title: Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.
abstract: The heparin-degrading endosulfatases sulfatase 1 (SULF1) and sulfatase 2 (SULF2) have opposing effects in hepatocarcinogenesis despite structural similarity. Using mRNA expression arrays, we analyzed the correlations of SULF expression with signaling networks in human hepatocellular carcinomas (HCCs) and the associations of SULF expression with tumor phenotype and patient survival. Data from two mRNA microarray analyses of 139 and 36 HCCs and adjacent tissues were used as training and validation sets. Partek and Metacore software were used to identify SULF correlated genes and their associated signaling pathways. Associations between SULF expression, the hepatoblast subtype of HCC, and survival were examined. Both SULF1 and 2 had strong positive correlations with periostin, IQGAP1, TGFB1, and vimentin and inverse correlations with HNF4A and IQGAP2. Genes correlated with both SULFs were highly associated with the cell adhesion, cytoskeletal remodeling, blood coagulation, TGFB, and Wnt/β-catenin and epithelial mesenchymal transition signaling pathways. Genes uniquely correlated with SULF2 were more associated with neoplastic processes than genes uniquely correlated with SULF1. High SULF expression was associated with the hepatoblast subtype of HCC. There was a bimodal effect of SULF1 expression on prognosis, with patients in the lowest or highest tertile having a worse prognosis than those in the middle tertile. SULFs have complex effects on HCC signaling and patient survival. There are functionally similar associations with cell adhesion, ECM remodeling, TGFB, and WNT pathways, but also unique associations of SULF1 and SULF2. The roles and targeting of the SULFs in cancer require further investigation.
authors.affiliation: Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Ju Dong
authors.initials: JD
authors.lastname: Yang
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.forename: Jinping
authors.initials: J
authors.lastname: Lai
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dove
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nakamura
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Koo Jeong
authors.initials: KJ
authors.lastname: Kang
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Chu
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D030541:Databases, Genetic / Q000592:standards; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D012333:RNA, Messenger; C470791:SULF1 protein, human; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases