The role of N-deacetylase/N-sulfotransferase 4 in regulation of angiogenic factor expression in colorectal cancer

• Main Authors: Yu-Chin Hsiao, 蕭羽芩
• Other Authors: Ya-Chien Yang
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/795rgk

碩士 === 國立臺灣大學 === 醫學檢驗暨生物技術學研究所 === 106 === Colorectal cancer (CRC) is the top of cancer incidence in Taiwan, caused by abnormal proliferation of intestinal epithelial cells with accumulation of genetic alterations which include inactivation of tumor suppressor genes (TSGs) and activation of oncogenes. In previous loss of heterozygosity study, we identified N-deacetylase/N-sulfotransferase 4 (NDST4) gene as a novel CRC-associated TSG at 4q26. NDST4 plays a role in heparan sulfate (HS) biosynthesis, which modulates heparan sulfate proteoglycans (HSPGs) to regulate growth factors, cytokines and chemokines. Previously our lab has established Tet-On inducible NDST4-expressing human CRC HCT116 cells, and showed NDST4 expression exhibited significant inhibition of tumorigenesis with lower microvessel density in mouse xenograft tumor models. Accordingly, a Human Angiogenesis Array was used to identify the angiogenic factors regulated by NDST4 expression. The results revealed that urokinase-type plasminogen activator (uPA) was obviously decreased in the conditioned medium harvested from NDST4-expressing HCT116 cells. In the study, we further aimed to investigate the mechanism of NDST4 expression on regulating angiogenesis of CRC. Using different concentration of doxycycline to induce various levels of NDST4 expression in CRC cells showed that NDST4 could suppress gene and protein expression of pro-angiogenesis factor uPA via decrease of NF-κB p65 phosphorylation. Furthermore, NDST4 expression could show similar effect on plasminogen activator (PA) system, in which uPA is involved. On the other hand, NDST4 could also inhibit the gene expression of other angiogenesis-related factors, including angiogenein, amphiregulin, vascular endothelial growth factor A (VEGFA) and tissue inhibitor of metalloproteinase-1 (TIMP-1). After treating cells with phorbol myristate acetate, NF-κB pathway was activated, resulting in enhancement of the expression of PA system and angiogenesis-related factors in CRC cells. Then the inhibition effects of NDST4 expression on these genes were more obviously observed.