title: Osteopontin promotes the progression of gastric cancer through the NF-κB pathway regulated by the MAPK and PI3K.
abstract: To elucidate the biological functions of osteopontin (OPN) in gastric tumors and to better understand the molecular events of OPN responsible for the malignancy, the present studies were performed. Growth curve, apoptosis assay, invasion assay and migration assay revealed that OPN status significantly affected proliferation, apoptosis, invasion and migration in gastric cancer cell lines. In mouse xenograft models of human gastric cancer, OPN silencing significantly inhibited tumor growth and the incidence of metastasis compared with non-silenced control. Mechanistic investigations revealed that OPN silencing inhibited the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase (NF-κB) pathways, and OPN-mediated NF-κB activity was reduced in the presence of MAPK or PI3K inhibitor. Our findings also indicated that OPN through the NF-κB pathway promotes the expression of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA), the activation of MMP-2 and MMP-9, and the inhibition of caspase-3. Taken together, our results reveal that OPN promotes the progression of gastric cancer through the NF-κB pathway, which is regulated by the MAPK and PI3K pathways and leads to MMP-2, MMP-9 and uPA activation and caspase-3 inhibition. These findings identify OPN as a novel oncogene in gastric cancer and suggest that OPN is an attractive therapeutic target for this aggressive malignancy.
authors.affiliation: Department of Emergency Intensive Care Unit, Wuhan General Hospital of Guangzhou Command, Hubei, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Xianning Hospital, Hubei, P.R. China.
authors.forename: Qishen
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Emergency Intensive Care Unit, Wuhan General Hospital of Guangzhou Command, Hubei, P.R. China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Emergency Intensive Care Unit, Wuhan General Hospital of Guangzhou Command, Hubei, P.R. China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, Renmin Hospital of Wuhan University, Hubei, P.R. China.
authors.forename: Honggang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Renmin Hospital of Wuhan University, Hubei, P.R. China.
authors.forename: Hesheng
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Emergency Intensive Care Unit, Wuhan General Hospital of Guangzhou Command, Hubei, P.R. China.
authors.forename: Zhongzhi
authors.initials: Z
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology*; D009374:Neoplasms, Experimental; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053495:Osteopontin; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase