Dermatan sulfate is involved in the tumorigenic properties of Esophagus Squamous Cell Carcinoma.

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Dermatan sulfate is involved in the tumorigenic properties of Esophagus Squamous Cell Carcinoma. / Thelin, Martin; Svensson, Katrin; Shi, Xiaofeng; Bagher, Mariam; Axelsson, Jakob B; Isinger Ekstrand, Anna; van Kuppevelt, Toin H; Johansson, Jan; Nilbert, Mef; Zaia, Joseph; Belting, Mattias; Maccarana, Marco; Malmström, Anders.

I: Cancer Research, Vol. 72, Nr. 8, 2012, s. 1943-1952.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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T1 - Dermatan sulfate is involved in the tumorigenic properties of Esophagus Squamous Cell Carcinoma.

AU - Thelin, Martin

AU - Svensson, Katrin

AU - Shi, Xiaofeng

AU - Bagher, Mariam

AU - Axelsson, Jakob B

AU - Isinger Ekstrand, Anna

AU - van Kuppevelt, Toin H

AU - Johansson, Jan

AU - Nilbert, Mef

AU - Zaia, Joseph

AU - Belting, Mattias

AU - Maccarana, Marco

AU - Malmström, Anders

PY - 2012

Y1 - 2012

N2 - 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 up-regulated 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, wasdownregulated 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 de-regulated actin cytoskeleton dynamics and focal adhesion formation. Our findings demonstrate that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, down-regulation of IdoA by DS-epi1 inhibitors may represent a new anti-cancer therapy.

AB - 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 up-regulated 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, wasdownregulated 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 de-regulated actin cytoskeleton dynamics and focal adhesion formation. Our findings demonstrate that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, down-regulation of IdoA by DS-epi1 inhibitors may represent a new anti-cancer therapy.

U2 - 10.1158/0008-5472.CAN-11-1351

DO - 10.1158/0008-5472.CAN-11-1351

M3 - Article

VL - 72

SP - 1943

EP - 1952

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 8

ER -