title: Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma.
abstract: Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632-45. ©2016 AACR.
authors.affiliation: Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.|Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nakamura
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.|Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California.
authors.forename: Renumathy
authors.initials: R
authors.lastname: Dhanasekaran
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Eriko
authors.initials: E
authors.lastname: Iguchi
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ezequiel J
authors.initials: EJ
authors.lastname: Tolosa
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Romecin
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Renzo E
authors.initials: RE
authors.lastname: Vera
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miamen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.|Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
authors.forename: Roongruedee
authors.initials: R
authors.lastname: Chaiteerakij
authors.affiliation: Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Mengtao
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Asiedu
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Han
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Bubu A
authors.initials: BA
authors.lastname: Banini
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Oseini
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Dongye
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Shaleh
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.|Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Dehai
authors.initials: D
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Tao
authors.initials: T
authors.lastname: Song
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: INSERM U1242, Chemistry, Oncogenesis Stress Signaling, Université Rennes 1, and Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.|Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota. roberts.lewis@mayo.edu.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D013429:Sulfatases; D015238:Sulfotransferases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases