title: SULF1/SULF2 splice variants differentially regulate pancreatic tumour growth progression.
abstract: 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.
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK.
authors.forename: Roop M S
authors.initials: RM
authors.lastname: Gill
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Michael
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK.
authors.forename: Leah
authors.initials: L
authors.lastname: Westley
authors.affiliation: Centre for Tumour Biology, Barts and the London School of Medicine and Dentistry, Queen Mary College, University of London, London EC1M 6BQ, UK.
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Murphy
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 OTU, UK. Electronic address: tdhoot@rvc.ac.uk.
authors.forename: Gurtej K
authors.initials: GK
authors.lastname: Dhoot
mesh_terms: D000328:Adult; D000818:Animals; D002642:Chick Embryo; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics / Q000502:physiology*; D047368:Tumor Burden / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D007527:Isoenzymes; C470791:SULF1 protein, human; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases
keywords: Inflammation; Pancreatic cancer; Pancreatitis; SULF1; SULF2; Splice variants