Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells
© Hsieh et al.; licensee BioMed Central Ltd. 2014
Received: 4 March 2014
Accepted: 22 May 2014
Published: 14 June 2014
Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells.
Human gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity.
Resistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.
Gastric cancer ranks as the fourth most frequent of malignant tumors . Although it is the second or third most frequent cause of cancer death worldwide , its etiology is not well understood. The disease is often the result of long-term interactions of many factors relating to individual habits, diet, environment, and genetics, as well as chronic gastritis, gastric polyps, gastric dysplasia, post-surgery gastric remnants, and long-term infection by Helicobacter pylori. H. pylori is recognized as a causative factor of chronic gastritis, gastroduodenal ulcers, gastric cancer, and mucosa-associated lymphatic tissue lymphoma. In previous study, chronic gastritis related human diseases, including gastroduodenal ulcers, gastric cancer, and mucosa-associated lymphatic tissue lymphoma, were found to result from an excessive formation of epithelial cells or gastric mucin injury and inflammation caused by chronic H. pylori infection . Several studies have indicated that the typical LPSs recognized by the Toll-like receptor 4 (TLR4) complex expressed on host cells, contributing to activation of the p38 mitogen-activated protein kinase (MARK) pathway [5, 6].
Obesity is a risk factor for gastric cancer mainly because obesity enhances the incidence of gastroesophageal reflux, which may damage the mucosa around the gastric cardia, resulting in an increased likelihood of cancer. Obesity is defined as a very high ratio of body fat to other tissue . Too much body fat has a significant impact on health, particularly in terms of insulin resistance. The proteins secreted by the fat tissues play a very important role in regulating metabolism . The regulation of resistin in carbohydrate metabolism is considered to be associated with insulin resistance. Resistin is capable of regulating the insulin-stimulated metabolism of carbohydrates in many insulin target organs . Since the discovery of resistin, most studies have focused on the relationship of resistin to obesity and diabetes. An increasing number of studies have focused on the role of resistin in cancer development, and the impact of resistin on inflammation is the focus of several current academic studies [10, 11]. These studies have found that resistin is negatively correlated with high density lipoproteins in diabetic patients; however, resistin is positively correlated with C-reactive protein (CRP), an indicator of inflammation . This association indicates that higher levels of the resistin may be related to inflammatory responses. In addition, studies have found that adipose tissue is not the exclusive source of resistin; large amounts of resistin and resistin-like molecules are also found in non-adipose tissues under inflammation . Inflammatory response can release interleukin (IL)-6, IL-8, IL-1β, and tumor necrosis factor alpha (TNFα) through the NF-κB pathway . Thus far, no study has investigated the association of resistin and any known receptor to activate downstream MAPK kinase that further activate nuclear factor-κB (NF-κB p50/p65) in human gastric cancer.
Chemoattractant proteins are a group of small proteins of molecular weight ranging from 8 to 12 kDa that can be induced by inflammatory substances to release into the extracellular environment. More than 40 types of human cell chemoattractant proteins have been identified . Chemoattractant proteins have a number of functions such as inducing the movement, growth, and differentiation of white blood cells. These inflammatory responses are closely related to gastric cancer . One of the causative factors of inflammatory responses is the production and induction of chemoattractant proteins. Previous studies have found that the stromal cell-derived factor-1 (SDF-1) can regulate cancerous cell movement and blood vessel regeneration via its specific receptors CXCR4 and CXCR7 . Gastric inflammation is an integral step in gastric cancer development; therefore, factors inducing and regulating responses to inflammation may play a key role in gastric cancer prognoses . From this viewpoint, because chemokines have certain roles in microbial immune and inflammation responses, the resistin-induced secretion of SDF-1 may be correlated to the control of gastric cancer.
Gastric cancer can be correlated with obesity. Researchers have pointed out that resistin is the blood biological indicator of gastric cancer and is related to patient prognosis . Moreover, SDF-1 acts in cancerous cells as a growth and survival factor; however, the implication of resistin stimulation by the chemoattractant SDF-1 has not been studied. In the present study, we investigated whether resistin stimulates the expression of SDF-1 by activating the p38 MAPK intracellular signaling cascades and the transcription factors NF-κB and p50. Our findings provide evidence of the molecular mechanisms of SDF-1 expression and its secretion by resistin via a TLR4-dependent pathway in gastric cancer cells.
Chemical reagents and antibodies
All culture materials were purchased from Gibco (Grand Island, NY). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), PD98059 (MEK1 inhibitor), SP600125 (JNK inhibitor), SB203580 (p38 inhibitor), SN50, and PDTC (pyrrolidinedithiocarbamate ammonium) were purchased from Sigma (St. Louis, MO). Mouse monoclonal antibodies against p38 MARK (9 F12) and phospho-p38 MARK (D-8) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Human CXCL12/SDF-1 enzyme-linked immunosorbent assay (ELISA) kit was obtained from Cell Sciences (Canton, MA). ERK siRNA (ordering number: s11137 and s11143), JNK siRNA (ordering number: 1452 and s11152), p38 siRNA (ordering number: 1312), p50 siRNA (ordering number: 5121), p65 siRNA (ordering number: s11916), and control siRNA (scrambled negative control containing random DNA sequences) were purchased from Invitrogen (Carlsbad, CA). TLR4 siRNA was purchased from Sigma-Proligo (Singapore). The bacterial lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS, TLR4 antagonist) was obtained from Invivogen (San Diego, CA).
The gastric carcinoma cell line TSGH 9201 and AGS cells was purchased from the Bioresources Collection and Research Center (BCRC) of the Food Industry Research and Development Institute (Hsinchu, Taiwan). Cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin in a CO2 incubator at 37°C.
Real-time quantitative PCR
Real-time PCR was performed using an ABI Prism 7900HT with the FastStart DNA SYBR Green I kit (Roche Diagnostics GMbH, Mannheim, Germany). The designed primers in this study were SDF-1 forward primer, 5'- ATTCTCAACACTCCAAACTGTGC-3'; SDF-1 reverse primer, 5'- ACTTTAGCTTCGGGTCAATGC-3'; 18S rRNA forward primer, 5'-CGGCG ACGAC CCATT CGAAC-3'; and 18S rRNA reverse primer, 5'-GAATC GAACC CTGAT TCCCC GTC-3'. Quantification was performed using the 2−ΔΔCt method . All samples were measured in duplicate. The average value of the duplicates was used as the quantitative value.
CXCL12/SDF-1 expression on the cancer cell surface was measured by ELISA as previously described . Release of SDF-1 into culture media was analyzed using commercially available ELISA kit purchased from Cell Sciences (Canton, MA). The assays and data calculations were performed according to the manufacturer’s instructions.
Preparation of total cell extracts and immunoblot analyses
TSGH 9201 cells were lysed with a buffer containing 1% NP-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS), and a protease inhibitor mixture (phenylmethylsulfonyl fluoride, aprotinin, and sodium orthovanadate). The total cell lysate (50 μg of protein) was separated by SDS-polyacrylamide gel electrophoresis (PAGE) (12% running, 4% stacking) and analyzed by using the designated antibodies and the Western-Light chemiluminescent detection system (Bio-Rad, Hercules, CA), as previously described .
DNA plasmid, siRNA, transfection, and luciferase assay
Human SDF-1 promoter constructs containing −1010/+30, −630/+30, −430/+122, −214/+30, −121/+30, and −20/+30 of SDF-1 5'-flanking DNA linked to the firefly luciferase reporter gene of plasmid pGL4 (Promega, Madison, WI) were used as previously reported . DNA plasmids at a concentration of 1 mg/ml were transfected into TSGH 9201 cells by Lipofectamine (Gibco, Carlsbad, CA). The pSV-β-galactosidase plasmid was cotransfected to normalize the transfection efficiency. For siRNA transfection, TSGH 9201 cells were transfected with the designated siRNA using an RNAiMAX transfection kit (Invitrogen, Carlsbad, CA) . The effectiveness of the silencing was validated: ERK-, JNK-, p38 MARK-, p65-, and p50-specific siRNAs (compared with control siRNA) caused at least 80% reduction in the protein expression of ERK, JNK, p38 MARK, p65, and p50, respectively. The cells were transfected with the specific TLR4 siRNA (CGAUGAUAUUAUUGACUUA[dT]; [dT]UAAGUCAAUAAUAUCAUGG[dT][dT]).
NFκB p50 transcription factor assay (TF ELISA assay)
Nuclear extracts of cells were prepared by nuclear protein extract kit (Panomics, Redwood City, CA). Equal amounts of nuclear proteins were used for quantitative measurements of NF-κB p50 activation using commercially available ELISA kit (Panomics, Redwood City, CA) that measure p50 DNA-binding activities .
Chromatin immunoprecipitation assay (ChIP)
The ChIP assay was carried out as previously described and ChIP assay kit used was from Upstate Biotechnology (Lake Placid, NY) . Cells were fixed with 1% formaldehyde, washed, then harvested in SDS lysis buffer. After sonication, lysates containing soluble chromatin were immunoprecipitated using 2 μg of antibody against p50. DNA was purified with a PCR Purification Kit (QIAGEN, Venlo, The Netherlands). The resulting DNA was used for PCR analysis, and the amplified DNA fragments were visualized on an agarose gel. PCR was performed with the following primers that amplify the parts of the human SDF-1 promoter that contain the p50 binding sites from −669 ~ −569: 5'- GTTTCCACAGGCGAATGG -3' and 5'- GGACCTCACAGCCTCAAGTC -3'.
The experiments were performed in triplicate independent experiments, and data were presented as three repeats from one independent experiment. Data were reported as the mean ± standard deviation or standard error of the mean and evaluated by one-way analysis of variance. SPSS version 16.0 (SPSS, Inc., Chicago, IL) was used for all statistical analyses. Significant differences were established at P < 0.05.
Effect of resistin on expression of SDF-1 in gastric carcinoma TSGH 9201 and AGS cells
Resistin-induced SDF-1 expression in gastric cancer is mediated by p38 MAPK
TLR4 regulates resistin-induced expression of SDF-1 and promoter activity
NF-κB is necessary for resistin induction of human SDF-1 promoter activity
MAPK signaling pathways are involved in resistin-induced SDF-1 promoter activity
Obesity has been associated with lower rates of survival in patients with gastric cancer . Adipocytokines such as TNFα, IL-6, adiponectin, leptin, visfatin, and resistin are cytokines secreted primarily by visceral adipose tissue and are thought to be involved in the positive correlation between obesity and the increased risk of gastric cancer . On the other hand, several observers have suggested that resistin mediates the induction of inflammation in both adipose and non-adipose tissue . The elevation of resistin and its role in inflammation in the intestine has resulted in the release of cytokines through the TLR4/ NF-κB pathway [26–28]. Recent studies have demonstrated the essential role of the resistin cascade, and a higher expression of resistin was evident in intestinal-type gastric carcinomas with tumor differentiation, tumor invasion, and lymph node metastasis . The essential role of resistin, as well as its association with gastric cancer, make it a factor of concern as well as a potential a biomarker for gastric cancer progression ; therefore, it is clinically relevant to study the mechanism by which resistin influences tumor cells. In this study, we evaluated the molecular mechanisms underlying the roles of resistin in controlling SDF-1 expression in gastric cancer cells. SDF-1 was upregulated by resistin stimulation in TSGH 9201 cells. Resistin-induced expression of SDF-1 was mediated by the p38 MAPK and NF-κB pathways, and interaction between resistin and TLR4 was required for resistin-induced intracellular signaling and SDF-1 expression.
SDF-1 also promotes tumor development by stimulating angiogenesis and by processing the metastasis of CXCR4-positive tumor cells to distant organs producing SDF-1 . Studies have shown that the level of plasma SDF-1 was higher in the high- incidence cancer group. In addition, SDF-1 modulates the angiogenic process directly (by binding to receptors CXCR4 expressed on endothelial cells) or indirectly (by inducing the secretion of matrix-metalloproteases or angiogenic factors) . It has been suggested that SDF-1 is produced by gastric tumor cells themselves and can act on the tumor cells in a paracrine or autocrine fashion . In summary, our study demonstrated that the effect of resistin on TSGH 9201 cells was mediated by the activation of p38 MAPK and that NF-κB transcriptional activation plays an important role in the expression of SDF-1. TF ELISA and luciferase assays demonstrated a resistin-induced increase in the NF-κB- and DNA-binding activity. In contrast, the inhibition of NF-κB and p38 MAPK activation in TSGH 9201 cells after treatment with NF-κB and p38 MAPK inhibitors and transfection with specific p50 and p38 siRNAs prohibited the resistin-induced expression and secretion of SDF-1.
The promoter region of the SDF-1 gene has several transcriptional factor binding sites . This study demonstrated the mechanism by which resistin induces SDF-1 gene expression of gastric cancer cells. The important findings are as follows: the expression of SDF-1 is mediated by the NF-κB p50 pathway. Construction and analyses of 5′-deletions in the −1010 to −430 region of the SDF-1 promoter showed that the activity decreased to 30% and was nearly abolished. ChIP DNA with anti-p50 antibody that was subjected to PCR analysis showed the SDF-1 promoter region (−1010 to −430) harboring the NF-κB p50 binding sites. NF-κB proteins are members of a superfamily of transcription factors whose activities play a crucial role in cellular activation, proliferation, and apoptosis, which can be triggered through the MAPK pathway in gastric cancer cells . During the early stages of invasion and metastasis of carcinoma cells, p38 MAPK plays a key role [5, 32, 33]. In our present study, we found that the gastric cell line, TSGH 9201, persisted in expressing activated p38 MAPK after exposure to resistin and high levels of this kinase are associated with an increased capacity to induce the binding of NF-κB p50 to the promoter region of SDF-1.
Previous data suggest that regulation of TLR receptors in gastric carcinogenesis might go beyond H. pylori infection, and is thought to be associated with tumor cancers . Resistin has been reported to be significantly correlated with stage progression of gastric cancer [18, 35]. We investigated the role of resistin signaling factors downstream of the p38 MARK and NF-κB activation sites that lead to SDF-1 transcriptional activation in TSGH 9201, and the pathophysiological implication of the role of resistin in gastric cancer should be further explored.
Taken together, our data suggest the mechanism by which resistin induces SDF-1 expression in gastric cancer cells. We found that treatment of gastric cancer cells with resistin resulted in the activation of signaling pathways mediated by TLR4. Further studies are required to explore the potential role of the resistin/ TLR4 axis as an effective therapeutic agent against gastric cancer.
This work was supported by Chang Gung Memorial Hospital or Chang Gung University of Science and Technology Chiayi Campus (grants CZRPG880253, CMRPG6C0301, CMRPG6A0163, CMRPF6C0032, CMRPG6A0062, CMRPG6C0012, CMRPG6B0272, CMRPF6A0073 and CMRPG6A0351) and grant of Taichung Veterans General Hospital, Taichung, Taiwan (TCVGH-1024302C) and the National Science Council, Taiwan (NSC101-2622-B-255-001-CC3, NSC102-2313-B-255-002 and 103-2622-B-255-001-CC3).
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