title: A GSDMB enhancer-driven HSV thymidine kinase-expressing vector for controlling occult peritoneal dissemination of gastric cancer cells.
abstract: BACKGROUND
  Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, and Japan and Korea have the highest incidence in the world. Because most of the cases that are refractory to therapies die due to peritoneal dissemination (PD) of the cancer cells, controlling PD is important for patient survival. GSDMB is a member of the gasdermin gene family. Because GSDMB is expressed in many types of cancer, including GC, it is likely that the gene contains a regulatory region that is utilized for therapy of occult PD through cancer cell-specific expression of cytotoxic genes.
  
  
  METHODS
  We performed reporter assays to identify the regulatory region for the cancer cell-specific expression. We also constructed a lentiviral therapeutic vector that expresses herpes simplex virus thymidine kinase (HSVtk) in a GC cell-specific manner, and tested it in a mouse model of PD.
  
  
  RESULTS
  We identified the regulatory region at +496 to +989 from the GSDMB transcription start site and designated it as a GSDMB enhancer. The lentiviral therapeutic vector suppressed proliferation of a GC cell line, 60As6, in vitro in the presence of ganciclovir, and intraperitoneal administration of the vector prolonged the survival term of mice that were intraperitoneally inoculated with 60As6 one week prior to the administration.
  
  
  CONCLUSIONS
  The GSDMB-driven HSVtk expression vector had a therapeutic effect on the occult PD model mice. This strategy can potentially be used to treat GC patients with PD.
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. nsaeki@ncc.go.jp.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Saeki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. rkomatsu@ncc.go.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Komatsuzaki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. fchiwaki@ncc.go.jp.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Chiwaki
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital East, Kashiwanoha 6-5-1, Kashiwa, Chiba, 277-8577, Japan. kyanagih@east.ncc.go.jp.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. hksasaki@ncc.go.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D010529:Peritoneal Cavity / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010537:Peritoneum / Q000473:pathology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D000094524:Gasdermins
chemical_list: D009363:Neoplasm Proteins; D013937:Thymidine Kinase; C527978:GSDMB protein, human; D000094524:Gasdermins