population of uncontrolled proliferation ofdifferent transformed cell types. The recent findings concerning tumorigeneses have highlightedthe fact that tumors can progress through tight relationships among tumor cells, cellular, andnon-cellular components which are present within tumor tissues. In recent years, studies haveshown that mesenchymal stem cells (MSCs) are essential components of non-tumor cells withinthe tumor tissues that can strongly affect tumor development. Several forms of MSCs have beenidentified within tumor stroma. Naïve (innate) mesenchymal stem cells (N-MSCs) derived fromdifferent sources are mostly recruited into the tumor stroma. N-MSCs exert dual and divergenteffects on tumor growth through different conditions and factors such as toll-like receptorpriming (TLR-priming), which is the primary underlying causes of opposite effects. Moreover,MSCs also have the contrary effects by various molecular mechanisms relying on direct cellto-cell connections and indirect communications through the autocrine, paracrine routes, andtumor microenvironment (TME).Overall, cell-based therapies will hold great promise to provide novel anticancer treatments.However, the application of intact MSCs in cancer treatment can theoretically cause adverseclinical outcomes. It is essential that to extensively analysis the effective factors and conditionsin which underlying mechanisms are adopted by MSCs when encounter with cancer.The aim is to review the cellular and molecular mechanisms underlying the dual effects ofMSCs followed by the importance of polarization of MSCs through priming of TLRs.<br />

scholarly journals Direct comparison of derivatization strategies for LC-MS/MS analysis of N-glycans

The Analyst ◽  
2017 ◽  
Vol 142 (23) ◽  
pp. 4446-4455 ◽  
Author(s):  
Shiyue Zhou ◽  
Lucas Veillon ◽  
Xue Dong ◽  
Yifan Huang ◽  
Yehia Mechref
Keyword(s):  
Protein Folding ◽  
Protein Glycosylation ◽  
Post Translational Modification ◽  
P Protein ◽  
Ms Analysis ◽  
And Function

Protein glycosylation is a common post-translational modification that has significant impacts on protein folding, lifespan, conformation, distribution and function.

scholarly journals Integrin Regulation of CAF Differentiation and Function

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 715 ◽  
Author(s):  
C. Michael DiPersio ◽  
Livingston Van De Water
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Extensive Literature ◽  
Cancer Associated Fibroblasts ◽  
Epithelial Tumor ◽  
And Function

Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs.

scholarly journals Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 3726 ◽  
Author(s):  
Christian Sordo-Bahamonde ◽  
Seila Lorenzo-Herrero ◽  
Ángel R. Payer ◽  
Segundo Gonzalez ◽  
Alejandro López-Soto
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Expression Patterns ◽  
Tumor Development ◽  
Death Receptor ◽  
Apoptosis Resistance ◽  
Altered Expression ◽  
Effector Cells ◽  
Development Of Resistance

Natural killer (NK) cells are major contributors to immunosurveillance and control of tumor development by inducing apoptosis of malignant cells. Among the main mechanisms involved in NK cell-mediated cytotoxicity, the death receptor pathway and the release of granules containing perforin/granzymes stand out due to their efficacy in eliminating tumor cells. However, accumulated evidence suggest a profound immune suppression in the context of tumor progression affecting effector cells, such as NK cells, leading to decreased cytotoxicity. This diminished capability, together with the development of resistance to apoptosis by cancer cells, favor the loss of immunogenicity and promote immunosuppression, thus partially inducing NK cell-mediated killing resistance. Altered expression patterns of pro- and anti-apoptotic proteins along with genetic background comprise the main mechanisms of resistance to NK cell-related apoptosis. Herein, we summarize the main effector cytotoxic mechanisms against tumor cells, as well as the major resistance strategies acquired by tumor cells that hamper the extrinsic and intrinsic apoptotic pathways related to NK cell-mediated killing.

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