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Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities

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Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 21331

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Special Issue Editors

Prof. Dr. Yuanyuan Ruan

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Guest Editor

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Interests: tumor glycobiology; signaling transduction; protein translation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Feng Guan

E-Mail Website
Guest Editor

College of Life Sciences, Northwest University, Xi'an 710069, China
Interests: glycosylation; glycoproteins; glycomics

Special Issue Information

Dear Colleagues,

Alterations in glycosylation are suggested to be involved in fundamental changes of molecular and biological processes occurring in tumorigenesis, including cellular signaling, proliferation, immune escape, invasion and metastasis. Specific glycans also serve as potential diagnostic biomarkers as well as therapeutic targets in several types of cancer. Hence, there is a strong requirement to identify cancer-associated glycan patterns and characterize the roles of glycosylation in controlling tumor initiation and development. This necessitates deep investigations into the molecular basis underlying how glycans affect protein activity and serve as cancer hallmarks. Novel technological developments in glycobiology and applications of glycans in the oncology field are also needed.

Potential subjects of this Special Issue include, but are not limited to: the alteration of glycosyltransferase activity and protein glycosylation pattern during oncogenesis and progression; the effects of aberrant glycosylation on cell-cell communication, signaling transduction, transcription and epigenetics, and metabolic reprogramming; the influence of tumor-associated glycans on modulating tumorigenic behavior and shaping the tumor microenvironment; novel high-throughput glycomic and glycoproteomic methods; the development of strategies targeting aberrant protein glycosylation; and natural and synthetic glycan-based medicine against tumor cells.

Prof. Dr. Yuanyuan Ruan
Prof. Dr. Feng Guan
Guest Editors

Manuscript Submission Information

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Keywords

protein glycosylation
tumorigenesis
lectin
glycosyltransferase
tumor behavior
tumor microenvironment
glycomics
glycoproteomics
diagnostic biomarker
therapeutic strategy

Published Papers (10 papers)

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Research

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16 pages, 6253 KiB

Open AccessArticle

Astragalus Polysaccharide Promotes Doxorubicin-Induced Apoptosis by Reducing O-GlcNAcylation in Hepatocellular Carcinoma

by Mingzhe Li, Fangfang Duan, Zhiqiang Pan, Xiaomei Liu, Wenli Lu, Chao Liang, Zhaoqin Fang, Peike Peng and Dongwei Jia

Cells 2023, 12(6), 866; https://doi.org/10.3390/cells12060866 - 10 Mar 2023

Cited by 8 | Viewed by 1766

Abstract

The toxicity and side effects of chemotherapeutic drugs remain a crucial obstacle to the clinical treatment of hepatocellular carcinoma (HCC). Identifying combination therapy from Chinese herbs to enhance the sensitivity of tumors to chemotherapeutic drugs is of particular interest. Astragalus polysaccharide (APS), one of the natural active components in Astragalus membranaceus, has been reported to exhibit anti-tumor properties in diverse cancer cell lines. The aim of this study was to determine the effect of APS on Doxorubicin (Dox)-induced apoptosis in HCC and the underlying mechanism. The results showed that APS dose-dependently promoted Dox-induced apoptosis and enhanced endoplasmic reticulum (ER) stress. Additionally, APS decreased the mRNA level and protein stability of O-GlcNAc transferase (OGT), and increased the O-GlcNAcase (OGA) expression. Furthermore, OGT lentiviral transfection or PugNAc (OGA inhibitor) treatment reversed the ER stress and apoptosis induced by the combination of Dox and APS. A xenograft tumor mouse model confirmed that the combination of APS and Dox showed an advantage in inhibiting tumor growth in vivo. These findings suggested that APS promoted Dox-induced apoptosis in HCC cells through reducing the O-GlcNAcylation, which led to the exacerbation of ER stress and activation of apoptotic pathways. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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20 pages, 7482 KiB

Open AccessArticle

FUT2 Facilitates Autophagy and Suppresses Apoptosis via p53 and JNK Signaling in Lung Adenocarcinoma Cells

by Yuqi Zhang, Enze Yao, Yijing Liu, Yining Zhang, Mengyang Ding, Jingyu Liu, Xiaoming Chen and Sairong Fan

Cells 2022, 11(24), 4031; https://doi.org/10.3390/cells11244031 - 13 Dec 2022

Cited by 4 | Viewed by 1518

Abstract

Lung cancer is the most common cancer with high morbidity and mortality worldwide. Our previous studies showed that fucosyltransferase 2 (FUT2) is highly expressed in lung adenocarcinoma (LUAD) and plays a vital role in the tumorigenesis of LUAD. However, the underlying mechanism is not fully understood. Autophagy has recently attracted increasing attention due to its pro-survival role in cancer progression and metastasis. Here, we found that FUT2 was up-regulated and had an AUC (Area Under Curve) value of 0.964 in lung adenocarcinoma based on the TCGA dataset. Knockdown of FUT2 weakened the autophagy response, as evidenced by a degradation of LC3-II and Beclin1. The phosphorylation levels of AMPK, ULK1, and PI3K III were significantly reduced by FUT2 knockdown. FUT2 promoted the translocation of p53 from the cytoplasm into the nucleus, which triggered the DRAM1 pathway and enhanced autophagy. Meanwhile, the knockdown of FUT2 increased the phosphorylation of JNK and promoted mitochondrial-mediated apoptosis. Furthermore, the knockdown of FUT2 inhibited the autophagy induced by Z-VAD-FMK and promoted the apoptosis suppressed by rapamycin. The autophagy and apoptosis regulated by FUT2 antagonized each other. Taken together, these findings provide a mechanistic understanding of how FUT2 mediated the crosstalk between autophagy and apoptosis, which determine lung cancer cell death and survival, leading to the progression of lung adenocarcinoma. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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12 pages, 11058 KiB

Open AccessArticle

Identification and Validation of Glycosyltransferases Correlated with Cuproptosis as a Prognostic Model for Colon Adenocarcinoma

by Wei Ma, Lingyuan Zhu, Shushu Song, Bo Liu and Jianxin Gu

Cells 2022, 11(23), 3728; https://doi.org/10.3390/cells11233728 - 22 Nov 2022

Cited by 3 | Viewed by 1381

Abstract

Cuproptosis is a newly defined programmed cell death pattern and is believed to play an important role in tumorigenesis and progression. In addition, many studies have shown that glycosylation modification is of vital importance in tumor progression. However, it remains unclear whether glycosyltransferases, the most critical enzymes involved in glycosylation modification, are associated with cuproptosis. In this study, we used bioinformatic methods to construct a signature of cuproptosis-related glycosyltransferases to predict the prognosis of colon adenocarcinoma patients. We found that cuproptosis was highly correlated with four glycosyltransferases in COAD, and our model predicted the prognosis of COAD patients. Further analysis of related functions revealed the possibility that cuproptosis-related glycosyltransferase Exostosin-like 2 (EXTL2) participated in tumor immunity. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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11 pages, 1115 KiB

Open AccessArticle

Loss of GNE Predicts Lymph Node Metastasis in Early Gastric Cancer

by Xinying Guo, Jie Gu, Anwei Xue, Shushu Song, Bo Liu, Xiaodong Gao, Jianxin Gu, Lei Chang and Yuanyuan Ruan

Cells 2022, 11(22), 3624; https://doi.org/10.3390/cells11223624 - 16 Nov 2022

Viewed by 1432

Abstract

Endoscopic surgery is increasingly utilized for the treatment of early gastric cancer (EGC) worldwide, whereas lymph node metastasis (LNM) remains a critical risk factor for the relapse of EGC after endoscopic surgery. Therefore, identifying potential predictive factors and understanding the molecular mechanisms are urgently needed for improving the outcome of EGC patients with LNM. UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme in the process of biosynthesis of CMP-Neu5Ac from UDP-N-acetylglucosamine (UDP-GlcNAc), which acts as a substrate for several reactions in glycan metabolism. In this study, we found that GNE was down-regulated in EGC patients with LNM. GNE expression as well as localization, tumor size, intravascular tumor thrombi and Lauren’s classification were further identified as independent predictive factors for LNM. Combining GNE expression with traditional risk factors, including tumor size and differentiation degrees, could generate a better model for predicting LNM in EGC patients. Overall, our study implies that low GNE expression is a potential predictor of LNM in EGC. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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18 pages, 12323 KiB

Open AccessArticle

ALG3 Promotes Peritoneal Metastasis of Ovarian Cancer through Increasing Interaction of α1,3-mannosylated uPAR and ADAM8

by Xinyuan Cui, Xiaosong Pei, Hao Wang, Ping Feng, Huamin Qin, Shuai Liu, Qiu Yan and Jiwei Liu

Cells 2022, 11(19), 3141; https://doi.org/10.3390/cells11193141 - 06 Oct 2022

Cited by 5 | Viewed by 1914

Abstract

Peritoneal metastasis is the main cause of poor prognoses and high mortality in ovarian cancer patients. Abnormal protein glycosylation modification is associated with cancer malignancy. Elevated α1,3-mannosyltransferase 3 (ALG3), which catalyzes the α1,3-mannosylation of glycoproteins, has been found in some malignant tumors. However, the pathological significance of ALG3 and its regulatory mechanism in ovarian cancer metastasis is unclear. The results showed that the level of ALG3/α1,3-mannosylation was higher in human ovarian cancer tissues compared with normal ovarian tissues, as measured by Lectin chip, Western blot and Lectin blot analyses, as well as ovarian tissue microarray analysis. ALG3 was also correlated with the poor prognosis of ovarian cancer patients, according to survival analysis. The downregulation of ALG3 decreased the proliferation, stemness and peritoneal metastasis of ovarian cancer cells. The increase in urokinase plasminogen activator receptor (uPAR) α1,3-mannosylation catalyzed by ALG3 enhanced urokinase plasminogen activator (uPA)/uPAR activation and the interaction of uPAR with a disintegrin and metalloproteinase 8 (ADAM8), which promoted ovarian cancer peritoneal metastasis via the ADAM8/Ras/ERK pathway. Furthermore, decreased ALG3 suppressed ascites formation and the peritoneal metastasis of ovarian cancer cells in mice. This study highlights ALG3 as a potential diagnostic biomarker and prospective therapeutic target for ovarian cancer. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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15 pages, 5267 KiB

Open AccessArticle

Hyaluronic Acid-Coated Bovine Milk Exosomes for Achieving Tumor-Specific Intracellular Delivery of miRNA-204

by Dan Li, Liang Gong, Han Lin, Surui Yao, Yuan Yin, Zhifang Zhou, Jie Shi, Zhimeng Wu and Zhaohui Huang

Cells 2022, 11(19), 3065; https://doi.org/10.3390/cells11193065 - 29 Sep 2022

Cited by 16 | Viewed by 2423

Abstract

Cell type-specific drug delivery is a straightforward strategy to achieve targeted cancer therapy and reduce side effects. Hyaluronic acid (HA), an U.S. Food and Drug Administration (FDA)-approved biocompatible carbohydrate polymer, has been extensively employed as a targeting ligand for a drug delivery system due to its natural ability to bind to tumor cells overexpressing cluster of differentiation 44 (CD44) receptors. Here, we report the preparation and antitumor efficacy of HA-coated bovine milk exosomes (HA-mExo) for tumor-specific delivery of microRNA-204-5p mimics (miR-204). The exosome-based delivery formulation was prepared with miR-204 encapsulated inside the lumen and HA displayed outside the membrane. The resultant formulation of HA-mExo-miR204 was able to specifically target CD44-positive cancer cells, with a concomitant increase in the intracellular uptake of miR-204. Compared to the uncoated mExo-miR204 formulation, HA-mExo-miR204 showed significantly increased antitumor efficacy both in vitro and in vivo. Importantly, HA-mExo-miR204 showed excellent biocompatibility and did not cause significant systemic toxicity. Given that both HA and bovine milk exosomes are low-cost and highly accessible biogenic materials with broad biomedical applications, HA-decorated bovine milk exosomes can be proven to be a practical drug delivery system of RNA drugs for targeted cancer therapy. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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Graphical abstract

13 pages, 5208 KiB

Open AccessArticle

Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

by Chunyan Yang, Zixuan Guan, Xincheng Pang, Zengqi Tan, Xiaomin Yang, Xiang Li and Feng Guan

Cells 2022, 11(17), 2642; https://doi.org/10.3390/cells11172642 - 25 Aug 2022

Cited by 9 | Viewed by 2031

Abstract

Hepatocellular carcinoma (HCC) is one of the dominating causes of cancer-related death throughout the world. Treatment options for patients with HCC vary, however, the lack of effective targeted drugs is the major reason for death in advanced HCC patients. In this study, a delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed. In this system, we initially erased terminal linked α2–3 and α2–6 sialic acids on the surface of EVs by neuraminidase. The exhibition of galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in treated MSC-EVs can specifically be recognized by asialoglycoprotein receptor (ASGPR) of hepatoma cells. Compared to free Dox and Dox-loaded EVs, desialylated EVs loaded with Dox significantly presented the improved cellular uptake, prioritized targeting efficacy, and had a better inhibiting effect in vitro and in vivo. Overall, the results of the present study of the demonstrated delivery system using desialylated MSC-EVs suggest its therapeutic potential for HCC. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 2785 KiB

Open AccessArticle

Phaseolus vulgaris Erythroagglutinin (PHA-E)-Positive Ceruloplasmin Acts as a Potential Biomarker in Pancreatic Cancer Diagnosis

by Shanshan Sha, Yating Wang, Menglu Liu, Gang Liu, Ning Fan, Zhi Li and Weijie Dong

Cells 2022, 11(15), 2453; https://doi.org/10.3390/cells11152453 - 08 Aug 2022

Cited by 2 | Viewed by 2035

Abstract

Pancreatic cancer (PC) remains one of the top 10 causes of cancer-related death in recent years. Approximately 80% of PC patients are diagnosed at the middle or advanced stage and miss the opportunity for surgery. The demand for early diagnostic methods and reliable biomarkers is increasing, although a number of tumor markers such as CA19-9 and CEA have already been utilized in clinics. In this study, we analyzed the alteration of N-glycan of serum glycoproteins by mass spectrometry and lectin blotting. The results showed that bisecting GlcNAc structures of glycoproteins are significantly increased in PC patients’ sera. With Phaseolus vulgaris Erythroagglutinin (PHA-E) lectin that specifically recognizes bisecting GlcNAc N-glycans, the serum glycoproteins bearing bisecting GlcNAc in PC patients’ sera were pulled down and identified by nano-LC-MS/MS. Among them, ceruloplasmin (Cp) was screened out with a satisfied sensitivity and specificity in identifying PC from acute pancreatitis patients (AUC: 0.757) and normal healthy persons (AUC: 0.972), suggesting a close association between Cp and PC development and diagnosis. To prove that, the Cp expression in tumor tissues of PC patients was examined. The results showed that Cp was significantly upregulated in PC tissues compared to that in adjacent normal tissues. All these results suggested that PHA-E-positive Cp could be a potential PC-specific glycoprotein marker to distinguish PC patients from acute pancreatitis patients and normal persons. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

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16 pages, 1325 KiB

Open AccessReview

A Sweet Warning: Mucin-Type O-Glycans in Cancer

by Yuhan Zhang, Lingbo Sun, Changda Lei, Wenyan Li, Jiaqi Han, Jing Zhang and Yuecheng Zhang

Cells 2022, 11(22), 3666; https://doi.org/10.3390/cells11223666 - 18 Nov 2022

Cited by 8 | Viewed by 2904

Abstract

Glycosylation is a common post-translational modification process of proteins. Mucin-type O-glycosylation is an O-glycosylation that starts from protein serine/threonine residues. Normally, it is involved in the normal development and differentiation of cells and tissues, abnormal glycosylation can lead to a variety of diseases, especially cancer. This paper reviews the normal biosynthesis of mucin-type O-glycans and their role in the maintenance of body health, followed by the mechanisms of abnormal mucin-type O-glycosylation in the development of diseases, especially tumors, including the effects of Tn, STn, T antigen, and different glycosyltransferases, with special emphasis on their role in the development of gastric cancer. Finally, tumor immunotherapy targeting mucin-type O-glycans was discussed. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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19 pages, 2159 KiB

Open AccessReview

Glycosylation in Renal Cell Carcinoma: Mechanisms and Clinical Implications

by Xinqing Zhu, Abdullah Al-Danakh, Lin Zhang, Xiaoxin Sun, Yuli Jian, Haotian Wu, Dan Feng, Shujing Wang and Deyong Yang

Cells 2022, 11(16), 2598; https://doi.org/10.3390/cells11162598 - 20 Aug 2022

Cited by 3 | Viewed by 2619

Abstract

Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors of the urinary system, accounting for around 2% of all cancer diagnoses and deaths worldwide. Clear cell RCC (ccRCC) is the most prevalent and aggressive histology with an unfavorable prognosis and inadequate treatment. Patients’ progression-free survival is considerably improved by surgery; however, 30% of patients develop metastases following surgery. Identifying novel targets and molecular markers for RCC prognostic detection is crucial for more accurate clinical diagnosis and therapy. Glycosylation is a critical post-translational modification (PMT) for cancer cell growth, migration, and invasion, involving the transfer of glycosyl moieties to specific amino acid residues in proteins to form glycosidic bonds through the activity of glycosyltransferases. Most cancers, including RCC, undergo glycosylation changes such as branching, sialylation, and fucosylation. In this review, we discuss the latest findings on the significance of aberrant glycans in the initiation, development, and progression of RCC. The potential biomarkers of altered glycans for the diagnosis and their implications in RCC have been further highlighted. Full article

(This article belongs to the Special Issue Glycobiology in Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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