title: HMGB1 attenuates anti-metastatic defence of the liver in colorectal cancer.
abstract: High mobility group box (HMGB) 1 induces apoptosis of monocyte-lineage cells. We examined the effect of HMGB1 on Kupffer cells (KCs). In 50 Dukes C and 12 liver-metastasised Dukes D colorectal cancers (CRCs), higher HMGB1 concentration in the primary tumours and metastatic foci, and fewer KCs were found in Dukes D cases than in Dukes C cases. The portal blood HMGB1 concentration was higher in Dukes D cases than in Dukes C cases. HMGB1 induced growth inhibition and apoptosis in mouse KCs in a dose-dependent manner, which was associated with the phosphorylation of c-Jun N-terminal kinase (JNK). JNK inhibition and knockdown of HMGB1 receptor abrogated growth inhibition and apoptosis. In a nude mouse liver metastasis model, the caecal administration of HMGB1 decreased the number of KCs and increased the embedment of Colo320 CRC cells in a dose-dependent manner. HMGB1 transfection increased the liver metastasis of Colo320 cells, and the metastasis was inhibited by anti-HMGB1 antibody administration. These results suggest that HMGB1 secreted from primary tumours decreases the number of KCs and attenuates the anti-metastatic defence of the liver in patients with CRCs.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Kiyomu
authors.initials: K
authors.lastname: Fujii
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Moriwaka
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.forename: Miyako
authors.initials: M
authors.lastname: Kurihara
authors.forename: Naokuni
authors.initials: N
authors.lastname: Tatsumoto
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000502:physiology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D024243:HMGB1 Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; D009363:Neoplasm Proteins