Genipin-activating PPARγ impedes CCR2-mediated macrophage infiltration into postoperative liver to suppress recurrence of hepatocellular carcinoma

Junyu Wu, Yau-Tuen Chan, Yuanjun Lu, Zixin Feng, Hongchao Yuan, Xiaoyu Xu, Lin Xu, Cheng Zhang, Yibin Feng, Hor-Yue Tan*, Ning Wang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

Abstract

A high postoperative tumour recurrence rate has significantly rendered a poorer prognosis in hepatocellular carcinoma (HCC) patients. The aim of this study is to identify a natural compound genipin as a potential and effective candidate to suppress the postoperative recurrence of HCC. Clinical analysis revealed that infiltration of macrophage into the adjacent tissue but not HCC predicted patients’ poor prognosis on recurrence-free survival. Genipin intervention suppressed the Ly6C+CD11b+F4/80+ pro-inflammatory macrophage infiltration in the postoperative liver of mice. Adoptive transfer of pro-inflammatory monocytic cells completely abolished the inhibitory effect of genipin on HCC recurrence. Transcriptomic analysis on FACs-sorted macrophages from the postoperative livers of mice revealed that PPARγ signalling was involved in the regulatory effect of genipin. Genipin is directly bound to PPARγ, causing PPARγ-induced p65 degradation, which in turn suppressed the transcriptional activation of CCR2 signalling. PPARγ antagonist GW9662 abrogated the effects of genipin on CCR2-medaited macrophage infiltration as well as HCC recurrence. Cytokine array analysis identified that genipin intervention potently suppressed the secretion of CCL2 further partially contributed to the pro-inflammatory macrophage infiltration into the postoperative liver. Multiplex immunostaining on tissue array of human HCC revealed that PPARγ expression was inversely associated with CCL2 and the macrophage infiltration in the adjacent liver of HCC patients. Our works provide scientific evidence for the therapeutic potential of genipin as a PPARγ agonist in preventing postoperative recurrence of HCC.

Original languageEnglish
Pages (from-to)5257-5274
Number of pages18
JournalInternational Journal of Biological Sciences
Volume19
Issue number16
DOIs
Publication statusPublished - Dec 2023

Scopus Subject Areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

User-Defined Keywords

  • HCC
  • postoperative recurrence
  • macrophage
  • chemotaxis
  • PPARγ
  • genipin

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