Glycosylation and metastases

Josić, Djuro; Martinović, Tamara; Pavelić, Krešimir

doi:10.1002/elps.201800238

Cited by 23 publications

(11 citation statements)

References 108 publications

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“…Protein glycosylation is an important type of posttranslational modification. Substantial data have revealed that abnormal glycosylation due to the aberrant expression of glycosylation transferases is closely correlated with tumor progression and metastasis [30][31][32] . FUT3, a type of fucosyltransferases (FUTs), adds L-fucose as a (1,4) linkage to GlcNAc residues in sialylated precursors to synthesize CA199 or adds L-fucose as a (1,3) linkage to GlcNAc residues in other sialylated precursors 33,34 .…”

Section: Discussionmentioning

confidence: 99%

The DDX39B/FUT3/TGFβR-I axis promotes tumor metastasis and EMT in colorectal cancer

Lai

et al. 2021

Cell Death Dis

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DDX39B is a member of the DEAD box (DDX) RNA helicase family required for nearly all cellular RNA metabolic processes. The exact role and potential molecular mechanism of DDX39B in the progression of human colorectal cancer (CRC) remain to be investigated. In the present study, we demonstrate that DDX39B expression is higher in CRC tissues than in adjacent normal tissues. Gain- and loss-of-function assays revealed that DDX39B facilitates CRC metastasis in vivo and in vitro. Mechanistically, RNA-sequencing (RNA-seq) and RNA-binding protein immunoprecipitation-sequencing (RIP-seq) showed that DDX39B binds directly to the FUT3 pre-mRNA and upregulates FUT3 expression. Splicing experiments in vitro using a Minigene assay confirmed that DDX39B promotes FUT3 pre-mRNA splicing. A nuclear and cytoplasmic RNA separation assay indicates that DDX39B enhances the mRNA export of FUT3. Upregulation of FUT3 accelerates the fucosylation of TGFβR-I, which activates the TGFβ signaling pathway and eventually drives the epithelial–mesenchymal transition (EMT) program and contributes to CRC progression. These findings not only provide new insight into the role of DDX39B in mRNA splicing and export as well as in tumorigenesis, but also shed light on the effects of aberrant fucosylation on CRC progression.

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Section: Discussionmentioning

confidence: 99%

The DDX39B/FUT3/TGFβR-I axis promotes tumor metastasis and EMT in colorectal cancer

Lai

et al. 2021

Cell Death Dis

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“…PSA is a glycoprotein whose glycan significantly changes with PCa development/progression [ 4 , 5 ]. Glycosylation is a driver for cancer development/progression [ 11 , 12 ], and thus, glycoprofiling PSA could outperform currently used PCa tests [ 13 ]. Murphy et al found that glycan analysis, in combination with other approaches (DNA analysis, transcriptomics, and proteomics), is a robust tool for tumor stratification [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

Bertók

Jáné

Bertóková

et al. 2020

Cancers

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Background: To compare the clinical performance of a new PCa serum biomarker based on fPSA glycoprofiling to fPSA% and PHI. Methods: Serum samples from men who underwent prostate biopsy due to increased PSA were used. A comparison between two equal groups (with histologically confirmed PCa or benign, non-cancer condition) was used for the clinical validation of a new glycan-based PCa oncomarker. SPSS and R software packages were used for the multiparametric analyses of the receiver operating curve (ROC) and for genetic algorithm metaheuristics. Results: When comparing the non-cancer and PCa cohorts, the combination of four fPSA glycoforms with two clinical parameters (PGI, prostate glycan index (PGI)) showed an area under receiver operating curve (AUC) value of 0.821 (95% CI 0.754–0.890). AUC values were 0.517 for PSA, 0.683 for fPSA%, and 0.737 for PHI. A glycan analysis was also applied to discriminate low-grade tumors (GS = 6) from significant tumors (GS ≥ 7). Conclusions: Compared to PSA on its own, or fPSA% and the PHI, PGI showed improved discrimination between presence and absence of PCa and in predicting clinically significant PCa. In addition, the use of PGI would help practitioners avoid 63.5% of unnecessary biopsies, while the use of fPSA% and PHI would help avoid 17.5% and 33.3% of biopsies, respectively, while missing four significant tumors (9.5%).

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“…Much data has revealed that abnormal glycosylation due to the aberrant expression of glycosylation transferases is closely correlated with tumor progression and metastasis. [30][31][32] FUT3, a kind of fucosyltransferases, adds Lfucose in an a(1,4)linkage to GlcNAc residues in sialylated precursors to synthesize CA199. [33,34] A previous study demonstrated that abnormal expression of FUT3 contributes to aberrant fucosylation of TGFβR-I, eventually causing abnormal activation of the TGFβ signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

The DDX39B/FUT3/TGFβR-I Axis Promotes Tumor Metastasis and EMT in Colorectal Cancer

Lai

et al. 2020

Preprint

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Background: DDX39B is a member of the DEAD box (DDX) RNA helicase family required for nearly all cellular RNA metabolism processes. The exact role and potential molecular mechanism of DDX39B in the progression of human colorectal cancer (CRC) remain to be investigated. Methods: Western blotting and quantitative real-time PCR (qRT-PCR) were conducted to detect the expression of DDX39B in CRC tissues and cell lines. Transwell and wound healing assays were conducted to assess the migration and invasion ability of CRC cells with DDX39B overexpressed or silencing. Orthotopic transplantation model of nude mice was performed to validate CRC metastasis in vivo. RNA sequencing (RNA-seq) and RNA binding protein immunoprecipitation (RIP) assay verified the direct regulation of DDX39B on the splicing and nuclear export of FUT3 mRNA, cytoplasmic and nuclear RNA isolation confirmed the nuclear export effect of DDX39B on FUT3. qRT-PCR was conducted to quantify FUT3 splicing variants. Lectin blotting was conducted to evaluate the fucosylation level of TGFβR-I.Results: In the present study, we demonstrate that DDX39B expression was higher in CRC tissues than in adjacent normal tissues. Gain- and loss- of- function assays revealed that DDX39B facilitated the metastasis of CRC in vivo and in vitro. Mechanistically, RNA-seq and RIP showed that DDX39B upregulated FUT3 expression by binding the first exon of FUT3 mRNA, which promote the mRNA splicing and export of FUT3. RNA-seq results and qRT-PCR showed that overexpression of DDX39B may favor the longer FUT3 mRNA products that contain the complete and longer exon 2, suggesting an alternative splicing of FUT3. Upregulation of FUT3 accelerated the fucosylation of TGFβR-I, thus activating the TGFβ/SMAD signaling pathway, eventually driving the epithelial-mesenchymal transition (EMT) program and contributing to CRC progression. Conclusions: Our finding demonstrated for the first time that the DDX39B/FUT3/TGFβR-I axis promotes the progression of CRC. These findings not only provide new insight into the role of DDX39B in mRNA splicing and export and tumorigenesis, but also shed light on the effect of aberrant fucosylation on CRC progression.

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Glycosylation and metastases

Cited by 23 publications

References 108 publications

The DDX39B/FUT3/TGFβR-I axis promotes tumor metastasis and EMT in colorectal cancer

The DDX39B/FUT3/TGFβR-I axis promotes tumor metastasis and EMT in colorectal cancer

Validating fPSA Glycoprofile as a Prostate Cancer Biomarker to Avoid Unnecessary Biopsies and Re-Biopsies

The DDX39B/FUT3/TGFβR-I Axis Promotes Tumor Metastasis and EMT in Colorectal Cancer

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