title: Late reactivation of sonic hedgehog by Helicobacter pylori results in population of gastric epithelial cells that are resistant to apoptosis: implication for gastric carcinogenesis.
abstract: As much as that a disturbance of tissue homeostasis through dysregulated apoptosis is generally associated with carcinogenesis, gastric carcinogenesis after Helicobacter pylori infection could be the accumulated consequence of imbalances between apoptosis and proliferation. Since sonic hedgehog (Shh) has been reported to play versatile roles in various tumorigenesis, we hypothesized that late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis. The Resistant Clones against H. pylori-induced Apoptosis (RCHA) were established and maintained up to 19th cell passages, during which the serial changes of Shh expression were measured. Apoptosis was measured in N-Shh over-expressed stable cell lines and compared with parent cell line after either infected with H. pylori or treated with cyclopamine. For clinical relevance, the expressions of Shh were compared in tissues from gastric adenoma or adenocarcinoma according to H. pylori infection. Longer passages of RCHA after H. pylori infection, the higher expressions of Shh, suggesting RCHA was associated with the reactivation of Shh. Significant decrement in subG1 phase of cell cycle and attenuated executions of apoptosis after H. pylori infection in cells of Shh overexpression, whereas either Shh siRNA or cyclopamine increased the H. pylori-induced cytotoxicity and significantly abrogated anti-apoptotic actions imposed by Shh. Significantly higher expressions of Shh were seen in H. pylori-associated gastric cancers than H. pylori-not associated gastric cancer. Late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis and imposes proliferative changes under the background of atrophic gastritis, providing the carcinogenic basis.
authors.affiliation: Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Kee Myung
authors.initials: KM
authors.lastname: Lee
authors.forename: Jeong Sang
authors.initials: JS
authors.lastname: Lee
authors.forename: Hyeon Sik
authors.initials: HS
authors.lastname: Jung
authors.forename: Dong Kyun
authors.initials: DK
authors.lastname: Park
authors.forename: Hyun Sun
authors.initials: HS
authors.lastname: Park
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D019938:Cyclin D1 / Q000032:analysis; D005753:Gastric Mucosa / Q000473:pathology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D013274:Stomach Neoplasms / Q000209:etiology*; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D014704:Veratrum Alkaloids; D019938:Cyclin D1; C000541:cyclopamine