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

• Published in: Journal of experimental & clinical cancer research Vol. 42; no. 1; p. 166
• Main Authors: Zhang, Chong, Li, Qing, Xu, Qi, Dong, Wei, Li, Chunmei, Deng, Bin, Gong, Jiao, Zhang, Li-Zhen, Jin, Junfei
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.07.2023; BioMed Central; BMC
• Subjects: Analysis; Angiogenesis; Animals; Antibodies; Breast cancer; Carcinoma, Hepatocellular - pathology; Cloning; Flow cytometry; Genes; HCC; Hepatoma; Humans; IL-1β; Immunohistochemistry; Interleukin-1beta; Interleukins; Laboratory animals; Liver; Liver cancer; Liver Neoplasms - pathology; Lung - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Matrix Metalloproteinase 9 - metabolism; Metastasis; Mice; MMP9; Ovarian cancer; Penicillin; Permeability; Plasmids; Pre-metastatic niche; RNA; RNA sequencing; SAA3; China; Beijing China; United States > US; HCC; Pre-metastatic niche; IL-1β; MMP9; SAA3
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-023-02748-4

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. 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. 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. 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.