title: Silencing of hHS6ST2 inhibits progression of pancreatic cancer through inhibition of Notch signalling.
abstract: Many of the ligands involved in developmental processes require HS (heparan sulfate) to modulate signal transduction. hHS6ST2 (human heparan sulfate D-glucosaminyl 6-O-sulfotransferase-2) is a Golgi-resident enzyme that usually acts on GlcA/IdoA(2S)-GlcNAc/NS disaccharide-6-sulfate modifications within the HS sequence. Emerging evidence indicates the importance of 6-O-sulfation in a number of developmental processes. However, any correlation with cancer-related events remains largely unexplored. In the present study, we found that hHS6ST2, but not other variants, was activated in human PC (pancreatic cancer). shRNA (short hairpin RNA)-mediated silencing of endogenous hHS6ST2 expression in the PC cell line PANC-1 inhibited cell invasion and migration. hHS6ST2 knockdown also resulted in markedly reduced tumorigenesis in immunocompromised mice. To specifically explore the molecular alterations resulting from depletion of hHS6ST2-generated 6-O-sulfation, we employed two-dimensional gel electrophoresis technology followed by nano-HPLC-ESI (electrospray ionization)-tandem MS to separate and identify total proteins from PC cells. Our data suggest that hHS6ST2 potentiates Notch signalling in PC cells. We also identified a role for hHS6ST2 in the growth and tumorigenicity of these cells which, at least in part, acts through Notch-mediated EMT (epithelial-mesenchymal transition) and angiogenesis. The results of the present study suggest that hHS6ST2 could be an attractive target for PC therapy.
authors: Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Ministry of Education, Nanjing, China.
authors: Kai
authors: K
authors: Song
authors: Qin
authors: Q
authors: Li
authors: Yong-Bo
authors: YB
authors: Peng
authors: Jie
authors: J
authors: Li
authors: Kan
authors: K
authors: Ding
authors: Li-Juan
authors: LJ
authors: Chen
authors: Cheng-Hao
authors: CH
authors: Shao
authors: Li-Jun
authors: LJ
authors: Zhang
authors: Ping
authors: P
authors: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics*
chemical_list: D051880:Receptors, Notch; C485757:HS6ST2 protein, human; D015238:Sulfotransferases