Abnormal sialylation and fucosylation of saliva glycoproteins: Characteristics of lung cancer-specific biomarkers

Abstract

Dysregulated surface glycoproteins play an important role in tumor cell proliferation and progression. Abnormal glycosylation of these glycoproteins may activate tumor signal transduction and lead to tumor development. The tumor microenvironment alters its molecular composition, some of which regulate protein glycosylation biosynthesis. The glycosylation of saliva proteins in lung cancer patients is different from healthy controls, in which the glycans of cancer patients are highly sialylated and hyperfucosylated. Most studies have shown that O-glycans from cancer are truncated O-glycans, while N-glycans contain fucoses and sialic acids. Because glycosylation analysis is challenging, there are few reports on how glycosylation of saliva proteins is related to the occurrence or progression of lung cancer. In this review, we discussed glycoenzymes involved in protein glycosylation, their changes in tumor microenvironment, potential tumor biomarkers present in body fluids, and abnormal glycosylation of saliva or lung glycoproteins. We further explored the effect of glycosylation changes on tumor signal transduction, and emphasized the role of receptor tyrosine kinases in tumorigenesis and metastasis.

Keywords: Glycoenzyme; Glycosylation; Mass spectrometry; Saliva; Tumor biomarker.

Graphical abstract

Fig. 1

Schematic diagram of abnormal protein glycosylation in tumor cells. (a) N-glycans and O-glycans are present on the surface glycoproteins of healthy cells. The process of glycosylation biosynthesis takes place in the endoplasmic reticulum (ER) and Golgi apparatus. Glycosylation occurs on transmembrane proteins, cell-matrix adhesion proteins, mucins, and receptor tyrosine kinases (RTKs). (b) Aberrant glycosylation of cancer cells by dysregulated glycoenzymes in the tumor microenvironment. Sialylated glycans and truncated O-glycans are synthesized on the surface glycoproteins of cancer cells. Mucin carries dense O-glycans of T, Tn, sT and sTn antigens. The metastatic cells upregulate fucosylation due to the increase of FUT genes, including FUT8 (α1,6 fucose) and FUT6 (α1,3 fucose). The core-fucosylation and branching-fucosylation are characteristics of metastatic cancer cells. Oncogenesis or metastatic tumors can alter the protein O-GlcNAcylation and hyperphosphorylation through the crosstalk between O-GlcNAcylation and phosphorylation.

Fig. 2

List of 238 human receptor tyrosine kinases present in tissues according to the Uniprot Homo Protein Database. (a). The cellular location of receptor tyrosine kinases (RTKs) is mostly cell membrane (79), membrane (26), nucleus (17), cytoplasm (74), and secreted (20). There are 20 membrane RTKs are found in most human tissues, of which 7 are in the brain, 3 are in the blood, 3 are in the lymph tissue, and 3 are in the pancreas. Among these cell membrane proteins, FGR, AGTR2, DDR2, MAGI3, EFNB2 and TRPC6 are particularly abundant in the lung, including MATK (cytoplasm), ROS1/LTK/AGER/SLC34A2 (membrane), and ANGPT4 (secreted). (b) The number of RTKs enriched and expressed in specific human tissues, including brain (36), lymphoid tissue (27), blood (20), lung (13), liver (11), intestine (10) and pancreas (7). Highly abundant RTKs in the lung include FGR, MATK, AGTR2, TRPC4, ROS1, DDR2, LTK, MAGI3, AGER, EFNB2, TRPC6, SLC34A2, and ROR1. (c) Glycosites of RTKs in human tissues. The glycosites of RTKs, from ABL2 to ZPR1 are listed in the red dashed line. NetNglyc predicts N-glycosylation (>0.1) and ISOGlyP predicts O-glycosylation (cutoff >3). The numbers in the doughnut chart represent the number of glycosites predicted by NetNglyc or ISOGlyP, or listed by Uniprot. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

List of 238 human receptor tyrosine kinases present in tissues according to the Uniprot Homo Protein Database. (a). The cellular location of receptor tyrosine kinases (RTKs) is mostly cell membrane (79), membrane (26), nucleus (17), cytoplasm (74), and secreted (20). There are 20 membrane RTKs are found in most human tissues, of which 7 are in the brain, 3 are in the blood, 3 are in the lymph tissue, and 3 are in the pancreas. Among these cell membrane proteins, FGR, AGTR2, DDR2, MAGI3, EFNB2 and TRPC6 are particularly abundant in the lung, including MATK (cytoplasm), ROS1/LTK/AGER/SLC34A2 (membrane), and ANGPT4 (secreted). (b) The number of RTKs enriched and expressed in specific human tissues, including brain (36), lymphoid tissue (27), blood (20), lung (13), liver (11), intestine (10) and pancreas (7). Highly abundant RTKs in the lung include FGR, MATK, AGTR2, TRPC4, ROS1, DDR2, LTK, MAGI3, AGER, EFNB2, TRPC6, SLC34A2, and ROR1. (c) Glycosites of RTKs in human tissues. The glycosites of RTKs, from ABL2 to ZPR1 are listed in the red dashed line. NetNglyc predicts N-glycosylation (>0.1) and ISOGlyP predicts O-glycosylation (cutoff >3). The numbers in the doughnut chart represent the number of glycosites predicted by NetNglyc or ISOGlyP, or listed by Uniprot. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Molecular interactions and signal transduction between lung tissue-specific proteins and salivary protein biomarkers. (a) Gene interactions of typical cancer biomarkers and their carcinogenic drivers. Thirty-one genes were analyzed by the Pathway Commons (www.pathwaycommons.org). The gene interaction includes protein binding, expression levels, and protein modification. (b) The network of pathways containing 31 genes. Pathway analysis showed that EGFR, ERBB2, ESR1 and KIT may negatively regulate PI3K/AKT signal, and PI5P, PP2A and IER3 also modulate PI3K/AKT signal. Genes including AGER, ANXA1, CD274 and LEP can regulate T-cell proliferation. (c) The canonical signal pathway, which is initiated by surface growth factor and transduces surface signal to downstream effectors. Mutation or up-regulation of these oncogenic drivers can promote cell growth, survival, and tumor cell proliferation.