Article

SULF-2: an extracellular modulator of cell signaling and a cancer target candidate

University of California, Department of Anatomy and Comprehensive Cancer Center, San Francisco, 94143, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 09/2010; 14(9):935-49. DOI: 10.1517/14728222.2010.504718
Source: PubMed

ABSTRACT

Importance of the field: Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans (HSPGs) on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers with Sulf-2 in particular implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer and hepatocellular carcinoma. Areas covered in this review: This review describes the novel activity of the Sulfs in altering the sulfation pattern of HSPG chains on the outside of cells. Thereby, the Sulfs can change the binding of growth factors to these chains and can either promote (e.g., Wnt) or inhibit (e.g., fibroblast growth factor-2) signaling. The review focuses on the widespread upregulation of both Sulfs in cancers and summarizes the evidence that Sulf-2 promotes the transformed behavior of several types of cancer cells in vitro as well as their tumorigenicity in vivo. What the reader will gain: Sulf-2 is a bonafide candidate as a cancer-causing agent in NSCLC and other cancers in which it is upregulated. Take home message: Sulf-2 is an extracellular enzyme and as such would be an attractive therapeutic target for the treatment of NSCLC and other cancers.

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Available from: ncbi.nlm.nih.gov
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    • "The negative effects of SULFs on FGF-2 signaling are consistent with the requirement for 6S on HSPGs in the FGF-2 signaling complex [33]. However, consistent with a potential oncogenic role, one or both SULF genes were soon found to be overexpressed in subsets of multiple tumors (breast, pancreatic, hepatocellular carcinoma, malignant astrocytoma, head and neck, lung, and multiple myeloma) [11] . In particular, SULF2 has been directly implicated as a candidate cancercausing gene in human breast cancer and mouse brain cancer [34,35]. "
    [Show abstract] [Hide abstract] ABSTRACT: Lung cancer is one of the most deadly cancers; median survival from diagnosis is less than one year in those with advanced disease. Novel lung cancer biomarkers are desperately needed. In this study, we evaluated SULF2 expression by immunohistochemistry and its association with overall survival in a cohort of patients with non-small cell lung cancer (NSCLC). We also looked for the presence of SULF2 protein in plasma to evaluate its potential as an early detection biomarker for NSCLC.
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    • "Heparan sulfate can also be modified by editing enzymes, such as 6-O-endo-sulfatases and heparanase (Ai et al., 2003; Ilan et al., 2006; Xu et al., 2007). The extracellular 6-O-endo-sulfatases, Sulf1 and Sulf2, selectively remove sulfate groups from the carbon 6 positions (Lamanna et al., 2008; Rosen and Lemjabbar-Alaoui, 2010; Nagamine et al., 2012), while heparanase cleaves HS chains from the protein core, generating free HS (Bernfield et al., 1999; Galvis et al., 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Heparan sulfate (HS) is a complex and highly variable polysaccharide, expressed ubiquitously on the cell surface as HS proteoglycans (HSPGs), and found in the extracellular matrix as free HS fragments. Its heterogeneity due to various acetylation and sulfation patterns endows a multitude of functions. In animal tissues, HS interacts with a wide range of proteins to mediate numerous biological activities; given its multiple roles in inflammation processes, characterization of HS in human serum has significant potential for elucidating disease mechanisms. Historically, investigation of HS was limited by its low concentration in human serum, together with the complexity of the serum matrix. In this study, we used a modified mass spectrometry method to examine HS disaccharide profiles in the serum of 50 women with rheumatoid arthritis (RA), and compared our results to 51 sera from healthy women. Using various purification methods and online LC-MS/MS, we discovered statistically significant differences in the sulfation and acetylation patterns between populations. Since early diagnosis of RA is considered important in decelerating the disease’s progression, identification of specific biomolecule characterizations may provide crucial information towards developing new therapies for suppressing the disease in its early stages. This is the first report of potential glycosaminoglycan biomarkers for RA found in human sera, while acknowledging the obvious fact that a larger population set, and more stringent collection parameters, will need to be investigated in the future.
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    • "Due to their roles in carcinogenesis, [30], [35]–[41] Sulfs represent attractive therapeutic target for cancer treatment. [38], [42] "
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    Full-text · Article · Aug 2014 · PLoS ONE
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