Abstract
BackgroundInhibition 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.MethodsWe 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.ResultsCXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-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-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. 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.ConclusionsCollectively, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-949) contains supplementary material, which is available to authorized users.
Highlights
Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy
CXCL16 expression enhances the sensitivity of metastatic colorectal cancer (CRC) cells to TNF-α-induced apoptosis We established a stable expression of CXCL16 in SL4, a metastatic mouse CRC cell line, and confirmed its expression (Figure 1)
SL4-CXCL16 cells was decreased in Interferon regulatory factor 8 (IRF8) knockdown cells (Figure 4D). These results suggested that CXCL16-mediated upregulation of TNF-α-induced apoptosis in IRF8-sensitized SL4-CXCL16 cells occurred via downstream caspase-3 and PARP signaling
Summary
Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. We focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. The chemokine/receptor axis has been shown to play a critical role in tumor progression and metastasis [14]. With respect to the CXCL16/CXCR6 axis, we were the first to report that CXCL16 expression by tumor cells enhances the recruitment of tumor-infiltrating lymphocytes, thereby bringing about a better prognosis for CRC patients [15]. Our studies have confirmed the expression of CXCL16 in various cancer cell lines and tumor tissues [16,17,18,19,20,21,22,23], indicating that CXCL16 might serve as a useful biomarker for various types of cancer
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