title: Dermatan sulfate is involved in the tumorigenic properties of esophagus squamous cell carcinoma.
abstract: Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue. The main IdoA-producing enzyme, DS epimerase 1 (DS-epi1), together with the 6-O- and 4-O-sulfotransferases, were highly upregulated in ESCC biopsies. Importantly, CS/DS structure in patient tumors was significantly altered compared with normal tissue, as determined by sensitive mass spectrometry. To further understand the roles of IdoA in tumor development, DS-epi1 expression, and consequently IdoA content, was downregulated in ESCC cells. IdoA-deficient cells exhibited decreased migration and invasion capabilities in vitro, which was associated with reduced cellular binding of hepatocyte growth factor, inhibition of pERK-1/2 signaling, and deregulated actin cytoskeleton dynamics and focal adhesion formation. Our findings show that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, downregulation of IdoA by DS-epi1 inhibitors may represent a new anticancer therapy.
authors.affiliation: Department of Experimental Medical Science, Biomedical Center D12, Lund University, Lund, Sweden. martin.thelin@med.lu.se
authors.forename: Martin A
authors.initials: MA
authors.lastname: Thelin
authors.forename: Katrin J
authors.initials: KJ
authors.lastname: Svensson
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Shi
authors.forename: Mariam
authors.initials: M
authors.lastname: Bagher
authors.forename: Jakob
authors.initials: J
authors.lastname: Axelsson
authors.forename: Anna
authors.initials: A
authors.lastname: Isinger-Ekstrand
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
authors.forename: Joseph
authors.initials: J
authors.lastname: Zaia
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
authors.forename: Marco
authors.initials: M
authors.lastname: Maccarana
authors.forename: Anders
authors.initials: A
authors.lastname: Malmström
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003871:Dermatan Sulfate / Q000737:chemistry / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007067:Iduronic Acid / Q000032:analysis / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D003871:Dermatan Sulfate; D007067:Iduronic Acid; D002809:Chondroitin Sulfates; C405383:DSE protein, human