Endothelial Heparan Sulfate 6-O-Sulfation Levels Regulate Angiogenic Responses of Endothelial Cells to Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor

Ferreras, Cristina; Rushton, Graham; Cole, Claire L.; Babur, Muhammad; Telfer, Brian A.; Kuppevelt, Toin H. Van; Gardiner, John M.; Williams, Kaye J.; Jayson, Gordon C; Avizienyte, Egle

doi:10.1074/jbc.m112.384875

Cited by 66 publications

(67 citation statements)

References 39 publications

(42 reference statements)

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“…Our previous study demonstrated that ovarian high grade serous carcinomas have high levels of 6-O-sulfation in tumor endothelium when compared with the vasculature of normal ovarian tissue (26). We also found through down-regulation of HS6ST-1 or HS6ST-2 in endothelial cells that sulfation at the glucosamine 6-O position was critical for endothelial cell functions in vitro and in vivo (26).…”

mentioning

confidence: 95%

“…retro.puro plasmid (Origene) were described in the supplemental data of our previously published study (26). Two rounds of 24-h infection were performed as described (26), after which cells were cultured in the media containing 2 g/ml puromycin.…”

Section: Methodsmentioning

confidence: 99%

“…RT-PCR-Extraction of RNA, generation of cDNA, HS6ST-1, and HS6ST-2 primer sequences and PCR cycling conditions were described in the supplemental data of our previously published study (26). The following primers were used for Sulf1 and Sulf2 genes: Sulf1 forward, 5Ј-ggatccatccaacagtcaaatcacttgcccaaat; Sulf1 reverse, 5Ј-ggatccccttccacgctctggccgattg; Sulf2 forward, 5Ј-ggatcccatcgaggtggacggcagg; and Sulf2 reverse, 5Ј-ggatccagccacaccttgtccttctc.…”

Section: Methodsmentioning

confidence: 99%

“…Real Time PCR-Extraction of RNA and generation of cDNA were described in the supplemental data of our previous study (26). Expression of HS6ST-1 and HS6ST-2 in a panel of ovarian cancer cell lines, IOSE cell lines, and TissueScan quantitative PCR array plates (HORT501; Amsbio) containing cDNA from 40 ovarian cancers and 8 normal ovaries was tested using TaqMan Universal PCR Master Mix (Invitrogen), specific probes (Roche), and the following primers: HS6ST-1 forward, 5Ј-atgcagctgtacgactacgc; HS6ST-1 reverse, 5Ј-ctgccgcttgtactggtagc; HS6ST-2 forward, 5Ј-tgcgatcttctccaagattttc; and HS6ST-2 reverse, 5Ј-cgatcacggcaaataggaag.…”

Section: Methodsmentioning

confidence: 99%

“…The following primers were used for Sulf1 and Sulf2 genes: Sulf1 forward, 5Ј-ggatccatccaacagtcaaatcacttgcccaaat; Sulf1 reverse, 5Ј-ggatccccttccacgctctggccgattg; Sulf2 forward, 5Ј-ggatcccatcgaggtggacggcagg; and Sulf2 reverse, 5Ј-ggatccagccacaccttgtccttctc. PCR cycling conditions were as for the HS6ST-1 gene (26).…”

Section: Methodsmentioning

confidence: 99%

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Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling

Cole

Rushton

Jayson³

et al. 2014

Journal of Biological Chemistry

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Background: Numerous angiogenic growth factors depend on heparan sulfate for their activity. Results: Heparan sulfate 6-O-sulfotransferases induce angiogenesis through HB-EGF/EGFR signaling and angiogenic cytokine expression in ovarian cancer cells. Conclusion: Ovarian cancer cell 6-O-sulfation levels influence angiogenic responses. Significance: HS6ST inhibitors and HS mimetics should be explored in the development of new anti-angiogenic agents.

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confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling

Cole

Rushton

Jayson³

et al. 2014

Journal of Biological Chemistry

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Heparan Sulfate D‐Glucosaminyl 3‐O‐Sulfotransferase‐3B1 (HS3ST3B1) Promotes Angiogenesis and Proliferation by Induction of VEGF in Acute Myeloid Leukemia Cells

Zhang

Song

Zhou

et al. 2015

J of Cellular Biochemistry

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Heparan sulfate (HS) are complex polysaccharides that reside on the plasma membrane of almost all mammalian cells, and play an important role in physiological and pathological conditions. Heparan sulfate D-glucosamine 3-O-sulfotransferase 3B1 (HS3ST3B1) participates in the last biosynthetic steps of HS and transfers sulfate to the 3-O-position of glucosamine residues to yield mature sugar chains. To date very few biological processes or proteins have been described that are modulated by HS3ST3B1. In this study, we observed that HS3ST3B1 positively contributed to acute myeloid leukemia (AML) progression in vitro and in vivo, and these activities were associated with an induction of the proangiogenic factor VEGF expression and shedding. Moreover, the effects of HS3ST3B1 on VEGF release can be attenuated after treatment of heparanase inhibitor suramin, which prevented VEGF secretion and subsequently blocked VEGF-induced activation of ERK and AKT, suggesting that 3-O-sulfation of HS by HS3ST3B1 facilitated VEGF shedding; the effects of HS3ST3B1 on activation of ERK and AKT can also be blocked by VEGFR inhibitor axitinib, suggestive of a relationship between 3-O-sulfation of HS and VEGF-activated signaling pathways. Taken together, our findings support that VEGF is an important functional target of HS3ST3B1 and provide a new mechanism of HS3ST3B1 in AML.

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VAR2HP recognizing heparin‐like epitopes in targeted therapy and diagnosis of tumors

Xu,

Liu,

Zou

et al. 2024

Proteoglycan Research

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The synthesis of glycosaminoglycans (GAGs) in vivo occurs with high spatiotemporal specificity, and any aberrant expression of GAGs is closely related to the occurrence of diseases. In terms of tumorigenesis, the abnormally expressed GAGs have become a potential target for the diagnosis and therapy of tumors. As previously reported, VAR2HP, a protein probe that recognizes the unique heparin (Hep)‐like epitopes, interacts with a decasaccharide structure containing at least three HexA2S(1‐4)GlcNS6S disaccharides. Its recognition epitopes are overexpressed in various tumor cells and appear promising as target molecules of multiple tumors. Herein, we found that VAR2HP used as an antineoplastic carrier could promote drug enrichment in tumor sites by targeting the specific Hep‐like epitopes on tumor cells, thereby reducing the damage to normal cells in vitro and in vivo. Moreover, VAR2HP acting on cells alone could inhibit cell proliferation, indicating that VAR2HP as a drug carrier has a dual effect of antitumor activity. Additionally, we observed that VAR2HP significantly stained cancer tissues more strongly than neighboring nonmalignant tissues. The staining was competitively inhibited by added exogenous Hep, indicating that the Hep‐like epitopes recognized by VAR2HP were a potential target molecule in tumor diagnosis. Moreover, the VAR2HP‐bound Hep‐like epitopes were found to be overexpressed in the sera of patients with hepatocellular carcinoma (HCC) but not in normal persons and patients with cirrhosis. Taken together, this study shows that VAR2HP and its heparin‐like epitopes have great potential in targeted therapy of tumors and HCC diagnosis.

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Endothelial Heparan Sulfate 6-O-Sulfation Levels Regulate Angiogenic Responses of Endothelial Cells to Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor

Cited by 66 publications

References 39 publications

Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling

Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling

Heparan Sulfate D‐Glucosaminyl 3‐O‐Sulfotransferase‐3B1 (HS3ST3B1) Promotes Angiogenesis and Proliferation by Induction of VEGF in Acute Myeloid Leukemia Cells

VAR2HP recognizing heparin‐like epitopes in targeted therapy and diagnosis of tumors

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