HSulf-1 Inhibits Angiogenesis and Tumorigenesis <i>In vivo</i>

Narita, Keishi; Staub, Julie; Chien, Jeremy; Meyer, Keith; Bauer, M.; Friedl, Andreas; Ramakrishnan, Sundaram; Shridhar, Viji

doi:10.1158/0008-5472.can-05-3582

Cited by 132 publications

(164 citation statements)

References 37 publications

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“…Forty-fold higher expression of heparan sulfate 6-O-endosulfatase1 (Sulf1) was noted in blood vessels from wound-site compared with that from intact skin. Sulf1 has been recently recognized to be anti-angiogenic (9). The ␣-1 chain of collagen IV (also known as arresten) or COL4A1 was overexpressed in blood vessels of wound site by 37-fold compared with that in vessels from intact skin.…”

Section: Resultsmentioning

confidence: 99%

Transcriptome-wide analysis of blood vessels laser captured from human skin and chronic wound-edge tissue

Roy

Patel

Khanna

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

131

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Chronic wounds represent a substantial public health problem. The development of tools that would enable sophisticated scrutiny of clinical wound tissue material is highly desirable. This work presents evidence enabling rapid specific identification and laser capture of blood vessels from human tissue in a manner which lends itself to successful high-density (U133A) microarray analysis. Such screening of transcriptome followed by real-time PCR and immunohistochemical verification of candidate genes and their corresponding products were performed by using 3 mm biopsies. Of the 18,400 transcripts and variants screened, a focused set of 53 up-regulated and 24 down-regulated genes were noted in woundderived blood vessels compared with blood vessels from intact human skin. The mean abundance of periostin in wound-site blood vessels was 96-fold higher. Periostin is known to be induced in response to vascular injury and its expression is associated with smooth muscle cell differentiation in vitro and promotes cell migration. Forty-fold higher expression of heparan sulfate 6-Oendosulfatase1 (Sulf1) was noted in wound-site vessels. Sulf1 has been recently recognized to be anti-angiogenic. During embryonic vasculogenesis, CD24 expression is down-regulated in human embryonic stem cells. Wound-site vessels had lower CD24 expression. The findings of this work provide a unique opportunity to appreciate the striking contrast in the transcriptome composition in blood vessels collected from the intact skin and from the wound-edge tissue. Sets of genes with known vascular functions but never connected to wound healing were identified to be differentially expressed in wound-derived blood vessels paving the way for innovative clinically relevant hypotheses.angiogenesis ͉ microarray ͉ wound healing

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Section: Resultsmentioning

confidence: 99%

Transcriptome-wide analysis of blood vessels laser captured from human skin and chronic wound-edge tissue

Roy

Patel

Khanna

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

105

131

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“…In this report we demonstrated that DNA methylation and histone modifications regulate HSulf-1 expression and Epigenetic silencing of HSulf-1 J Staub et al provided the first evidence of methylation in combination with chromatin histone modification as a mechanism of HSulf-1 inactivation in ovarian cancer. Re-expression of HSulf-1 has been shown to inhibit tumor growth (Dai et al, 2005;Lai et al, 2006;Narita et al, 2006). In this study, we analysed the relationship between HSulf-1 induction with 5-aza-dC and chemoresponse of ovarian cancer cell lines in vitro and correlated HSulf-1 expression in patient samples to a better therapeutic index.…”

Section: Discussionmentioning

confidence: 99%

“…Our data demonstrate that HSulf-1 expression is correlated with response to chemotherapy and thus may be useful in conjunction with other molecular markers, in predicting chemosensitivity. Given the observation that the presence of HSulf-1 also inhibits angiogenesis in vivo (Narita et al, 2006), a combination therapy that includes demethylating agents and or HDACs inhibitors with classical antineoplastic drugs such as carboplatin or taxol or antiangiogenic drug may benefit patients with tumors that lack HSulf-1 expression by promoting the expression of epigenetically controlled genes such as HSulf-1 involved in inhibiting growth and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

et al. 2007

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To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2 0 -deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P ¼ 0.0146, v 2 test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

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“…It is possible, therefore, that tumour growth in cancer cells overexpressing SULF2 is potentiated by tumour angiogenesis. In hepatocellular and breast carcinomas, however, overexpression of SULF1 inhibits tumour growth/angiogenesis partially by inhibiting FGF, HGF, and VEGF stimulation of tumour cell growth and metastasis (Lai et al, 2004b(Lai et al, , 2008 and correlates with the low levels of FGF/HS/FGFR2 signal complexes formed in SULF1-expressing cells in vitro (Lai et al, 2006;Narita et al, 2006). Clearly, in pathological conditions sulfatases can have both proand anti-angiogenic roles depending on the context of the perturbed signalling environment.…”

Section: Introductionmentioning

confidence: 99%

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

Gorsi

Whelan

2010

Developmental Dynamics

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The 6-O-endosulfatase enzymes (Sulfs) edit the final sulfation pattern and function of heparan sulfate (HS) by removal of 6-O-sulfate groups from the chain. To date, two mammalian sulf genes have been identified that regulate many signalling pathways during embryonic development. In zebrafish a sulf1 ortholog and duplicate copies of the mammalian sulf2 gene, sulf2a and sulf2, have been identified, which contain conserved motifs characteristic of vertebrate sulf genes. Zebrafish sulf1 and sulf2a are broadly expressed in the central nervous system (CNS) and non-neuronal tissue including heart, somite boundaries, olfactory system, and otic vesicle, whereas sulf2 expression is almost entirely restricted to the CNS. The duplicate copies of sulf2 have distinct expression patterns, which together mirror that of mouse sulf2, suggesting duplication in the teleost lineage has been followed by subfunctionalisation, whereby both genes need to be preserved by selection to ensure the ancestral gene's expression profile and function is maintained. Developmental Dynamics 239:3312-3323,

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HSulf-1 Inhibits Angiogenesis and Tumorigenesis In vivo

Abstract: We previously identified HSulf-1 as a down-regulated gene in several tumor types including ovarian, breast, and hepatocellular carcinomas. Loss of HSulf-1, which selectively removes 6-

Cited by 132 publications

References 37 publications

Transcriptome-wide analysis of blood vessels laser captured from human skin and chronic wound-edge tissue

Transcriptome-wide analysis of blood vessels laser captured from human skin and chronic wound-edge tissue

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

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