Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

Mehta, Anand; Comunale, Mary Ann; Rawat, Siddhartha; Casciano, Jessica C.; Lamontagne, Jason; Herrera, Harmin; Ramanathan, Aarti; Betesh, Lucy; Wang, Mengjun; Norton, Pamela A.; Steel, Laura F.; Bouchard, Michael J.

doi:10.1038/srep27965

Cited by 29 publications

(26 citation statements)

References 70 publications

(108 reference statements)

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“…Core fucosylation is elevated in liver and ovarian cancerous tissues in comparison to normal (Abbott et al, 2008; Mehta et al, 2016), and linked with EGFR dimerization and activation, TGF-β-activation, and HGF and EGF signaling pathways (Gu et al, 2013; Liu et al, 2011; Wang et al, 2015). However, a role for this enzyme in melanoma and the specific core fucosylated glycoproteins underlying its effects are unknown.…”

Section: Discussionmentioning

confidence: 99%

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

et al. 2017

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SUMMARY Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of α-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

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Section: Discussionmentioning

confidence: 99%

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

et al. 2017

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“…It is also known that these fucosylated antigens facilitate the invasion and spread of tumor cells [72][73][74][75]. In relation to cancer, a study conducted in 2016 by Mehta et al [76] showed that the increase in central fucosylation is associated with the dedifferentiation of primary hepatocytes and with the appearance of markers that are indicative of the transition of the cells from an epithelial to a mesenchymal state [76]. Another study reported that the inhibition of the fucosylation of annexin A4 inhibited cell proliferation in ovarian clear cell carcinoma [77].…”

Section: Discussionmentioning

confidence: 99%

Ascites from Ovarian Cancer Induces Novel Fucosylated Proteins

Alberto-Aguilar

Hernández‐Ramírez

Osorio-Trujillo

et al. 2019

Cancer Microenvironment

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Ovarian cancer is considered to be the most lethal type of gynecological cancer. During the advanced stages of ovarian cancer, an accumulation of ascites is observed. Fucosylation has been classified as an abnormal post-translational modification that is present in many diseases, including ovarian cancer. Ovarian cancer cells that are cultured with ascites stimulation change their morphology; concomitantly, the fucosylation process is altered. However, it is not known which fucosylated proteins are modified. The goal of this work was to identify the differentially fucosylated proteins that are expressed by ovarian cancer cell lines that are cultured with ovarian cancer patients' ascites. Aleuria aurantia lectin was used to detect fucosylation, and some changes were observed, especially in the cell membrane. Affinity chromatography and mass spectrometry (MALDI-TOF) were used to identify 6 fucosylated proteins. Four proteins (Intermediate filament family orphan 1 [IFFO1], PHD finger protein 20-like protein 1 [PHF20L1], immunoglobulin gamma 1 heavy chain variable region partial [IGHV1-2], and Zinc finger protein 224 [ZNF224]) were obtained from cell cultures stimulated with ascites, and the other two proteins (Peregrin [BRPF1] and Dystrobrevin alpha [DTNA]) were obtained under normal culture conditions. The fucosylated state of some of these proteins was further analyzed. The experimental results show that the ascites of ovarian cancer patients modulated the fucosylation process. The PHD finger protein 20-like protein 1, Zinc finger protein 224 and Peregrin proteins colocalize with fucosylation at different levels.

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“…In our recent study, we showed that increased core fucosylation was directly associated with de-differentiation of hepatocytes and the transition of cells from an epithelial to a mesenchymal state (EMT)(48). However, this modification was not present in the all patients and may be directly related to the underlying genetic abnormalities associated with the cancer.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC

Wang

Šanda

Comunale

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Hepatocellular carcinoma (HCC) has the greatest increase in mortality among all solids tumors in the United States related to low rates of early tumor detection. Development of non-invasive biomarkers for early detection of HCC may reduce HCC-related mortality. Methods We have developed an algorithm that combines routinely observed clinical values into a single equation that in a study of > 3,000 patients from 5 independent sites, improved detection of HCC as compared to the currently used biomarker, alpha-feto-protein (AFP), by 4–20%. However, this algorithm had limited benefit in those with AFP <20 ng/mL. To that end, we have developed a secondary algorithm that incorporates a marker, fucosylated kininogen, to improve the detection of HCC, especially in those with AFP <20 ng/mL and early stage disease. Results The ability to detect early stage AFP negative (AFP< 20 ng/mL) HCC increased from 0% (AFP alone) to 89% (for the new algorithm). Glycan analysis revealed that kininogen has several glycan modifications that have been associated with HCC, but often not with specific proteins, including increased levels of core and outer-arm fucosylation and increased branching. Conclusions An algorithm combining fucosylated kininogen, alpha fetoprotein, and clinical characteristics is highly accurate for early HCC detection. Impact Our biomarker algorithm could significantly improve early HCC detection and curative treatment eligibility in patients with cirrhosis.

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Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

Cited by 29 publications

References 70 publications

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Ascites from Ovarian Cancer Induces Novel Fucosylated Proteins

Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC

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