title: Uncontrolled inflammation induced by AEG-1 promotes gastric cancer and poor prognosis.
abstract: Gastric cancer is one of the most common causes of cancer-related death worldwide. Helicobacter pylori infection plays an important role in the development and progression of gastric cancer. The expression of astrocyte-elevated gene-1 (AEG-1) is increased in gastric cancer tissues, thereby contributing to the inflammatory response. We investigated whether and how AEG-1 regulated proinflammatory signaling in gastric cancer cells. We used human gastric cancer cell lines and athymic nude mice to investigate the role of AEG-1 in the regulation of the TLR4/nuclear factor-κB (NF-κB) signaling pathway and cancer invasion and compared the expression of AEG-1 and related proteins in 93 patients with gastric cancer by immunohistochemistry. In human gastric cancer cells, both AEG-1 and TLR4 could be induced by lipopolysaccharide (LPS) stimulation. AEG-1 was upregulated via LPS-TLR4 signaling and in turn promoted nuclear translocation of the NF-κB p65 subunit. At the same time, AEG-1 overexpression decreased the levels of suppressor of cytokine signaling (SOCS) protein SOCS-1, a negative regulator of the TLR4 pathway. Furthermore, nude mice engrafted with AEG-1/TLR4-expressing cells demonstrated larger tumor volumes than control animals. In patients with gastric cancer, the expression of AEG-1 correlated with that of TLR4, SOCS-1, and NF-κB and was higher in tumors compared with noncancerous adjacent tissues. Overall survival in patients with gastric cancer with simultaneous expression of AEG-1 and TLR4 was poor. Our results demonstrate that AEG-1 can promote gastric cancer progression by a positive feedback TLR4/NF-κB signaling-related mechanism, thus providing new mechanistic explanation for the role of inflammation in cancer progression.
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Jinning
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Wu
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Chuangqi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. xjianb@mail.sysu.edu.cn ylh@medmail.com.cn.
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. xjianb@mail.sysu.edu.cn ylh@medmail.com.cn.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Xu
mesh_terms: D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology* / Q000473:pathology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D008070:Lipopolysaccharides; C483039:MTDH protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4