IRE1? inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma.

ABSTRACT: 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 IRE1?-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 IRE1? on TAMs in genipin-treated HCC-implanted mice. Diminishing IRE1? neutralised the inhibitory effect of genipin on TAMs. Silencing the expression of IRE1? greatly reduced TAMs migration and expression of inflammatory cytokines that prime HCC proliferation. Suppression of IRE1? led to reduced XBP-1 splicing and NF-?B activation. The reduced association of IRE1? with TRAF2 and IKK complex may be responsible for the genipin-mediated inactivation of NF-?B. The findings show the important role of TAMs in inhibitory effect of genipin on HCC, and TAMs-expressing IRE1? as a promising target for disrupting the tumour environment that favor of HCC development.

SUBMITTER: Tan HY 

PROVIDER: S-EPMC5190060 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature