Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has firmly been established as one of the most lethal solid human tumors worldwide [1]
Gene silencing was measured by real-time RT-PCR, and carbohydrate sulfotransferase 15 (CHST15) expression was reduced in PANC-1 cells by 1%, 85% and 87% in samples treated with target-specific siRNA for 24 h, 48 h and 72 h, respectively
It is known that the high mortality associated with PDAC is mainly attributed to its peerless aggressiveness due to its early invasion and distant metastases
Summary
Pancreatic ductal adenocarcinoma (PDAC) has firmly been established as one of the most lethal solid human tumors worldwide [1]. Tumor progression involves a multi-step process, such as proliferation, invasion, metastasis and angiogenesis, yet, these processes remain poorly understood in PDAC. Accumulating evidence has revealed the involvement of CS-E in tumor cell invasion and metastasis in the lung [6, 13], ovary [7, 14], breast [15] and skin [16]. The role of CS-E in initiating tumor cell invasion was demonstrated, suggesting the potential of CS-E as a key molecule in establishing novel therapeutics against various solid tumors including PDAC [17]
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