title: Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells.
abstract: BACKGROUND
  Pancreatic cancer is characterized by constitutive activation of mitogen-activated protein kinase (MAPK). Activation of MAPK is associated with the upregulation of genes implicated in the proliferation and survival of pancreatic cancer cells. We hypothesized that knockdown of these MAPK-associated molecules could produce notable anticancer phenotypes.
  
  
  METHODS
  A RNA interference-mediated knockdown screening of 78 MAPK-associated molecules previously identified was performed to find molecules specifically associated with proliferation of pancreatic cancer cells in vitro. Expression of an identified molecule in pancreatic cancer tissues was examined by immunohistochemistry. In vivo tumorigenicity of cancer cells with stable knockdown of the molecule was assayed by using xenograft models. Flow cytometry and live cell imaging were employed to assess an association of the molecule with cell cycle.
  
  
  RESULTS
  The knockdown screening revealed that knockdown of SON, the gene encoding SON, which is a large serine/arginine-rich protein involved in RNA processing, substantially suppressed pancreatic cancer cell proliferation and survival in vitro and tumorigenicity in vivo. SON expression was higher in ductal adenocarcinomas than in cells of normal ducts and precursor lesions in pancreatic cancer tissues. Knockdown of SON induced G2/M arrest and apoptosis in cultured cancer cells. The suppressive effect of SON knockdown on proliferation was less pronounced in cultured normal duct epithelial cells. SON formed nuclear speckles in the interphase of the cell cycle and dispersed in the cytoplasm during mitosis. Live cell imaging showed that SON diffusely dispersed in the early mitotic phase, accumulated in some foci in the cytoplasm in the late mitotic phase, and gradually reassembled into speckles after mitosis.
  
  
  CONCLUSIONS
  These results indicate that SON plays a critical role in the proliferation, survival, and tumorigenicity of pancreatic cancer cells, suggesting that SON is a novel therapeutic molecular target for pancreatic cancer.
authors.affiliation: Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. furukawa.toru@twmu.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
authors.forename: Etsuko
authors.initials: E
authors.lastname: Tanji
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kuboki
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatori
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shibata
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiratori
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; C088203:SON protein, human; D020928:Mitogen-Activated Protein Kinases