Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells.
UDP-glucose dehydrogenase (UGDH) catalyzes oxidation of UDP-glucose to yield UDP-glucuronic acid, a precursor of hyaluronic acid (HA) and other glycosaminoglycans (GAGs) in extracellular matrix. Although association of extracellular matrix with cell proliferation and migration has been well documented, the importance of UGDH in these behaviors is not clear. Using UGDH-specific small interference RNA to treat HCT-8 colorectal carcinoma cells, a decrease in both mRNA and protein levels of UGDH, as well as the cellular UDP-glucuronic acid and GAG production was observed. Treatment of HCT-8 cells with either UGDH-specific siRNA or HA synthesis inhibitor 4-methylumbelliferone effectively delayed cell aggregation into multicellular spheroids and impaired cell motility in both three-dimensional collagen gel and transwell migration assays. The reduction in cell aggregation and migration rates could be restored by addition of exogenous HA. These results indicate that UGDH can regulate cell motility through the production of GAG. The enzyme may be a potential target for therapeutic intervention of colorectal cancers.
Wang
Tsung-Pao
TP
Institute of Molecular Medicine, National Tsing Hua University, Hsin Chu, Taiwan, Republic of China.
Pan
Yun-Ru
YR
Fu
Chien-Yu
CY
Chang
Hwan-You
HY
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000235:genetics*
D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; D014533:Uridine Diphosphate Glucose Dehydrogenase