IRE1α inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma.
Accumulating evidences postulated the influential roles of macrophages in mediating hepatocellular carcinoma (HCC) initiation and progression. In this study, we demonstrate that a small molecule, genipin reduced HCC growth through suppressing IRE1α-mediated infiltration and priming of tumour associated macrophages (TAMs). Oral administration of genipin (30mg/kg/2days) suppressed orthotopic HCC tumour growth without challenging the viability and proliferation of HCC cells. Genipin reduced infiltration of inflammatory monocytes into liver and tumour thereby suppressed TAMs presence in HCC microenvironment. Suppression of HCC growth was diminished in HCC-implanted mice with depletion of TAMs by liposome clodronate. Genipin inhibited the TAMs migration, and reduced expression of TAMs-derived inflammatory cytokines that favors HCC proliferation. This is revealed by the in vivo deletion of IRE1α on TAMs in genipin-treated HCC-implanted mice. Diminishing IRE1α neutralised the inhibitory effect of genipin on TAMs. Silencing the expression of IRE1α greatly reduced TAMs migration and expression of inflammatory cytokines that prime HCC proliferation. Suppression of IRE1α led to reduced XBP-1 splicing and NF-κB activation. The reduced association of IRE1α with TRAF2 and IKK complex may be responsible for the genipin-mediated inactivation of NF-κB. The findings show the important role of TAMs in inhibitory effect of genipin on HCC, and TAMs-expressing IRE1α as a promising target for disrupting the tumour environment that favor of HCC development.
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, P.R. of China.
Hor-Yue
HY
Tan
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, P.R. of China.
Ning
N
Wang
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, P.R. of China.
Sai-Wah
SW
Tsao
State Key Laboratory of Synthetic Chemistry, Chemical Biology Centre, and Department of Chemistry, The University of Hong Kong, Hong Kong S.A.R, P. R. China.
Chi-Ming
CM
Che
Division of Gastroenterology and Hepatology, Queen Mary Hospital and Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, P. R. of China.
Man-Fung
MF
Yuen
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, P.R. of China.
Yibin
Y
Feng
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D039823:Iridoids / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*
D039823:Iridoids; C007834:genipin; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
IRE1α; NF-κB; genipin; hepatocellular carcinoma; tumour-associated macrophage