Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation

  • J Exp Clin Cancer Res. 2023 Jul 13;42(1):166. doi: 10.1186/s13046-023-02748-4.
Chong Zhang  1  2  3  4 ,  Qing Li  1  2  3  4 ,  Qi Xu  1 ,  Wei Dong  1 ,  Chunmei Li  1  2  3  4 ,  Bin Deng  1  2  3  4 ,  Jiao Gong  5 ,  Li-Zhen Zhang  6 ,  Junfei Jin  7  8  9  10
Affiliations
  • 1. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 2. Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 3. Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 4. China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 5. Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, China.
  • 6. Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China. [email protected].
  • 7. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 8. Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 9. Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 10. China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
PMID: 37443052 DOI: 10.1186/s13046-023-02748-4
Abstract

Background: Increasing evidence suggests a vital role of the pre-metastatic niche in the formation of distant metastasis of many cancers. However, how the pre-metastatic niche is formed and promotes pulmonary metastasis of hepatocellular carcinoma (HCC) remains unknown.

Methods: Orthotopic liver tumor models and RNA-Seq were used to identify dysregulated genes in the pre-metastatic lung. Il1b knockout (Il1b-/-) mice and lentivirus-mediated gene knockdown/overexpression were utilized to demonstrate the role of interleukin 1 beta (IL-1β)/serum amyloid A3 (SAA3) in the pre-metastatic niche formation and pulmonary metastasis. The potential molecular mechanisms were investigated by RNA-Seq, real-time quantitative PCR (qPCR), western blotting, immunohistochemistry (IHC), flow cytometry, luciferase reporter assay, double immunofluorescent staining and H&E staining.

Results: Accumulation of myeloid cells and upregulation of IL-1β were observed in the pre-metastatic lung of orthotopic liver tumor models. Myeloid cells accumulation and pulmonary metastasis were suppressed in Il1b-/- mice and Il1r1-silencing mice. Mechanistically, SAA3 and matrix metallopeptidase 9 (MMP9) were identified as potential downstream targets of IL-1β. Overexpression of SAA3 in the lungs of Il1b-/- mice restored myeloid cells accumulation and pulmonary metastasis of the orthotopic HCC xenografts. Moreover, alveolar macrophages-derived IL-1β dramatically enhanced SAA3 expression in alveolar epithelial cells in an NF-κB dependent manner and increased MMP9 levels in an autocrine manner. Furthermore, SAA3 recruited myeloid cells to the lung without affecting the expression of MMP9 in myeloid cells.

Conclusions: Our study suggests a key role of pulmonary IL-1β and SAA3 in creating a permissive lung pre-metastatic niche by enhancing MMP9 expression and recruiting myeloid cells, respectively, thus promoting pulmonary metastasis of HCC.

Keywords
HCC; IL-1β; MMP9; Pre-metastatic niche; SAA3.
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