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CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages
- Ji-Ye Kee†1,
- Aya Ito†1, 2,
- Shozo Hojo3,
- Isaya Hashimoto3,
- Yoshiko Igarashi2,
- Koichi Tsuneyama4,
- Kazuhiro Tsukada3,
- Tatsuro Irimura5,
- Naotoshi Shibahara2,
- Ichiro Takasaki9,
- Akiko Inujima2,
- Takashi Nakayama6,
- Osamu Yoshie7,
- Hiroaki Sakurai8,
- Ikuo Saiki1 and
- Keiichi Koizumi†2Email author
© Kee et al.; licensee BioMed Central. 2014
Received: 8 April 2014
Accepted: 8 December 2014
Published: 15 December 2014
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.
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.
CXCL16 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.
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.
Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide . Metastasis is the major cause of CRC mortality, and surgery is the only feasible therapy with very low mortality. However, only 10-20% of CRC patients with liver metastasis are candidates for surgery . Consequently, gene therapy is viewed as a promising treatment strategy that can complement the use of existing chemotherapy, radiation therapy and surgery strategies in these patients .
Chemokines are a family of small cytokines that function as chemoattractants for several immune effector cell types . Recent studies demonstrated that various chemokines have the potential to suppress tumor growth and metastasis [4, 5]. One unique membrane-bound chemokine is chemokine (C-X-C motif) ligand 16 (CXCL16), which exists as a transmembrane form (TM-CXCL16) as well as a soluble form (sCXCL16) that is cleaved by proteolytic enzymes [6–11]. TM-CXCL16 can function as a cell adhesion molecule for its receptor cells that express CXCR6, such as activated CD8 T cells and natural killer T cells (NKT cells), whereas sCXCL16 is a chemoattractant for CXCR6-expressing cells [12, 13]. Recently, the chemokine/receptor axis has been shown to play a critical role in tumor progression and metastasis . 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 . Our studies have confirmed the expression of CXCL16 in various cancer cell lines and tumor tissues [16–23], indicating that CXCL16 might serve as a useful biomarker for various types of cancer.
Macrophages function in both innate and adaptive immunity as immune regulatory cells. In particular, tumor-associated macrophages (TAMs) play an important role in the progression and metastasis of cancer . TAMs have been typically defined as M1- and M2-type macrophages. M1 macrophages are potent effector cells that induce Th1 responses such as cytotoxicity against microorganisms and cancer cells and enhancement of pro-inflammatory cytokine production [25, 26]. Tumor-infiltrating macrophages are reported to reduce the development of peritoneal colorectal carcinoma metastasis , while liver macrophages exert a protective function against cancer cells and inhibit liver metastasis due to their cytotoxic action against cancer cells through the production of tumor necrosis factor-alpha (TNF-α) [28–30].
TNF-α is typically produced by macrophages that show antitumor activity . TNF-α stimulates intracellular signaling pathways involving caspases, mitogen-activated protein kinases (MAPKs), and nuclear factor kappa B (NF-κB). Activation of the caspases involved in apoptosis results in the cleavage of a large number of nuclear proteins that are essential for apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse .
Interferon regulatory factor 8 (IRF8) is expressed in cells of myeloid and lymphoid lineages and serves as a key transcription factor [33, 34]. IRF8 has been shown to regulate Fas-mediated apoptosis in myeloid cells and soft tissue sarcoma cells [35, 36]. Deficiency of IRF8 in metastatic human CRC cells leads to decreased spontaneous apoptosis and enhanced resistance to the induction of extrinsic apoptosis [37, 38]. IRF8 is also an essential regulator of the apoptosis pathway and a suppressor of metastasis .
In a previous study, we identified genes which expression was changed by CXCL16 expression in metastatic CRC cells. Among these genes, the expression of IRF8 was correlated with CXCL16 expression and showed sensitivity to TNF-α-induced apoptosis. In addition, CXCL16 expression induced the infiltration of M1 macrophages into metastatic tumors and inhibited liver metastasis by releasing TNF-α, thereby inducing the apoptosis of CXCL16-expressing metastatic CRC cells.
Antibodies and reagents
Anti-phospho p65 (Ser-536), Akt (Ser-473), JNK (Thr183/Tyr185), ERK (Thr-202, Tyr-204), p38 (Thr-180/Tyr-182), PARP (46D11) and caspase-3 (8G10) antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). Antibodies against Akt (C-20), p38 (C-20), JNK (FL), ERK1 (C-16), p65 (C-20-G), IκBα (L35A5), IRF8 (C-19) and β-actin (C-11) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). CXCL16 antibody and recombinant mouse TNF-α were obtained from R&D Systems (Minneapolis, MN, USA). Mouse TNF-α neutralizing antibody and 2-chloroadenosine were purchased from eBioscience (San Diego, CA, USA) and Sigma (St Louis, MO, USA), respectively.
The mouse colon carcinoma cell lines, colon 38 and colon 38 SL4 (SL4), were maintained in a 1:1 mixture of Dulbecco’s modified Eagle’s medium and Ham’s F-12 medium (DMEM/F12; Invitrogen, Carlsbad, CA, USA). The mouse leukemic monocyte macrophage cell line, RAW 264.7, was maintained in DMEM. The media contained 10% heat-inactivated fetal calf serum (FCS), 100 units/ml penicillin, and 100 μg/ml streptomycin.
Generation of CXCL16-expressing CRC cell line
We generated pcDNA3.1 (+)-CXCL16, which was based on the pcDNA 3.1 (+) expression vector (Life Technologies Japan Ltd., Tokyo, Japan), to express the mouse membrane-bound CXCL16. Nucleofector (Amaxa, Gaithersburg, MD, USA) was used to transfect colon 38 SL4 cells with pcDNA3.1 (+)-CXCL16 or the empty vector. DNA was adjusted to 1 μg with the empty vector. After transfection, CXCL16-positive colon 38 SL4 cells were selected using the antibiotic G418 (Invitrogen). Cells stably expressing CXCL16 (SL4-CXCL16) and control cells (SL4-Cont) were maintained in DMEM/F12 supplemented with 10% FCS and antibiotics.
Cell viability was quantified using the cell proliferation reagent WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium, monosodium salt) (Dojindo, Kumamoto, Japan). Cells were seeded in 96-well microplates (2 × 103 cells) and then TNF-α was added. After 24-48 h incubation, WST-8 solution was added and the absorbance was measured at 450 nm.
Gene expression was analyzed using a GeneChip1 system with the mouse Expression Array 430.2 (Affymetrix, Santa Clara, CA, USA). Samples were prepared for array hybridization following the manufacturer’s instructions. In brief, 2 μg total RNA was used to synthesize double-stranded cDNA with a GeneChip1 Expression 30-Amplification Reagents One-Cycle cDNA Synthesis Kit (Affymetrix). Subsequently, biotin-labeled cRNA was synthesized from cDNA using the GeneChip1 Expression 30-Amplification Reagents for IVT Labeling (Affymetrix). Following fragmentation, biotinylated cRNA was hybridized to arrays at 45°C for 16 h. The arrays were washed, stained with streptavidin–phycoerythrin, and scanned with a probe array scanner. The scanned chip was analyzed using GeneChip Microarray Suite software (Affymetrix). Hybridization intensity data were converted into a presence/absence call for each gene, and changes in gene expression between experiments were detected via comparison analysis. Data were further analyzed using GeneSpring (Silicon Genetics, Redwood City, CA, USA). The GeneSpring Filter on the Volcano Plot tool was implemented to obtain a list of differentially expressed significant genes. A fold change value greater (upregulated) or less than 2 (downregulated) was considered biologically important. The statistical significance of the fold change was calculated for 2 groups by Student’s t-test and P values less than 0.05 were considered significant.
Reverse-transcription PCR (RT-PCR)
Total RNA was extracted using an RNeasy Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s directions. First-strand cDNA was prepared from an RNA template (2 μg) using oligo (dT) 18 primer and SuperScript III reverse transcriptase (Invitrogen). Reverse transcription was performed at 42°C for 50 min and then at 70°C for 15 min. PCR amplification was performed by denaturation at 94°C for 5 s, annealing at 60°C for 5 s, and extension at 72°C for 10 s for 28 cycles using a SappireAmp Fast PCR Master Mix (TaKaRa, Kyoto, Japan). Forward/reverse RT-PCR primer pairs for mouse cDNAs were as follows: CD11b (5′-ACACCATCGCATCTAAGCCA-3′/5′-GAACATCACCACCAAGCCAA-3′); CD11c (5′-CTTCTGCTGTTGGGGTTTGT-3′/5′-CACGATGTCTTGGTCTTGCT-3′); F4/80 (5′-CTTGCTGGAGACTGTGGAA-3′/5′-TGGATGTGCTGGAGGGTAT-3′); TNF-α (5′-GATCTCAAAGACAACCAACTAGTG-3′/5′-CTCCAGCTGGAAGACTCCTCCCAG-3′); GAPDH (5′-TGAAGGTCGGAGTCAACGGATTTGGT-3′/5′-CATGTGGGCCATGAGGTCCACCAC-3′). PCR products were electrophoresed on 1.5% agarose gels and stained with SYBR green. Images were acquired by Gel Doc EZ Imager (Bio-Rad, Hercules, CA, USA).
Real-time RT-PCR (qRT-PCR)
The cDNAs were amplified using FastStart Essential DNA Green Master (Roche, Pleasanton, CA, USA). Forward/reverse RT-PCR primer pairs for mouse cDNAs were as follows: CXCL16 (5′-TGAACTAGTGGACTGCTTTGAGC-3′/5′-GCAAATGTTTTTGGTGGTGA-3′); IRF8 (5′-GAGCCAGATCCTCCCTGACT-3′/5′-GGCATATCCGGTCACCAGT-3′); CD11b (5′-AAGGATGCTGGGGAGGTC-3′/5′-GTCATAAGTGACAGTGCTCTGGAT-3′); CD11c (5′-GAGCCAGAACTTCCCAACTG-3′/5′-TCAGGAACACGATGTCTTGG-3′); F4/80 (5′-GGAGGACTTCTCCAAGCCTATT-3′/5′-AGGCCTCTCAGACTTCTGCTT-3′); TNF-α (5′-CTGTAGCCCACGTCGTAGC-3′/5′-TTGAGATCCATGCCGTTG-3′); β-actin (5′-CTAAGGCCAACCGTGAAAAG-3′/5′-ACCAGAGGCATACAGGGACA-3′). Real-time quantitative RT-PCR (qRT-PCR) was performed using a Lightcycler nano system (Roche). The gene expression data were normalized to the β-actin. The relative expression levels of genes were measured according to the formula 2-ΔCt , where ΔCt is the difference in threshold cycle values between the targets and β-actin.
Transfection with small interfering RNA (siRNA)
Mouse IRF8 siRNA and control siRNA were purchased from Santa Cruz Biotechnology. Mouse CXCL16 siRNA was purchased from Ambion Life Technologies (Carlsbad, CA, USA). SL4 cells were transfected with siRNAs at a final concentration of 20 nM (si-IRF8) or 100 nM (si-CXCL16) using Lipofectamine reagents (Invitrogen). After 5 h, the medium was changed to normal medium and cells were cultured for a further 24 h.
Annexin V assay
The Annexin V assay was carried out using Annexin V Apoptosis Detection Kit I (BD Biosciences, San Diego, CA, USA). In brief, harvested cells (1 × 106 cells) were washed twice with phosphate-buffered saline (PBS) and cells were resuspended in 1 ml Annexin V binding buffer. Then, 100 μl of the solution was transferred to a 5 ml culture tube and labeled with 2 μl titrated FITC Annexin V and Propidium Iodide Staining Solution (PI). The cells were vortexed and incubated for 15 min at room temperature in the dark. The volume was then made up to 500 μl and the cells were analyzed with the FACSCalibur system (BD Biosciences).
Western blot analysis
Cells were harvested, plated on a 6 cm dish (1 × 106 cells) and stimulated with TNF-α (10 ng/ml). Whole-cell lysates were prepared with lysis buffer (25 mM HEPES pH 7.7, 0.3 M NaCl, 1.5 mM MgCl2, 0.2 mM EDTA, 10% Triton X-100, 20 mM β-glycerophosphate, 1 mM sodium orthovanadate, 1 mM dithiothreitol (DTT), 10 μg/ml aprotinin, and 10 μg/ml leupeptin). Cell lysates were collected from the supernatant after centrifugation for sulfate-polyacrylamide gel electrophoresis and transferred to an immobilon-P-nylon membrane (Millipore, Bedford, MA, USA). The membrane was blocked with Block Ace (Dainippon Pharmaceutical, Osaka, Japan) and probed with primary antibodies. The antibodies were detected using horseradish peroxidase-conjugated anti-rabbit and anti-mouse immunoglobulin G (Dako, Glostrup, Denmark) and blots were detected using the ECL system (GE Healthcare, Piscataway, NJ, USA).
Experimental liver metastasis
For experimental liver metastasis, colon 38 SL4 cells (7.5 × 104 cells/200 μl PBS) were injected into the intraportal vein of mice. The animals were sacrificed 17 days later and the increases in liver weight and the numbers of tumor colonies in the livers were measured to evaluate tumor metastasis. All experimental protocols were approved by the Laboratory Animal Care and Use Committee of Toyama University and were performed according to the Guidelines for the Care and Use of Laboratory Animals of Toyama University. Five-week-old female C57BL/6 mice (supplied by Japan SLC, Inc., Hamamatsu, Japan) were used in all experiments. Room temperature was maintained between 23 and 25°C, and relative humidity was maintained between 45 and 60%. The institutional laboratory housing the cages provided a 12-hour light cycle.
Data were analyzed for statistical significance using Student’s t-test. P < 0.05 was considered significant. The mean and SD were calculated for all variables.
CXCL16 expression enhances the sensitivity of metastatic CRC cells to TNF-α-induced apoptosis
Comparison of colon38 SL4-Cont and SL4-CXCL16 cells
Interferon regulatory factor 8
Bcl2-associated athanogene 4
Mitogen-activated protein kinase 1
Lymphotoxin B receptor
Tumor necrosis factor receptor superfamily, member 22
TNF receptor associated factor 4
Mitogen-activated protein kinase kinase kinase 7
TRAF and TNF receptor associated protein
Interleukin-1 receptor-associated kinase 1
TNF receptor associated factor 6
Tumor necrosis factor, alpha-induced protein 2
Interleukin-1 receptor-associated kinase 4
Tumor necrosis factor receptor superfamily, member 11a
Troponin I, skeletal, fast 2
Myosin, heavy polypeptide 3, skeletal muscle embryonic
Peptidase inhibitor 16
Troponin I, skeletal, slow 1
Expression of CXCL16 correlates with IRF8 expression in metastatic CRC cells
Silencing of IRF8 expression leads to resistance to TNF-α-induced apoptosis
Tumor-derived CXCL16 expression inhibited liver metastasis
Macrophages mediated the inhibition of liver metastasis by CXCL16 through secretion of TNF-α
Chemokines have potential use in cancer gene therapy due to their ability to attract immune cells. However, the metastatic effect of tumor cell-derived CXCL16 on colorectal liver metastasis has not been clarified. The forced expression of CXCL16 in our SL4 subline affected the expression of genes involved in the TNF and apoptosis pathways (Table 1), which provided the first clue to the role of CXCL16 as an intracellular signaling molecule.
IRF8, which was strongly upregulated in SL4-CXCL16 cells (Table 1), has been reported to sensitize Fas-mediated apoptosis in soft tissue sarcoma cells and to modulate the metastatic phenotype of CRC by regulating Fas expression [37, 38]. We confirmed increased IRF8 expression in SL4-CXCL16 cells (Figure 3A) and that knockdown of CXCL16 decreased IRF8 expression in these cells (Figure 3B and C). Conversely, CXCL16 expression was decreased by knockdown of IRF8 in SL4-CXCL16 cells (data not shown), indicating mutual regulation of CXCL16 and IRF8 expression.
Knockdown of IRF8 expression also significantly decreased TNF-α-induced apoptosis in SL4-CXCL16 cells (Figure 4B and C). The Bcl-2 family is regulated by IRF8 in soft tissue sarcoma cells and myeloid cells [40–42], but we found no effect of IRF8 on the Bcl-2 family in SL4 cells (data not shown). Instead, IRF8 appeared to regulate the caspase-3- and PARP-mediated apoptosis pathways following TNF-α treatment (Figure 4). Based on these data, we conclude that CXCL16 upregulates the expression of IRF8, which in turn determines the sensitivity to TNF-α-induced apoptosis. This result provides the first clue in elucidating the role of CXCL16 as an intracellular signaling molecule. Further studies are now needed to determine how the constitutive expression of CXCL16 mediates intracellular signaling.
Soluble CXCL16 is a chemoattractant that induces directed migration of CXCR6-expressing cells [7, 12, 13]. Macrophages do not express CXCR6 and therefore are not attracted by CXCL16. However, CXCL16 positively regulates macrophage accumulation in injured muscle , suggesting that an indirect mechanism exists for the attraction of macrophages by CXCL16. Our analysis of the metastatic tumor tissues of SL4-CXCL16 cells indicated the accumulation of NKT cells .
Suppression of liver metastasis by CXCL16 expression was partially dampened in NKT cells-depleted mice (data not shown) and infiltration of M1 macrophages was also decreased in these mice (data not shown). NKT cell activation has also been reported following injection of α-galactosylceramide, which induced the infiltration of M1 macrophages and production of TNF-α . Therefore, NKT cells attracted by CXCL16 may have induced M1 macrophage infiltration to the liver and thus indirectly affected liver metastasis through TNF-α production; however, further studies are needed to elucidate the relationship between NKT cells and macrophages.
M1 macrophages produce TNF-α, which has cytotoxic activity against tumor cells . We showed that co-cultured M1 macrophage-like RAW 264.7 cells induced apoptosis in SL4-CXCL16 cells (Figure 6B). Furthermore, liver metastasis by SL4-CXCL16 cells was significantly increased in mice treated with 2-chloroadenosine (Figure 6C and D) to deplete macrophage numbers and depletion of macrophages also reduced TNF-α production (data not shown).
In conclusion, we have shown that tumor-derived CXCL16 is a key factor in colorectal liver metastasis. Overexpression of CXCL16 sensitizes metastatic CRC cells to TNF-α-induced apoptosis via IRF8. Moreover, CXCL16 also indirectly induces the infiltration of M1 macrophages, which induce tumor cell apoptosis by secreting TNF-α. CXCL16 may be an attractive candidate for gene therapy in colorectal liver metastasis because of its effective dual approach of not only accumulating TAMs, but also increasing cancer cell apoptosis. Although further studies are required to obtain greater insight into the function of this molecule, CXCL16 may have a vital role in the study of cancer immunology and cancer biology.
Grant support: This study was supported by a Grant-in-Aid for Scientific Research (C) (No. 22501042).
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