title: Autophagy-mediated HMGB1 release promotes gastric cancer cell survival via RAGE activation of extracellular signal-regulated kinases 1/2.
abstract: High mobility group box-B1 (HMGB1), an autophagy activator, is crucial in tumorigenesis. However, its extracellular role and signaling in gastric cancer remain unclear. Samples were collected from gastric cancer patients and healthy controls. Immunohistochemistry and immunocytochemistry were used to determine the localization of HMGB1 in gastric cancer tissues, four gastric carcinoma cell lines (BGC-823, SGC-7901, MKN-28 and MKN-45) and a gastric epithelial cell line GES-1. Western blot analysis and ELISA were used to assess the effects of gefitinib, an epidermal growth factor receptor inhibitor, on autophagy and HMGB1 release in BGC-823 cells. MTT assay and western blot analysis assessed the effects of extracellular HMGB1 on cell proliferation and signaling transduction. Released HMGB1 promoted proliferation through activation of ERK1/2 MAPK. HMGB1 expression in gastric cancer tissues and serum was significantly increased compared to the controls and healthy serum. Gastric carcinoma cells showed an increased HMGB1 in the nuclei and cytoplasm, whereas GES-1 cells exhibited a lower HMGB1 with nuclear localization. Gefitinib increased autophagy and cytoplasmic HMGB1 release from the BGC-823 cells. Extracellular HMGB1 in autophagic cell supernatant promoted proliferation that was abolished by glycyrrhizic acid, an HMGB1 inhibitor. BGC-823 cells incubated with HMGB1 had increased ERK1/2 phosphorylation, while levels of JNK, p38 or AKT were not affected. Blocking RAGE‑HMGB1 interaction with antibody or siRNA suppressed the ERK1/2 activation and gastric cancer cell growth, indicating that RAGE-mediated ERK1/2 signaling was necessary for tumor progression.
authors: Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
authors: Qiu-Yu
authors: QY
authors: Zhang
authors: Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
authors: Lin-Qing
authors: LQ
authors: Wu
authors: Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
authors: Tao
authors: T
authors: Zhang
authors: Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
authors: Yan-Fei
authors: YF
authors: Han
authors: Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
authors: Xu
authors: X
authors: Lin
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000737:chemistry / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D045604:Extracellular Fluid / Q000737:chemistry; D000077156:Gefitinib; D024243:HMGB1 Protein / Q000097:blood / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000097:blood / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000502:physiology*; D013274:Stomach Neoplasms / Q000097:blood / Q000737:chemistry / Q000473:pathology*; D014162:Transfection
chemical_list: C000593871:AGER protein, human; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077156:Gefitinib
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