iduronate and Carcinoma--Squamous-Cell

The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions. Iduronic acid is formed by two epimerases (i.e. dermatan sulfate epimerase 1 and 2) that have different tissue distribution and properties. The role of iduronic acid in chondroitin/dermatan sulfate is highlighted by the vast changes in connective tissue features in patients with a new type of Ehler-Danlos syndrome: adducted thumb-clubfoot syndrome. Future research aims to understand the roles of the two epimerases and their interplay with the sulfotransferases involved in chondroitin sulfate/dermatan sulfate biosynthesis. Furthermore, a better definition of chondroitin/dermatan sulfate functions using different knockout models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation, as well as the role of iduronic acid in health and disease.

Topics: Amino Acid Motifs; Animals; Antigens, Neoplasm; Carbohydrate Epimerases; Carcinoma, Squamous Cell; Cell Movement; Chondroitin Sulfates; Dermatan Sulfate; DNA-Binding Proteins; Ehlers-Danlos Syndrome; Extracellular Matrix; Eye Abnormalities; Foot Deformities, Congenital; Hand Deformities, Congenital; Humans; Iduronic Acid; Joint Instability; Molecular Conformation; Neoplasm Proteins; Skin Abnormalities; Stem Cells; Sulfotransferases; Thumb

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.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Carcinoma, Squamous Cell; Cell Movement; Chondroitin Sulfates; Dermatan Sulfate; DNA-Binding Proteins; Esophageal Neoplasms; Female; Flow Cytometry; Gene Knockdown Techniques; Humans; Iduronic Acid; Immunohistochemistry; Male; Mass Spectrometry; Middle Aged; Neoplasm Proteins