title: Combined targeting of high-mobility group box-1 and interleukin-8 to control micrometastasis potential in gastric cancer.
abstract: Micrometastasis is the major cause of treatment failure in gastric cancer (GC). Because epithelial-to-mesenchymal transition (EMT) is considered to develop prior to macroscopic metastasis, EMT-promoting factors may affect micrometastasis. This study aimed to evaluate the role of extracellular high-mobility group box-1 (HMGB1) in EMT and the treatment effect of combined targeting of HMGB1 and interleukin-8 (IL-8) at early-stage GC progression through interrupting EMT promotion. Extracellular HMGB1 was induced by human recombinant HMGB1 and pCMV-SPORT6-HMGB1 plasmid transfection. EMT activation was evaluated by immunoblotting, immunofluorescence and immunohistochemistry. Increased migration/invasion activities were evaluated by in vitro transwell migration/invasion assay using all histological types of human GC cell lines (N87, MKN28 SNU-1 and KATOIII), N87-xenograft BALB/c nude mice and human paired serum-tissue GC samples. HMGB1-induced soluble factors were measured by chemiluminescent immunoassay. Inhibition effects of tumor growth and EMT activation by combined targeting of HMGB1 and IL-8 were evaluated in N87-xenograft nude mice. Serum HMGB1 increases along the GC carcinogenesis and reaches maximum before macroscopic metastasis. Overexpressed extracellular HMGB1 promoted EMT activation and increased cell motility/invasiveness through ligation to receptor for advanced glycation end products. HMGB1-induced IL-8 overexpression contributed the HMGB1-induced EMT in GC in vitro and in vivo. Blocking HMGB1 caused significant reduction of tumor growth, and addition of human recombinant IL-8 rescues this antitumor effects. Our results imply the role of HMGB1 in EMT through IL-8 mediation, and a potential mechanism of GC micrometastasis. Our observations suggest combination strategy of HMGB1 and IL-8 as a promising diagnostic and therapeutic target to control GC micrometastasis.
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Chung
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sunphil
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Baeck
authors.initials: JB
authors.lastname: Lim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D061206:Neoplasm Micrometastasis; D013274:Stomach Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D016209:Interleukin-8; D016328:NF-kappa B
keywords: EMT; HMGB1; IL-8; gastric cancer; metastasis