HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma

Lai, Jenn‐Haung; Chien, Jeremy; Strome, Scott E.; Staub, Julie; Montoya, Damian P.; Greene, Eddie L.; Smith, Jeremy C.; Roberts, Lewis R.; Shridhar, Viji

doi:10.1038/sj.onc.1207258

Cited by 128 publications

(171 citation statements)

References 38 publications

(38 reference statements)

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“…The regulatory role of the Sulfs is equally apparent in pathological conditions where upregulation of Sulfs in different cancer cell lines have opposite roles in tumour growth via similar signalling cascades (Lai et al, 2004a;Nawroth et al, 2007). In pancreatic tumours, human SULF2 increases tumour growth mediated by WNT signalling (Nawroth et al, 2007), which is consistent with a pro-angiogenic role of SULF2 in the chick chorioallantoic membrane assay (Morimoto-Tomita et al, 2005).…”

Section: Introductionmentioning

confidence: 56%

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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Section: Introductionmentioning

confidence: 56%

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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“…We have shown previously that the loss of HSulf-1 in cancer cells results in an increase in HS glycosaminoglycan sulfation, promoting various heparin-binding growth factor activities to induce the MAPK signaling pathway (13)(14)(15). Our recent study using the MDA468 breast cancer cell line also demonstrates that HSulf-1 inhibits tumorigenesis and angiogenesis in vivo (17).…”

Section: Discussionmentioning

confidence: 87%

“…Studies by us and other groups (13)(14)(15)(16)(17) demonstrate that the loss of HSulf-1 expression results in increased sulfation of HS glycosaminoglycans, leading to the increased affinity of various heparin-binding growth factors to their cognate receptor tyrosine kinases to enhance downstream signaling, culminating in higher cell proliferation, angiogenesis, and chemoresistance. However, most of the studies elucidating the regulatory role of HSulf-1 in heparin binding growth factor signaling have utilized exogenously added heparin-binding growth factors.…”

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confidence: 99%

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

Narita

Chien

Mullany

et al. 2007

Journal of Biological Chemistry

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Heparan sulfate (HS) glycosaminoglycans are the oligosaccharide chains of heparan sulfate proteoglycans. The sulfation of HS glycosaminoglycan residues is required for its interaction with various heparin-binding growth factors to promote their biological activities to activate their high affinity receptor tyrosine kinases. We have identified HS glycosaminoglycan-6-O-endosulfatase HSulf-1 as a down-regulated gene in ovarian, breast, and several other cancer cell lines. Here we have shown that HSulf-1 inhibits autocrine activation of the EGFR-ERK (epidermal growth factor receptor-extracellular signal-regulated kinase) pathway induced by serum withdrawal in MDA-MB-468 breast cancer cells. Short hairpin RNA-mediated down-regulation of HSulf-1 in HSulf-1 clonal lines of MDA-MB-468 led to a significant increase in autocrine activation of ERK compared with vector only control. The autocrine signaling was also inhibited with neutralization antibodies against amphiregulin and HB-EGF, the heparin-binding growth factor family of the EGF superfamily. Furthermore, HSulf-1-mediated inhibition of autocrine signaling was associated with reduced cyclin D1 levels, leading to decreased S phase fraction and increased G 2 -M fraction, as well as increased cell death. Finally, evaluation of HSulf-1 expression levels in primary invasive breast tumors by RNA in situ hybridization indicated that HSulf-1 is down-regulated in the majority (60%) of tumors, with a predominant association with lobular histology. These data suggest a potential role of HSulf-1 down-regulation in mammary carcinogenesis.Breast cancer is the most common type of cancer among women in the United States. Despite the advances in early detection and therapeutic treatment options, an estimated 215,000 new cases and 41,000 deaths were reported in 2006 (1). One of the molecular signatures known to be associated with poor prognosis is the epidermal growth factor receptor (EGFR).2 The EGFR expression in breast cancer is often associated with resistance to endocrine hormone therapy (2, 3). Recent studies also indicate that hormone-induced estrogen receptor (ER) activation leads to activation of EGFR, suggesting that cross-talk between the two signaling pathways may be a crucial drug-resistant mechanism in ER-positive breast tumors (4). In addition, gene expression profiling studies identified the basal-like tumor as one of the breast tumor subtypes characterized with EGFR expression and poor prognosis (5, 6). EGFR signaling is induced by various EGF-like growth factor family ligands, such as EGF, amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), betacellulin, epiregulin, and transforming growth factor-␣ (7). Amphiregulin is one of the most investigated EGFR ligands in relation to breast cancer. Amphiregulin is a heparin-binding growth factor that requires heparan sulfate (HS) glycosaminoglycans as a low affinity coreceptor (8) and is overexpressed in the majority of primary breast tumors (9). Expression of amphiregulin and EGFR are seen both in breast tumors a...

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“…We have identified recently HSulf-1 as a downregulated gene in several tumor types including ovarian and breast cancer cell lines and primary ovarian tumors (Lai et al, 2003(Lai et al, , 2004a. Our initial analysis indicated that loss of heterozygosity (LOH) may represent a mechanism of HSulf-1 inactivation in ovarian tumors.…”

Section: Introductionmentioning

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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HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma

Cited by 128 publications

References 38 publications

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

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

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

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

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