title: Ablation of osteopontin suppresses N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric cancer development in mice.
abstract: Several clinical studies have reported increased expression of osteopontin (OPN) in various types of human cancer, including gastric cancer. However, the precise mechanisms underlying tumor development remain unclear. In the present study, we investigated the pathogenic roles of OPN in Helicobacter pylori-induced gastric cancer development. Wild-type (WT) and OPN knockout (KO) mice were treated with N-methyl-N-nitrosourea (MNU) and infected with H.pylori. Mice were killed 50 weeks after treatment, and stomach tissues were assessed by histopathological examination, immunohistochemistry, quantitative real-time RT-PCR and western blotting. To clarify the carcinogenic effects of OPN, we also conducted an in vitro study using AGS human gastric cancer cell line and THP-1 human monocytic cell line. The overall incidence of gastric tumors was significantly decreased in OPN KO mice compared with WT mice. Apoptotic cell death was significantly enhanced in OPN KO mice and was accompanied by upregulation of signal transducer and activator of transcription 1 (STAT1) and inducible nitric oxide synthase (iNOS). In vitro study, OPN suppression also caused STAT1 upregulation and iNOS overexpression in AGS and THP-1 cells, which resulted in apoptosis of AGS cells. In addition, a negative correlation was clearly identified between expression of OPN and iNOS in human gastric cancer tissues. Our data demonstrate that loss of OPN decreases H.pylori-induced gastric carcinogenesis by suppressing proinflammatory immune response and augmenting STAT1 and iNOS-mediated apoptosis of gastric epithelial cells. An important implication of these findings is that OPN actually contributes to the development of gastric cancer.
authors.forename: Su-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Du-Min
authors.initials: DM
authors.lastname: Go
authors.affiliation: Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea.
authors.forename: Hark Kyun
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 305-764, South Korea and.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Surgery, Ajou University Medical Center, Ajou University School of Medicine, Suwon 443-749, South Korea.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Han
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D055786:Gene Knockout Techniques; D016481:Helicobacter Infections / Q000235:genetics* / Q000382:microbiology; D006801:Humans; D008297:Male; D008770:Methylnitrosourea; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology
chemical_list: D050794:STAT1 Transcription Factor; C506896:Spp1 protein, mouse; C494080:Stat1 protein, mouse; D053495:Osteopontin; D008770:Methylnitrosourea; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse