Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer

Mereiter, Stefan; Magalhães, Ana; Adamczyk, B; Jin, Chunsheng; Almeida, Andreia; Drici, Lylia; Ibáñez-Vea, María; Gomes, Catarina; Ferreira, José Alexandre; Afonso, Luís Pedro; Santos, Lúcio Lara; Larsen, Martin R.; Kolarich, Daniel; Karlsson, Niclas G.; Reis, Celso A.

doi:10.1016/j.bbagen.2015.12.016

Cited by 49 publications

(51 citation statements)

References 76 publications

(89 reference statements)

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“…The upregulation of ST3GAL4 in MKN45 leads to an increase in α2,3 sialylation and a decrease in α2,6 sialylation on N‐glycans and significantly decreases the amount of bisected structures . On O‐glycans, ST3GAL4 leads to the earlier termination due to the increase in one specific structure: the di‐sialylated core 2 structure . Both the ST6GALNAC1 overexpression and the COSMC deletion induce alteration on O‐glycans and lead to an upregulation of STn by two differential mechanisms .…”

Section: Discussionmentioning

confidence: 99%

“…1C,D) [30]. The M3 and ST3 models have previously been characterized by O-glycomic analysis and thus allowed us to estimate the induced alterations [45,50]. In this regard, the major O-glycans of M3 with the composition Hex-NAc 5 Hex 5 Neu5Ac 2 and HexNAc 4 Hex 4 Neu5Ac 2 , with the average masses of 2427.2 and 2061.9 Da, respectively, were altered in the ST3 model to HexNAc 2 Hex 2 Neu5Ac 2 , with an average mass of 1331.2 Da.…”

Section: Truncation Of O-glycans Affects the Molecular Weight Of Cd44mentioning

confidence: 99%

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O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

et al. 2019

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CD44 isoforms are often upregulated in gastric cancer and have been associated with increased metastatic potential and poor survival. To evaluate the functional impact of O‐glycan truncation on CD44 we have analysed glyco‐engineered cancer cell models displaying shortened O‐glycans. Here, we demonstrate that induction of aberrant O‐glycan termination through various molecular mechanisms affects CD44 molecular features. We show that CD44 is a major carrier of truncated O‐glycans and that this truncation is accompanied by an increased hyaluronan binding capacity and affects extracellular shedding. In addition, short O‐glycans promoted the colocalization of CD44v6 with the receptor tyrosine kinase RON and concomitantly increased activation. Our in vitro findings were validated in gastric cancer clinical samples.

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Section: Discussionmentioning

confidence: 99%

Section: Truncation Of O-glycans Affects the Molecular Weight Of Cd44mentioning

confidence: 99%

O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

et al. 2019

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“…Taken together, GnT-III could regulate the ␣2,3-sialylation through many mechanisms. Interestingly, a recent glycomic analysis of gastric carcinoma cells showed that overexpression of ST3GAL4, which could produce the ␣2,3-linked sialic acids on N-glycans, significantly suppressed the expression of the bisected N-glycans (47). Considering also our data here, there may exist a negative interplay between the expression of ␣2,3-sialylation and bisecting structures, so it is reasonable to spec- ulate that altered expression in one glycosyltransferase may affect the enzymatic products of the others, thereby having a major impact in the glycoproteome of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Isaji

et al. 2016

Journal of Biological Chemistry

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N-Acetylglucosaminyltransferase III (GnT-III), which catalyzes the addition of the bisecting GlcNAc branch on N-glycans, is usually described as a metastasis suppressor. Overexpression of GnT-III inhibited migration in multiple types of tumor cells. However, these results seem controversial to the clinical observations for the increased expression of GnT-III in human hepatomas, glioma, and ovarian cancers. Here, we present evidence that these inconsistencies are mainly attributed to the different expression pattern of cell sialylation. In detail, we show that overexpression of GnT-III significantly inhibits ␣2,3-sialylation but not ␣2,6-sialylation. The migratory ability of cells without or with a low level of ␣2,6-sialylation is consistently suppressed after GnT-III overexpression. In contrast, the effects of GnT-III overexpression are variable in tumor cells that are highly ␣2,6-sialylated. Overexpression of GnT-III promotes the cell migration in glioma cells U-251 and hepatoma cells HepG2, although it has little influence in human breast cancer cell MDA-MB-231 and gastric cancer cell MKN-45. Interestingly, up-regulation of ␣2,6-sialylation by overexpressing ␤-galactoside ␣2,6-sialyltranferase 1 in the ␣2,6-hyposialylated HeLa-S3 cells abolishes the anti-migratory effects of GnT-III. Conversely, depletion of ␣2,6-sialylation by knock-out of ␤-galactoside ␣2,6-sialyltranferase 1 in ␣2,6-hypersialylated HepG2 cells endows GnT-III with the anti-migratory ability. Taken together, our data clearly demonstrate that high expression of ␣2,6-sialylation on the cell surface could affect the anti-migratory role of GnT-III, which provides an insight into the mechanistic roles of GnT-III in tumor metastasis.Alterations in N-linked glycosylation have been observed in various malignant diseases such as cancer. Certain glycan structures resulting from the dysregulated glycosyltransferases and glycosidases are well known tumor markers and closely associated with the malignant progression (1). As examples, the ␣1,6-fucosylated ␣-fetoprotein catalyzed by ␣1,6-fucosyltransferase has been developed as a biomarker for primary hepatoma by Abelev (2). An increase in ␤1,6-GlcNAc branching of N-glycans as a consequence of enhanced expression of N-acetylglucosaminyltransferase V (GnT-V) 2 is convincingly correlated with the increased frequency of tumor metastasis (3-6). N-Acetylglucosaminyltransferase III (GnT-III) is one more important glycosyltransferase that has been receiving much attention for its involvement in the biology of tumor (7,8). It catalyzes the transfer of N-acetylglucosamine (GlcNAc) in a ␤1,4 linkage to mannose on N-glycans forming a bisecting GlcNAc structure. This step plays critical roles in determining the structure of N-glycans because introduction of the bisecting GlcNAc residue could preclude further processing and elongation of N-glycans, such as the formation of ␤1,6-GlcNAc branching structures (9). Considering also that overexpression of GnT-III inhibited the metastasis of multiple types of carcinomas (10, 1...

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“…Adding glycosylation to the equation may prove to be fruitful, since differential glycosylation of proteins may give rise to distinct mAb binding affinity and may constitute reliable predictors of tumor response to therapy . Besides, the differential glycosylation of distinct RTKs has been previously demonstrated to strongly influence receptor signaling and response to specific inhibitors, in glycoengineered in vitro models of GC …”

Section: Future Perspectivesmentioning

confidence: 99%

“…48 Besides, the differential glycosylation of distinct RTKs has been previously demonstrated to strongly influence receptor signaling and response to specific inhibitors, in glycoengineered in vitro models of GC. [49][50][51] In conclusion, the improvement of the current gloom scenario surrounding the clinical management of GC will greatly depend on…”

Section: Future Per S Pec Tive Smentioning

confidence: 99%

Gastric cancer: Basic aspects

et al. 2018

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Despite major breakthroughs in the field of personalized medicine, gastric cancer (GC) remains a clinically challenging disease, characterized by scarce effective treatment options and the lack of reliable molecular tools for the prediction of patient outcome and response to therapy. The pronounced molecular heterogeneity that dictates the phenotypical aggressiveness of gastric neoplasms severely limits the antitumor efficacy of targeted agents brought to clinical trials, and constitutes a favorable setting for the emergence of refractory tumors exhibiting multidrug resistance. We will review the most recent advances in our understanding of GC biology, which are underlying the development and clinical testing of novel targeted therapeutic agents. We will also emphasize how their efficacy and acquired resistance relate to the aberrant molecular signatures that drive gastric malignancy.

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Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer

Abstract: This study provides novel targets and points to an integrative tumor glycomic/proteomic-profiling for gastric cancer patients' stratification. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.

Cited by 49 publications

References 76 publications

O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Gastric cancer: Basic aspects

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