Gene Summary

Gene:SULF1; sulfatase 1
Aliases: SULF-1
Summary:This gene encodes an extracellular heparan sulfate endosulfatase. The encoded enzyme selectively removes 6-O-sulfate groups from heparan sulfate chains of heparan sulfate proteoglycans (HSPGs). The enzyme is secreted through the Golgi and is subsequently localized to the cell surface. The expression of this gene may be down-regulated in several types of cancer, including hepatocellular (HCC), ovarian and breast cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:extracellular sulfatase Sulf-1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SULF1 (cancer-related)

Schultz S, Bartsch H, Sotlar K, et al.
Progression-specific genes identified in microdissected formalin-fixed and paraffin-embedded tissue containing matched ductal carcinoma in situ and invasive ductal breast cancers.
BMC Med Genomics. 2018; 11(1):80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is an important step during breast carcinogenesis. Understanding its molecular changes may help to identify high-risk DCIS that progress to IBC. Here, we describe a transcriptomic profiling analysis of matched formalin-fixed and paraffin-embedded (FFPE) DCIS and IBC components of individual breast tumours, containing both tumour compartments. The study was performed to validate progression-associated transcripts detected in an earlier gene profiling project using fresh frozen breast cancer tissue. In addition, FFPE tissues from patients with pure DCIS (pDCIS) were analysed to identify candidate transcripts characterizing DCIS with a high or low risk of progressing to IBC.
METHODS: Fifteen laser microdissected pairs of DCIS and IBC were profiled by Illumina DASL technology and used for expression validation by qPCR. Differential expression was independently validated using further 25 laser microdissected DCIS/IBC sample pairs. Additionally, laser microdissected epithelial cells from 31 pDCIS were investigated for expression of candidate transcripts using qPCR.
RESULTS: Multiple statistical calculation methods revealed 1784 mRNAs which are differentially expressed between DCIS and IBC (P < 0.05), of which 124 have also been identified in the gene profiling project using fresh frozen breast cancer tissue. Nine mRNAs that had been selected from the gene list obtained using fresh frozen tissues by applying pathway and network analysis (MMP11, GREM1, PLEKHC1, SULF1, THBS2, CSPG2, COL10A1, COL11A1, KRT14) were investigated in tissues from the same 15 microdissected specimens and the 25 independent tissue samples by qPCR. All selected transcripts were also detected in tumour cells from pDCIS. Expression of MMP11 and COL10A1 increased significantly from pDCIS to DCIS of DCIS/IBC mixed tumours.
CONCLUSION: We confirm differential expression of progression-associated transcripts in FFPE breast cancer samples which might mediate the transition from DCIS to IBC. MMP11 and COL10A1 may characterize pure DCIS with a high risk developing IDC.

Hauptman N, Boštjančič E, Žlajpah M, et al.
Bioinformatics Analysis Reveals Most Prominent Gene Candidates to Distinguish Colorectal Adenoma from Adenocarcinoma.
Biomed Res Int. 2018; 2018:9416515 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the leading causes of death by cancer worldwide. Bowel cancer screening programs enable us to detect early lesions and improve the prognosis of patients with CRC. However, they also generate a significant number of problematic polyps, e.g., adenomas with epithelial misplacement (pseudoinvasion) which can mimic early adenocarcinoma. Therefore, biomarkers that would enable us to distinguish between adenoma with epithelial misplacement (pseudoinvasion) and adenoma with early adenocarcinomas (true invasion) are needed. We hypothesized that the former are genetically similar to adenoma and the latter to adenocarcinoma and we used bioinformatics approach to search for candidate genes that might be potentially used to distinguish between the two lesions. We used publicly available data from Gene Expression Omnibus database and we analyzed gene expression profiles of 252 samples of normal mucosa, colorectal adenoma, and carcinoma. In total, we analyzed 122 colorectal adenomas, 59 colorectal carcinomas, and 62 normal mucosa samples. We have identified 16 genes with differential expression in carcinoma compared to adenoma:

Lyu Y, Cheng Y, Wang B, et al.
Sulfatase 1 expression in pancreatic cancer and its correlation with clinicopathological features and postoperative prognosis.
Cancer Biomark. 2018; 22(4):701-707 [PubMed] Related Publications
BACKGROUND: Recent studies have shown that Sulfatase 1 (SULF1) plays a crucial role in the genesis, development, and progression of tumors. However, there have been few studies on the role of SULF1 in pancreatic cancer.
OBJECTIVE: The present study examined the differences in SULF1 expression levels between pancreatic cancer and normal tissues, and their correlation with the clinicopathological features and prognosis.
METHODS: A total of 65 pancreatic cancer samples were enrolled in this study. An immunohistochemical assay were used in this study. The relationship between SULF1 expression and clinicopathological features were tested using χ2 test or Fisher's exact test. The Kaplan-Meier method was used to calculate the cumulative survival rates of the patients.
RESULTS: The study showed that the SULF1 expression level was higher in pancreatic cancer tissues than in normal tissues. Analysis of the clinical and pathological data of patients revealed that high SULF1 expression was associated with later T, N, and TNM stages, higher CA19-9 levels, smaller tumor size, and poorer prognosis.
CONCLUSIONS: These findings suggested that SULF1 could be an indicator of the clinicopathological features and prognosis of pancreatic cancer.

Krishnakumar K, Chakravorty I, Foy W, et al.
Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events.
Exp Cell Res. 2018; 364(1):16-27 [PubMed] Related Publications
This study demonstrates highly dynamic spatial and temporal pattern of SULF1/SULF2 expression in a number of neuronal cell types growing in normal culture medium that included their transient nuclear mobilisation. Their nuclear translocation became particularly apparent during cell proliferation as both SULF1/SULF2 demonstrated not only cell membrane associated expression, their known site of function but also transient nuclear mobilisation during nuclear cell division. Nuclear localisation was apparent not only by immunocytochemical staining but also confirmed by immunoblotting staining of isolated nuclear fractions of C6, U87 and N2A cells. Immunocytochemical analysis demonstrated rapid nuclear exit of both SULF1/SULF2 following cell division that was slightly delayed but not blocked in a fraction of the polyploid cells observed in C6 cells. The overexpression of both Sulf1 and Sulf2 genes in C6 and U87 cells markedly promoted in vitro growth of these cells accompanied by nuclear mobilisation while inhibition of both these genes inhibited cell proliferation with little or no nuclear SULF1/SULF2 mobilisation. SULF1/SULF2 activity in these cells thus demonstrated a clear co-ordination of extracellular cell signalling with nuclear events related to cell proliferation.

Fei HJ, Chen SC, Zhang JY, et al.
Identification of significant biomarkers and pathways associated with gastric carcinogenesis by whole genome-wide expression profiling analysis.
Int J Oncol. 2018; 52(3):955-966 [PubMed] Related Publications
The incidence of gastric cancer (GC) is extremely high in East Asia. GC is also one of the most common and lethal forms of cancer from a global perspective. However, to date, we have not been able to determine one or several genes as biomarkers in the diagnosis of GC and have also been unable to identify the genes which are important in the therapy of GC. In this study, we analyzed all genome-wide expression profiling arrays uploaded onto the Gene Expression Omnibus (GEO) database to filtrate the differentially expressed genes (DEGs) between normal stomach tissues and GC tissues. GSE13911, GSE19826 and GSE79973 were based on the GPL570 platform, and GSE29272 was based on the GPL96 platform. We screened out the DEGs from the two platforms and by selecting the intersection of these two platforms, we identified the common DEGs in the sequencing data from different laboratories. Finally, we obtained 3 upregulated and 34 downregulated DEGs in GC from 384 samples. As the number of downregulated DEGs was greater than that of the upregulated DEGs, functional analysis and pathway enrichment analysis were performed on the downregulated DEGs. Through our analysis, we identified the most significant genes associated with GC, such as secreted phosphoprotein 1 (SPP1), sulfatase 1 (SULF1), thrombospondin 2 (THBS2), ATPase H+/K+ transporting beta subunit (ATP4B), gastric intrinsic factor (GIF) and gastrokine 1 (GKN1). The prognostic power of these genes was corroborated in the Oncomine database and by Kaplan-Meier plotter (KM-plotter) analysis. Moreover, gastric acid secretion, collecting duct acid secretion, nitrogen metabolism and drug metabolism were significantly related to GC. Thus, these genes and pathways may be potential targets for improving the diagnosis and clinical effects in patients with GC.

Ushakov VS, Tsidulko AY, de La Bourdonnaye G, et al.
Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation.
Int J Mol Sci. 2017; 18(11) [PubMed] Free Access to Full Article Related Publications
Heparan sulfate (HS) is an important component of the extracellular matrix and cell surface, which plays a key role in cell-cell and cell-matrix interactions. Functional activity of HS directly depends on its structure, which determined by a complex system of HS biosynthetic enzymes. During malignant transformation, the system can undergo significant changes, but for glioma, HS biosynthesis has not been studied in detail. In this study, we performed a comparative analysis of the HS biosynthetic system in human gliomas of different grades. RT-PCR analysis showed that the overall transcriptional activity of the main HS biosynthesis-involved genes (

Guo L, Zhang K, Bing Z
Application of a co‑expression network for the analysis of aggressive and non‑aggressive breast cancer cell lines to predict the clinical outcome of patients.
Mol Med Rep. 2017; 16(6):7967-7978 [PubMed] Free Access to Full Article Related Publications
Breast cancer metastasis is a demanding problem in clinical treatment of patients with breast cancer. It is necessary to examine the mechanisms of metastasis for developing therapies. Classification of the aggressiveness of breast cancer is an important issue in biological study and for clinical decisions. Although aggressive and non‑aggressive breast cancer cells can be easily distinguished among different cell lines, it is very difficult to distinguish in clinical practice. The aim of the current study was to use the gene expression analysis from breast cancer cell lines to predict clinical outcomes of patients with breast cancer. Weighted gene co‑expression network analysis (WGCNA) is a powerful method to account for correlations between genes and extract co‑expressed modules of genes from large expression datasets. Therefore, WGCNA was applied to explore the differences in sub‑networks between aggressive and non‑aggressive breast cancer cell lines. The greatest difference topological overlap networks in both groups include potential information to understand the mechanisms of aggressiveness. The results show that the blue and red modules were significantly associated with the biological processes of aggressiveness. The sub‑network, which consisted of TMEM47, GJC1, ANXA3, TWIST1 and C19orf33 in the blue module, was associated with an aggressive phenotype. The sub‑network of LOC100653217, CXCL12, SULF1, DOK5 and DKK3 in the red module was associated with a non‑aggressive phenotype. In order to validate the hazard ratio of these genes, the prognostic index was constructed to integrate them and examined using data from the Cancer Genomic Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Patients with breast cancer from TCGA in the high‑risk group had a significantly shorter overall survival time compared with patients in the low‑risk group (hazard ratio=1.231, 95% confidence interval=1.058‑1.433, P=0.0071, by the Wald test). A similar result was produced from the GEO database. The findings may provide a novel strategy for measuring cancer aggressiveness in patients with breast cancer.

Lee HY, Yeh BW, Chan TC, et al.
Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract.
Oncotarget. 2017; 8(29):47216-47229 [PubMed] Free Access to Full Article Related Publications
Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 (SULF1) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro. In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.

Tao Y, Han T, Zhang T, Sun C
Sulfatase-2 promotes the growth and metastasis of colorectal cancer by activating Akt and Erk1/2 pathways.
Biomed Pharmacother. 2017; 89:1370-1377 [PubMed] Related Publications
The molecular mechanisms underlying the growth and metastasis of colorectal cancer (CRC) remain largely unknown. Sulfatase-2 (SULF2) was found to play critical roles in human cancers. Recent study reported that SULF1/2 overexpression resulted in increased viability and proliferation, and augmented cell migration in CRC cells. However, the expression of SULF2 and its underlying molecular mechanisms in CRC remain unknown. In this study, we found that the expressions of SULF2 in CRC tissues and cell lines were significantly increased compared to control groups. Increased expression of SULF2 was associated with malignant clinical features and poor prognosis of CRC patients. Loss of SULF2 significantly prohibited the proliferation, cell cycle progression, migration and invasion of HT29 cells, while restoration of SULF2 significantly promoted these cellular functions of SW480 cells. In vivo tumorigenicity and liver metastasis assays confirmed that SULF2 knockdown significantly reduced the growth and metastatic abilities of HT29 cells in nude mice. Furthermore, SULF2 knockdown reduced the levels of p-Akt and p-Erk1/2 in HT29 cells, while SULF2 overexpression showed opposite effects on the expressions of these proteins in SW480 cells. In all, SULF2 promotes the growth and metastasis of CRC probably by activating Akt and Erk1/2 pathways. SULF2 potentially serves as a promising biomarker and therapeutic target in CRC.

Roy D, Mondal S, Khurana A, et al.
Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.
Sci Rep. 2017; 7:41977 [PubMed] Free Access to Full Article Related Publications
Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2

Lou X, Sun B, Song J, et al.
Human sulfatase 1 exerts anti-tumor activity by inhibiting the AKT/ CDK4 signaling pathway in melanoma.
Oncotarget. 2016; 7(51):84486-84495 [PubMed] Free Access to Full Article Related Publications
Human sulfatase 1 (hSulf-1) has aryl sulfatase activity. It can reduce the sulfation of cell surface heparan sulfate proteoglycan (HSPG) and inhibit various growth factor receptor-mediated signaling pathways. In most cancers, hSulf-1 is inactivated, which endows cancer cells with increasesed cell proliferation and metastatic activities, inhibition of apoptosis, and decreased sensitivity to radio- and chemotherapy. In this study, we found that hSulf-1 overexpression in melanoma cells can inhibit cell proliferation and induce cell cycle arrest and apoptosis by decreasing the protein kinase B (AKT) phosphorylation and limiting CDK4 nuclear import. We further confirmed that hSulf-1 overexpression can inhibit AKT phosphorylation and CDK4 nuclear localization and retard the growth of melanoma xenograft tumors in nude mice. Overall, hSulf-1 function in melanoma cells provides an ideal molecular treatment target. An important anti-tumor mechanism of hSulf-1 operates by decreasing downstream AKT signaling pathway activity and inhibiting the nuclear import of CDK4.

Lee KW, Lee SS, Hwang JE, et al.
Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer.
Clin Cancer Res. 2016; 22(24):6228-6235 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.
EXPERIMENTAL DESIGN: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.
RESULTS: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02-2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1-7.9; P = 0.03) and was the only significant independent predictor of recurrence.
CONCLUSIONS: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228-35. ©2016 AACR.

Graham K, Murphy JI, Dhoot GK
SULF1/SULF2 reactivation during liver damage and tumour growth.
Histochem Cell Biol. 2016; 146(1):85-97 [PubMed] Related Publications
Both SULF1 and SULF2 enzymes are undetectable in normal adult liver tissue despite their high level expression during foetal development. Most hepatocellular carcinomas unlike the normal adult liver, however, express variable levels of these enzymes with a small proportion not expressing either SULF1 or SULF2. SULF1 expression, however, is not restricted to only foetal and tumour tissues but is also abundant in liver tissues undergoing injury-induced tissue regeneration as we observed during fatty liver degeneration, chronic hepatitis and cirrhosis. Unlike SULF1, the level of SULF2 activation during injury-induced regeneration, however, is much lower when compared to foetal or tumour growth. Although a small fraction of liver tumours and some liver tumour cell lines can grow in the absence of Sulf1 and/or Sulf2, the in vitro overexpression of these genes further confirms their growth-promoting effect while transient reduction in their levels by neutralisation antibodies reduces growth. Hedgehog signalling appeared to regulate the growth of both Hep3B and PRF5 cell lines since cyclopamine demonstrated a marked inhibitory effect while sonic hedgehog (SHH) overexpression promoted growth. All Sulf isoforms promoted SHH-induced growth although the level of increase in PRF5 cell line was higher with both Sulf2 variants than Sulf1. In addition to promoting growth, the Sulf variants, particularly the shorter Sulf2 variant, markedly promoted PRF5 cell migration in a scratch assay. The SULF1/SULF2 activation thus does not only promote regulated foetal growth and injury-induced liver regeneration but also dysregulated tumour growth.

Tsidulko AY, Matskova L, Astakhova LA, et al.
Proteoglycan expression correlates with the phenotype of malignant and non-malignant EBV-positive B-cell lines.
Oncotarget. 2015; 6(41):43529-39 [PubMed] Free Access to Full Article Related Publications
The involvement of proteoglycans (PGs) in EBV-host interactions and lymphomagenesis remains poorly investigated. In this study, expression of major proteoglycans (syndecan-1, glypican-1, perlecan, versican, brevican, aggrecan, NG2, serglycin, decorin, biglycan, lumican, CD44), heparan sulphate (HS) metabolic system (EXT1/2, NDST1/2, GLCE, HS2ST1, HS3ST1/2, HS6ST1/2, SULF1/2, HPSE) and extracellular matrix (ECM) components (collagen 1A1, fibronectin, elastin) in primary B cells and EBV carrying cell lines with different phenotypes, patterns of EBV-host cell interaction and viral latency stages (type I-III) was investigated. Primary B cells expressed a wide repertoire of PGs (dominated by serglycin and CD44) and ECM components. Lymphoblastoid EBV+ B cell lines (LCLs) showed specific PG expression with down-regulation of CD44 and ECM components and up-regulation of serglycin and perlecan/HSPG2. For Burkitt's lymphoma cells (BL), serglycin was down-regulated in BL type III cells and perlecan in type I BL cells. The biosynthetic machinery for HS was active in all cell lines, with some tendency to be down-regulated in BL cells. 5'-aza-dC and/or Trichostatin A resulted in transcriptional upregulation of the genes, suggesting that low expression of ECM components, proteoglycan core proteins and HS biosynthetic system is due to epigenetic suppression in type I cells. Taken together, our data show that proteoglycans are expressed in primary B lymphocytes whereas they are not or only partly expressed in EBV-carrying cell lines, depending on their latency type program.

Mondal S, Roy D, Camacho-Pereira J, et al.
HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer.
Oncotarget. 2015; 6(32):33705-19 [PubMed] Free Access to Full Article Related Publications
Warburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.

Wang J, Xie H, Ling Q, et al.
Coding-noncoding gene expression in intrahepatic cholangiocarcinoma.
Transl Res. 2016; 168:107-121 [PubMed] Related Publications
Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in human cancers. However, the function of lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of intrahepatic cholangiocarcinoma (ICC). In the present study, we performed transcriptomic profiling of ICC and paired adjacent noncancerous tissues (N) by using lncRNA and messenger RNA (mRNA) microarrays. Quantitative real-time polymerase chain reaction was used to validate the microarray results. We tested for correlations between the expression levels of lncRNAs and target genes. Clinicopathologic characteristics and overall survival were compared using the t test and the Kaplan-Meier method, respectively. A total of 2773 lncRNAs were significantly upregulated in ICC tissues compared with the noncancerous tissues, whereas 2392 lncRNAs were downregulated. Bioinformatic analysis indicated that most of the genes were involved in carcinogenesis, hepatic system diseases, and signal transductions. Positive correlations were found between 4 lncRNA-mRNA pairs (RNA43085 and SULF1, RNA47504 and KDM8, RNA58630 and PCSK6, and RNA40057 and CYP2D6). When the clinicopathologic characteristics were accounted for, the cumulative overall survival rate was found to be associated with low expression levels of CYP2D6 (P = 0.005) and PCSK6 (P = 0.038). Patients with high expression levels of CYP2D6 and RNA40057 had a better prognosis (P = 0.014). Our results suggested that the lncRNA expression profiling in ICC tissues is profoundly different from that in noncancerous tissues. Thus, lncRNA may be a potential diagnostic and prognostic biomarker for ICC. Furthermore, the combined assessment of lncRNA and mRNA expressions might predict the survival of patients with ICC.

Heidari-Hamedani G, Vivès RR, Seffouh A, et al.
Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma.
Cell Signal. 2015; 27(10):2054-67 [PubMed] Related Publications
Syndecan-1 is a proteoglycan that acts as co-receptor through its heparan sulfate (HS) chains and plays important roles in cancer. HS chains are highly variable in length and sulfation pattern. This variability is enhanced by the SULF1/2 enzymes, which remove 6-O-sulfates from HS. We used malignant mesothelioma, an aggressive tumor with poor prognosis, as a model and demonstrated that syndecan-1 over-expression down-regulates SULF1 and alters the HS biosynthetic machinery. Biochemical characterization revealed a 2.7-fold reduction in HS content upon syndecan-1 over-expression, but an overall increase in sulfation. Consistent with low SULF1 levels, trisulfated disaccharides increased 2.5-fold. ERK1/2 activity was enhanced 6-fold. Counteracting ERK activation, Akt, WNK1, and c-Jun were inhibited. The net effect of these changes manifested in G1 cell cycle arrest. Studies of pleural effusions showed that SULF1 levels are lower in pleural malignancies compared to benign conditions and inversely correlate with the amounts of syndecan-1, suggesting important roles for syndecan-1 and SULF1 in malignant mesothelioma.

Suhovskih AV, Domanitskaya NV, Tsidulko AY, et al.
Tissue-specificity of heparan sulfate biosynthetic machinery in cancer.
Cell Adh Migr. 2015; 9(6):452-9 [PubMed] Free Access to Full Article Related Publications
Heparan sulfate (HS) proteoglycans are key components of cell microenvironment and fine structure of their polysaccharide HS chains plays an important role in cell-cell interactions, adhesion, migration and signaling. It is formed on non-template basis, so, structure and functional activity of HS biosynthetic machinery is crucial for correct HS biosynthesis and post-synthetic modification. To reveal cancer-related changes in transcriptional pattern of HS biosynthetic system, the expression of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, 3OST1/HS3ST1, SULF1/2, HPSE) in human normal (fibroblasts, PNT2) and cancer (MCF7, LNCaP, PC3, DU145, H157, H647, A549, U2020, U87, HT116, KRC/Y) cell lines and breast, prostate, colon tumors was studied. Real-time RT-PCR and Western-blot analyses revealed specific transcriptional patterns and expression levels of HS biosynthetic system both in different cell lines in vitro and cancers in vivo. Balance between transcriptional activities of elongation- and post-synthetic modification- involved genes was suggested as most informative parameter for HS biosynthetic machinery characterization. Normal human fibroblasts showed elongation-oriented HS biosynthesis, while PNT2 prostate epithelial cells had modification-oriented one. However, cancer epithelial cells demonstrated common tendency to acquire fibroblast-like elongation-oriented mode of HS biosynthetic system. Surprisingly, aggressive metastatic cancer cells (U2020, DU145, KRC/Y) retained modification-oriented HS biosynthesis similar to normal PNT2 cells, possibly enabling the cells to keep like-to-normal cell surface glycosylation pattern to escape antimetastatic control. The obtained results show the cell type-specific changes of HS-biosynthetic machinery in cancer cells in vitro and tissue-specific changes in different cancers in vivo, supporting a close involvement of HS biosynthetic system in carcinogenesis.

Melaiu O, Melissari E, Mutti L, et al.
Expression status of candidate genes in mesothelioma tissues and cell lines.
Mutat Res. 2015; 771:6-12 [PubMed] Related Publications
In order to broaden knowledge on the pathogenesis of malignant pleural mesothelioma (MPM), we reviewed studies on the MPM-transcriptome and identified 119 deregulated genes. However, there was poor consistency among the studies. Thus, the expression of these genes was further investigated in the present work using reverse transcriptase-quantitative PCR (RT-qPCR) in 15 MPM and 20 non-MPM tissue samples. Fifty-nine genes showed a statistically significant deregulation and were further evaluated in two epithelioid MPM cell lines (compared to MET-5A, a non-MPM cell line). Nine genes (ACSL1, CCNO, CFB, PDGFRB, SULF1, TACC1, THBS2, TIMP3, XPOT) were deregulated with statistical significance in both cell lines, 12 (ASS1, CCNB1, CDH11, COL1A1, CXADR, EIF4G1, GALNT7, ITGA4, KRT5, PTGIS, RAN, SOD1) in at least one cell line, whereas 7 (DSP, HEG1, MCM4, MSLN, NME2, NMU, TNPO2) were close but did not reach the statistical significance in any of the cell line. Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. Although MPM is a poorly studied cancer, some features are starting to emerge. Novel cancer genes are suggested here, in particular those involved in cell-cell and cell-matrix interactions.

Vicente CM, Lima MA, Yates EA, et al.
Enhanced tumorigenic potential of colorectal cancer cells by extracellular sulfatases.
Mol Cancer Res. 2015; 13(3):510-23 [PubMed] Related Publications
UNLABELLED: Heparan sulfate endosulfatase-1 and -2 (SULF1 and SULF2) are two important extracellular 6-O-endosulfatases that remove 6-O sulfate groups of N-glucosamine along heparan sulfate (HS) proteoglycan chains often found in the extracellular matrix. The HS sulfation pattern influences signaling events at the cell surface, which are critical for interactions with growth factors and their receptors. SULFs are overexpressed in several types of human tumors, but their role in cancer is still unclear because their molecular mechanism has not been fully explored and understood. To further investigate the functions of these sulfatases in tumorigenesis, stable overexpression models of these genes were generated in the colorectal cancer cells, Caco-2 and HCT-116. Importantly, mimicking overexpression of these sulfatases resulted in increased viability and proliferation, and augmented cell migration. These effects were reverted by shRNA-mediated knockdown of SULF1 or SULF2 and by the addition of unfractionated heparin. Detailed structural analysis of HS from cells overexpressing SULFs showed reduction in the trisulfated disaccharide UA(2S)-GlcNS(6S) and corresponding increase in UA(2S)-GlcNS disaccharide, as well as an unexpected rise in less common disaccharides containing GlcNAc(6S) residues. Moreover, cancer cells transfected with SULFs demonstrated increased Wnt signaling. In summary, SULF1 or SULF2 overexpression contributes to colorectal cancer cell proliferation, migration, and invasion.
IMPLICATIONS: This study reveals that sulfatases have oncogenic effects in colon cancer cells, suggesting an important role for these enzymes in cancer progression.

Wade A, Engler JR, Tran VM, Phillips JJ
Measuring sulfatase expression and invasion in glioblastoma.
Methods Mol Biol. 2015; 1229:507-16 [PubMed] Free Access to Full Article Related Publications
Extracellular sulfatases (SULF1 and SULF2) selectively remove 6-O-sulfate groups from heparan sulfate proteoglycans (HSPGs) and by this process control important interactions of HSPGs with extracellular factors including morphogens, growth factors, and extracellular matrix components. The expression of SULF1 and SULF2 is dynamically regulated during development and is altered in pathological states such as glioblastoma (GBM), a highly malignant and highly invasive brain cancer. SULF2 protein is increased in an important subset of human GBM and it helps regulate receptor tyrosine kinase signaling and tumor growth in a murine model of the disease. By altering ligand binding to HSPGs, SULF2 has the potential to modify the extracellular availability of factors important in a number of cell processes including proliferation, chemotaxis, and migration. Diffuse invasion of malignant tumor cells into surrounding healthy brain is a characteristic feature of GBM that makes therapy challenging. Here, we describe methods to assess SULF2 expression in human tumor tissue and cell lines and how to relate this to tumor cell invasion.

Xu G, Ji W, Su Y, et al.
Sulfatase 1 (hSulf-1) reverses basic fibroblast growth factor-stimulated signaling and inhibits growth of hepatocellular carcinoma in animal model.
Oncotarget. 2014; 5(13):5029-39 [PubMed] Free Access to Full Article Related Publications
The human sulfatase 1 (hSulf-1) gene encodes an endosulfatase that functions to inhibit the heparin-binding growth factor signaling, including the basic fibroblast growth factor (bFGF)-mediated pathway, by desulfating the cell surface heparan sulfate proteoglycans (HSPGs). bFGF could stimulate cell cycle progression and inhibit cell apoptosis, this biological effect can be reversed by hSulf-1. However, molecular mechanisms have not been fully reported. In the current study, by reactivation of hSulf-1 expression and function in the hSulf-1-negative hepatocellular carcinoma (HCC) cell lines and HCC xenograft tumors, we found that hSulf-1 blocked the bFGF effect on the promotion of cell cycle and inhibition of apoptosis. The bFGF-stimulated activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways was suppressed by hSulf-1, which led to a decreased expression of the target genes Cyclin D1 and Survivin, then finally induced cell cycle arrest and apoptosis in HCC cells. Our data suggested that hSulf-1 may be a suitable target for cancer therapy.

Gill RM, Michael A, Westley L, et al.
SULF1/SULF2 splice variants differentially regulate pancreatic tumour growth progression.
Exp Cell Res. 2014; 324(2):157-71 [PubMed] Related Publications
This study highlights the highly dynamic nature of SULF1/SULF2 splice variants in different human pancreatic cancers that regulate the activities of multiple cell signalling pathways in development and disease. Most pancreatic tumours expressed variable levels of both SULF1 and SULF2 variants including some expression during inflammation and pancreatitis. Many ductal and centro-acinar cell-derived pancreatic tumours are known to evolve into lethal pancreatic ductal adenocarcinomas but the present study also detected different stages of such tumour progression in the same tissue biopsies of not only acinar cell origin but also islet cell-derived cancers. The examination of caerulein-induced pancreatic injury and tumorigenesis in a Kras-driven mouse model confirmed the activation and gradual increase of SULF1/SULF2 variants during pancreatitis and tumorigenesis but with reduced levels in Stat3 conditional knockout mice with reduced inflammation. The significance of differential spatial and temporal patterns of specific SULF1/SULF2 splice variant expression during cancer growth became further apparent from their differential stimulatory or inhibitory effects on growth factor activities, tumour growth and angiogenesis not only during in vitro but also in vivo growth thus providing possible novel therapeutic targets.

He X, Khurana A, Roy D, et al.
Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.
Int J Cancer. 2014; 135(8):1783-9 [PubMed] Free Access to Full Article Related Publications
The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.

Cheng L, Zhang Q, Yang S, et al.
A 4-gene panel as a marker at chromosome 8q in Asian gastric cancer patients.
Genomics. 2013; 102(4):323-30 [PubMed] Related Publications
A widely held viewpoint is that the use of multiple markers, combined in some type of algorithm, will be necessary to provide high enough discrimination between diseased cases and non-diseased. We applied stepwise logistic regression analysis to identify the best combination of the 32 biomarkers at chromosome 8q on an independent public microarray test set of 80 paired gastric samples. A combination of SULF1, INTS8, ATP6V1C1, and GPR172A was identified with a prediction accuracy of 98.0% for discriminating carcinomas from adjacent noncancerous tissues in our previous 25 paired samples. Interestingly, the overexpression of SULF1 was associated with tumor invasion and metastasis. Function prediction analysis revealed that the 4-marker panel was mainly associated with acidification of intracellular compartments. Taken together, we found a 4-gene panel that accurately discriminated gastric carcinomas from adjacent noncancerous tissues and these results had potential clinical significance in the early diagnosis and targeted treatment of gastric cancer.

Bao L, Yan Y, Xu C, et al.
MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways.
Cancer Lett. 2013; 337(2):226-36 [PubMed] Related Publications
MicroRNAs (miRNAs) have been believed to associate with malignant progression including cancer cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, the functions of miRNAs are intricate, one miRNA can directly or indirectly target multiple genes and function as oncogene or tumor suppressor gene. In this study, we found that miR-21 inhibits PTEN and human sulfatase-1 (hSulf-1) expression in hepatocellular carcinoma (HCC) cells. The hSulf-1 is a heparin-degrading endosulfatase, which can inhibit the heparin binding growth factor-mediated signaling transduction into cells. Therefore, miR-21-mediated suppression of both hSulf-1 and PTEN led to activation of AKT/ERK pathways and epithelial-mesenchymal transition (EMT) in HCC cells, and finally enhance the activity of HCC cell proliferation and movement and promote HCC xenograft tumor growth in mouse models. These findings may provide candidate targets for prevention and treatment of HCC.

Yuen HF, McCrudden CM, Huang YH, et al.
TAZ expression as a prognostic indicator in colorectal cancer.
PLoS One. 2013; 8(1):e54211 [PubMed] Free Access to Full Article Related Publications
The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic), and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.

Zhang Y, Fang L, Zhang Q, et al.
An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.
Mol Oncol. 2013; 7(3):346-58 [PubMed] Free Access to Full Article Related Publications
Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment.

Liu P, Gou M, Yi T, et al.
The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer.
Int J Oncol. 2012; 41(4):1504-12 [PubMed] Related Publications
HSulf-1 (heparan sulfate 6-O-endosulfatase 1), a commonly downregulated gene in the majority of ovarian cancer cell lines, has been identified to play an important role in regulating tumorigenesis. Our previous studies demonstrated that HSulf-1 could inhibit angiogenesis and tumorigenesis in vivo. The employment of polymeric nanoparticles to deliver functional gene holds much promise as an effective therapeutic strategy against ovarian cancer. To develop more effective therapy, in this study, we investigated the antitumor effect of heparin-polyethyleneimine (HPEI) nanogels delivering HSulf-1 combined with cisplatin (DDP) on ovarian cancer. Expression of HSulf-1 in vitro and in vivo was determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A SKOV3 intraperitoneal ovarian carcinomatosis model in nude mice was established to assess the antitumor efficacy. Mice were treated with NS, pEP/HPEI complexes, pHSulf-1/HPEI complexes, DDP or pHSulf-1/HPEI plus DDP, respectively. Intraperitoneal tumors were weighed. Antiangiogenic effect in vivo was evaluated by CD31 immunostaining and alginate-encapsulate tumor cell assay. Detection of the proliferative cells and apoptotic cells in tumor tissues were performed by Ki-67 staining and TUNEL assay. Stable expression of HSulf-1 was detected in the pHSulf-1/HPEI and pHSulf-1/HPEI plus DDP groups. The combination of pHSulf-1/HPEI complexes with DDP exhibited enhanced antitumor activity, compared with the monotherapy of HSulf-1 or DDP alone (P<0.01). the combination therapy exerted significant antitumor activity through enhanced antiangiogenesis, induction of apoptosis and suppression of cell proliferation. Collectively, these observations provide evidence that HPEI nanogels delivering HSulf-1 combined with DDP may have a promising application in the therapy of human ovarian cancer.

Gill RB, Day A, Barstow A, et al.
Mammalian Sulf1 RNA alternative splicing and its significance to tumour growth regulation.
Tumour Biol. 2012; 33(5):1669-80 [PubMed] Related Publications
SULF1/SULF2 enzymes regulate the activities of several growth factors by selective hydrolysis of 6-O-sulphates of heparan sulphate proteoglycan co-receptors, the sulfation of which is essential for signal transduction of some ligand/receptor interactions but not others. This study demonstrates the existence of SULF1 variants with a wide spectrum of splicing patterns in mammalian tumours. The levels and relative proportions of SULF1/SULF2 splice variants markedly vary in different tumours with a potential to regulate cell growth differentially. Although mammalian Sulf1 compared with Sulf2 gene generates a much larger number of splice variants, both enzymes follow generally similar distribution and signalling association trends in hepatocellular carcinomas.

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