Abstract
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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Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson Jr CP. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science. 2001;293:1663–6.
Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem. 2002;277:49175–85.
DA Pye VR, Turnbull JE, Hyde P, Gallagher JT. Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. J Biol Chem. 1998;273:22936–42.
Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson Jr CP. QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol. 2003;162:341–51.
Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One. 2007;2:e392.
Langsdorf A, Schumacher V, Shi X, Tran T, Zaia J, Jain S, Taglienti M, Kreidberg JA, Fine A, Ai X. Expression regulation and function of heparan sulfate 6-O-endosulfatases in the spermatogonial stem cell niche. Glycobiology. 2011;21:152–61.
Viviano BL, Paine-Saunders S, Gasiunas N, Gallagher J, Saunders S. Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist noggin. J Biol Chem. 2004;279:5604–11.
Wang S, Ai X, Freeman SD, Pownall ME, Lu Q, Kessler DS, Emerson Jr CP. Qsulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis. Proc Natl Acad Sci U S A. 2004;101:4833–8.
Lai J, Chien J, Staub J, Avula R, Greene EL, Matthews TA, Smith DI, Kaufmann SH, Roberts LR, Shridhar V. Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. J Biol Chem. 2003;278:23107–17.
Lai JP, Chien J, Strome SE, Staub J, Montoya DP, Greene EL, Smith DI, Roberts LR, Shridhar V. HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. Oncogene. 2004;23:1439–47.
Li J, Kleeff J, Abiatari I, Kayed H, Giese NA, Felix K, Giese T, Buchler MW, Friess H. Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer. Mol Cancer. 2005;4:14.
Rosen SD, Lemjabbar-Alaoui H. Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate. Expert Opin Ther Targets. 2010;14:935–49.
Dhoot G. Recent progress and related patents on the applications of SULF1/SULF2 enzymes in regenerative medicine and cancer therapies. Recent Pat Regen Med. 2012;2:137–45.
Lai JP, Chien JR, Moser DR, Staub JK, Aderca I, Montoya DP, Matthews TA, Nagorney DM, Cunningham JM, Smith DI, Greene EL, Shridhar V, Roberts LR. Hsulf1 sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling. Gastroenterology. 2004;126:231–48.
Lai JP, Sandhu DS, Yu C, Han T, Moser CD, Jackson KK, Guerrero RB, Aderca I, Isomoto H, Garrity-Park MM, Zou H, Shire AM, Nagorney DM, Sanderson SO, Adjei AA, Lee JS, Thorgeirsson SS, Roberts LR. Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology. 2008;47:1211–22.
Yang JD, Sun Z, Hu C, Lai J, Dove R, Nakamura I, Lee JS, Thorgeirsson SS, Kang KJ, Chu IS, Roberts LR. Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival. Genes Chromosomes Cancer. 2011;50:122–35.
Bret C, Moreaux J, Schved JF, Hose D, Klein B. SULFs in human neoplasia: implication as progression and prognosis factors. J Transl Med. 2011;9:72.
Sahota AP, Dhoot GK. A novel SULF1 splice variant inhibits Wnt signalling but enhances angiogenesis by opposing SULF1 activity. Exp Cell Res. 2009;315:2752–64.
Knaust A, Schmidt B, Dierks T, von Bulow R, von Figura K. Residues critical for formylglycine formation and/or catalytic activity of arylsulfatase A. Biochemistry. 1998;37:13941–6.
Gill RB, Day A, Barstow A, Liu H, Zaman G, Dhoot GK. Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications. Biochem Biophys Res Commun. 2011;414(3):468–73.
Gill RM, Hitchins L, Fletcher F, Dhoot GK. Sulf1A and HGF regulate satellite-cell growth. J Cell Sci. 2010;123:1873–83.
Ai X, Do AT, Kusche-Gullberg M, Lindahl U, Lu K, Emerson Jr CP. Substrate specificity and domain functions of extracellular heparan sulfate 6-O-endosulfatases, QSulf1 and QSulf2. J Biol Chem. 2006;281:4969–76.
Tang R, Rosen SD. Functional consequences of the subdomain organization of the sulfs. J Biol Chem. 2009;284:21505–14.
Tennenbaum TBA, Glick AB, Tamura R, Quaranta V, Yuspa SH. A splice variant of alpha 6 integrin is associated with malignant conversion in mouse skin tumorigenesis. Proc Natl Acad Sci U S A. 1995;92:7041–5.
Zhang XMC, Sun S, Ketchandji M, Nelson PS, True LD, Vakar-Lopez F, Vessella RL, Plymate SR. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS One. 2011;6:e27970.
Witek A, Paul-Samojedny M, Stojko R, Seifert B, Mazurek U. Coexpression index of estrogen receptor alpha mRNA isoforms in simple, complex hyperplasia without atypia, complex atypical hyperplasia and adenocarcinoma. Gynecol Oncol. 2007;106:407–12.
Lai JP, Thompson JR, Sandhu DS, Roberts LR. Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets. Future Oncol. 2008;4:803–14.
Acknowledgments
We thank ARC and the Wellcome Trust for the financial support of some sections of this work through a project grant and some vacation studentships. We would also like to thank Dr. Steve Allen for his critical reading of the manuscript. The human embryonic and fetal material was provided by the Joint MRC grant G0700089 and Wellcome Trust grant GR082557 through Human Developmental Biology Resource, ICH, UCL.
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Gill, R.B.S., Day, A., Barstow, A. et al. Mammalian Sulf1 RNA alternative splicing and its significance to tumour growth regulation. Tumor Biol. 33, 1669–1680 (2012). https://doi.org/10.1007/s13277-012-0423-2
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DOI: https://doi.org/10.1007/s13277-012-0423-2