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, Claire L.; Rushton, Graham; Jayson, Gordon C; Avizienyte, Egle

doi:10.1074/jbc.m113.534263

Cited by 49 publications

(39 citation statements)

References 41 publications

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“…Following the 6-O-sulfation of HS, HSPGs participate in the regulation of numerous signaling pathways by binding and activating cytokines. Growth factors including epidermal growth factor (EGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are dependent on the 6-O-sulfation of HS to assemble tri-molecular signaling complexes (HS-growth factor-receptor) for signal transduction (29)(30)(31)(32). Previous emerging evidence has indicated that HS6ST2 is a critical factor involved in regulating processes of angiogenesis and epithelial-mesenchymal transition (EMT) during carcinogenesis.…”

Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

“…In thyroid carcinomas, HS6ST2 was identified as a target gene of twist family bhlh transcription factor 1, a critical regulator of EMT (10,35). Inhibition of H6ST2 in tumor cells impairs cell migration, invasion, tubule formation, and may reverse EMT (10,13,32). Notably, previous reports revealed that the specific inhibition of HS6ST2 by a high molecular weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS), prevented tumor progression in a mouse model of breast cancer metastasis (15).…”

Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

“…Previous emerging evidence has indicated that HS6ST2 is a critical factor involved in regulating processes of angiogenesis and epithelial-mesenchymal transition (EMT) during carcinogenesis. Through the regulation of HS 6-O-sulfation, HS6ST2 influences angiogenic processes by inducing heparin-binding (HB)-EGF receptor signaling in ovarian cancer (32). EMT is an important mechanism which induces tumor-related epithelial cells to acquire mesenchymal features; including increased motility and reduced cell-cell contact in the early stage of tumorigenesis (33).…”

Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

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Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer

Jin

et al. 2017

Oncol Lett

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Abstract. The purpose of the present study was to investigate the clinical significance of the expression of heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) in gastric cancer (GC). The Affymetrix GeneChip ® Human Genome U133 Plus 2.0 Array (Affymetrix; Thermo Fisher Scientific, Inc., Waltham, MA, USA) was used to identify differentially expressed genes in GC tissues vs. adjacent non-tumor gastric tissues. Candidate genes were further verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). In addition, an independent dataset was obtained from the Gene Expression Omnibus, and a survival analysis was performed. Microarray analysis demonstrated that HS6ST2 was upregulated (>12-fold) in GC tissues compared with that in adjacent non-tumor tissues. RT-qPCR and IHC analysis of HS6ST2 in GC tissues and adjacent non-tumor tissues confirmed the microarray data. Furthermore, a positive association was demonstrated between HS6ST2 overexpression with the depth of tumor invasion, distant metastasis, and tumor-node metastasis stage. Survival analysis revealed an association between patients with increased expression of HS6ST2 and a poor prognosis of gastric cancer. Cox regression analysis indicated that the expression of HS6ST2 was an independent negative prognostic factor for GC. The expression of HS6ST2 in GC was significantly associated with specific clinicopathological parameters and prognosis of disease, thus we propose that HS6ST2 may represent a novel biomarker for GC.

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Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

Section: Hs6st2 Expression ------------------------------------mentioning

confidence: 99%

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Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer

Jin

et al. 2017

Oncol Lett

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“…The 12 remaining down-regulated transcripts included 2010111I01Rik, Sorbs2, Phf17, Ubr3 and Fth1 , catalogued under the term GO:0046914 ( transition metal ion binding ). On the other hand, the 3 up-regulated genes persisting until p28 were Hs6st2 , a heparan-sulfate sulfotransferase linked to EGF-like induced angiogenesis in OC cells [28], Hmga1 , coding for a non-histone chromosomal protein recently proposed as a diagnostic urine marker in serous epithelial OC [29] and Mmp2 , a matrix metallopeptidase implicated in OC metastasis [30]. Interestingly, though high Malat1 expression has been linked to cell proliferation and metastasis, a recent study suggest a tumor-suppressor role of Malat1 in gliomas through inhibition of ERK/MAPK signaling and Mmp2 -mediated invasiveness [31], findings consistent with its down-regulation in our model.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

et al. 2016

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BackgroundBased in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model.ResultsAt passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05) comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1), Birc5 (Survivin), Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci.ConclusionPrior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes suggests altered control of nuclear RNA maturation, features recently linked to impaired DNA damage response leading to genome instability. These results, combined with cytogenetic analysis by other authors in this model, suggest that transcriptional profile at passage 14 might induce cytokinesis failure by which tetraploid cells approach a near-tetraploid stage containing primary chromosome aberrations that initiate the tumorigenic drive.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3068-5) contains supplementary material, which is available to authorized users.

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“…The induced expression of specific sulfation motifs is associated with human diseases, including certain cancers, 16,17 Alzheimer’s disease, 18 osteoarthritis, 19,20 malaria, 21,22 herpes, 23 and macular corneal dystrophy, 24 but surprisingly, pharmacological tools for manipulating GAG sulfation have been lacking. Cellular sulfation levels can be modulated genetically or by using sodium chlorate, which inhibits PAPS synthetase.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation

et al. 2017

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Glycosaminoglycans (GAGs) play critical roles in diverse processes ranging from viral infection to neuroregeneration. Their regiospecific sulfation patterns, which are generated by sulfotransferase enzymes, are key structural determinants that underlie their biological activity. Small-molecule modulators of these sulfotransferases could serve as powerful tools for understanding the physiological functions of GAGs, as well as potential therapeutic leads for human diseases. Here, we report the development of the first selective, cell-permeable small-molecule inhibitor of GAG sulfotransferases, which was obtained using a high-throughput screen targeted against Chst15, the sulfotransferase responsible for biosynthesis of the chondroitin sulfate-E (CS-E) motif. We demonstrate that the molecule specifically inhibits GAG sul-fotransferases in vitro, decreases CS-E and overall sulfation levels on cell-surface and secreted chondroitin sulfate proteoglycans (CSPGs), and reverses CSPG-mediated inhibition of axonal growth. These studies pave the way toward a new set of pharmacological tools for interrogating GAG sulfation-dependent processes and may represent a novel potential therapeutic approach for neuroregeneration.

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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

Cited by 49 publications

References 41 publications

Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer

Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer

Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation

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