Chondroitin sulfate E (CS-E), a highly
sulfated glycosaminoglycan, is known to promote
tumor invasion and
metastasis. Because the presence of CS-E is detected in both
tumor and stromal cells in pancreatic ductal
adenocarcinoma (PDAC), multistage involvement of CS-E in the development of PDAC has been considered. However, its involvement in the early stage of PDAC progression is still not fully understood. In this study, to clarify the direct role of CS-E in
tumor, but not stromal, cells of PDAC, we focused on
carbohydrate sulfotransferase 15 (CHST15), a specific
enzyme that biosynthesizes CS-E, and investigated the effects of the CHST15
siRNA on
tumor cell proliferation in vitro and growth in vivo. CHST15
mRNA is highly expressed in the human
pancreatic cancer cell lines PANC-1, MIA PaCa-2, Capan-1 and Capan-2. CHST15
siRNA significantly inhibited the expression of CHST15
mRNA in these four cells in vitro. Silencing of the CHST15 gene in the cells was associated with significant reduction of proliferation and up-regulation of the cell cycle inhibitor-related gene p21CIP1/WAF1. In a subcutaneous xenograft
tumor model of PANC-1 in nude mice, a single intratumoral injection of CHST15
siRNA almost completely suppressed
tumor growth. Reduced CHST15
protein signals associated with
tumor necrosis were observed with the treatment with CHST15
siRNA. These results provide evidence of the direct action of CHST15 on the proliferation of pancreatic
tumor cells partly through the p21CIP1/WAF1 pathway. Thus, CHST15-CS-E axis-mediated
tumor cell proliferation could be a novel therapeutic target in the early stage of PDAC progression.