HMGB1 attenuates anti-metastatic defence of the liver in colorectal cancer.
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.
Luo
Yi
Y
Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
Ohmori
Hitoshi
H
Fujii
Kiyomu
K
Moriwaka
Yukiko
Y
Sasahira
Tomonori
T
Kurihara
Miyako
M
Tatsumoto
Naokuni
N
Sasaki
Takamitsu
T
Yamashita
Yuichi
Y
Kuniyasu
Hiroki
H
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
D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; D009363:Neoplasm Proteins