Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation
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...
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Published in | Journal of experimental & clinical cancer research Vol. 42; no. 1; p. 166 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
BioMed Central Ltd
13.07.2023
BioMed Central BMC |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1756-9966 0392-9078 1756-9966 |
DOI: | 10.1186/s13046-023-02748-4 |