期刊
BMC CANCER
卷 14, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1471-2407-14-949
关键词
CXCL16; IRF8; TNF-alpha; Apoptosis; Colorectal liver metastasis
类别
资金
- SRC 22501042
- Grants-in-Aid for Scientific Research [25293011, 25670175, 24659029] Funding Source: KAKEN
Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. Results: CXCL16 expression enhanced TNF-alpha-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-kappa B-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-alpha-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-alpha-induced apoptosis through the induction of M1 macrophages, which released TNF-alpha. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. Conclusions: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
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