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Original Article Expression of Chemokine Receptor CXCR5 in Gastric Cancer and Its Clinical Significance

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Original Article Expression of Chemokine Receptor CXCR5 in Gastric Cancer and Its Clinical Significance Int J Clin Exp Pathol 2016;9(7):7202-7208 www.ijcep.com /ISSN:1936-2625/IJCEP0023559 Original Article Expression of chemokine receptor CXCR5 in gastric cancer and its clinical significance Qing Sun*, Lujun Chen*, Bin Xu, Qi Wang, Xiao Zheng, Peng Du, Dachuan Zhang, Changping Wu, Jingting Jiang Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China. *Equal contributors. Received January 8, 2016; Accepted March 22, 2016; Epub July 1, 2016; Published July 15, 2016 Abstract: The increased expression of chemokine receptor CXCR5 in cancers has been demonstrated. In order to characterize the expression pattern of CXCR5 in cell lines and tissues of gastric cancer and to assess clinical implications, the expression of CXCR5 mRNA in gastric cancer tissues and adjacent tissues was evaluated by real- time RT-PCR. Meanwhile, the expression of CXCR5 in cell lines of human gastric cancer was also analyzed by flow cytometry. Tissue microarray and immunohistochemistry were used to detect the protein expression of CXCR5 in human gastric cancer tissues and adjacent normal tissues. Flow cytometry results revealed the positive expression of CXCR5 in human gastric cancer cell lines such as BGC-823, SGC-7901 and HGC-27 cells. The immunohistochem- istry results showed higher expression of CXCR5 in 52.87% of gastric cancer tissues. The expression of CXCR5 in patients with tumor size less than 2.8 cm subgroup was significantly lower than that in patients with tumor size larger than 2.8 cm subgroup (P = 0.0456). There was no significant correlation between the expression of CXCR5 and other clinical parameters in gastric cancer. Moreover, the survival analysis showed that the overall survival rate of the patients with higher CXCR5 expression was lower than that of the patients with lower CXCR5 expression (P = 0.0579, HR = 1.810, 95% CI: 0.9803-3.341). The results suggest that CXCR5 is involved in the oncogenesis and progression of gastric cancer. Keywords: Gastric cancer, CXCR5, immunohistochemistry, microarray, flow cytometry Introduction through their receptors, which plays an essen- tial role in the recruitment of leukocytes from Gastric cancer is the most common malignant the circulation system to local inflammatory tumor of upper digestive tract. Lymph node sites [3]. Chemokines are able to regulate the metastasis and abdominal implantation are infiltration of leukocytes in tumor, activate spe- the major causes of metastasis, which finally cific immune response, and stimulate the prolif- leads to cancer recurrence or cancer-related eration and migration of tumor cells by auto- death [1]. Despite extensive studies on the crine or paracrine models. The overwhelming identification of novel diagnostic and therapeu- evidences have supported that chemokine-che- tic agents, patients with advanced gastric can- mokine receptor systems can regulate transfor- cer often suffer from a poor prognosis, and the mation, growth, neovascularization and metas- treatment is still mainly dependent on conven- tasis of tumor cells [4]. tional cytotoxic chemotherapy [2]. Thus, the advances in understanding novel factors The chemokine receptor CXCR5 expressed by B involved in the progression of gastric cancer, cells and certain T cells can control the migra- and the development of prognostic and predic- tion of these cells into and within lymph nodes tive markers, can potentially improve the thera- [5]. The abnormal expression of CXCR5 could peutic outcomes of this malignancy. be observed in many tumors and was closely associated with tumor progression [6]. However, As a group of small molecule proteins, chemo- the role of CXCR5 and its ligand in gastric can- kines can bind target cells by chemotaxis cer has not been investigated. The aim of the CXCR5 expression in gastric cancer Table 1. Correlation of clinical parameters in patients with motherapy or radiotherapy before the expression of CXCR5 surgical resection. The clinical para- meters of these patients are shown Clinical CXCR5 Case P-value in Table 1. parameters High Low χ2 Gender Total RNA extraction, reverse tran- Male 59 29 (49.2%) 30 (50.8%) 0.3020 0.5826 scription and real-time PCR Female 28 12 (42.9%) 16 (57.1%) In brief, total RNA was extracted from Age (years) tissues using a total RNA purification < 60 33 17 (51.5%) 16 (48.5%) 0.4110 0.5215 kit (BiocolorBioScience and Tech- ≥ 60 54 24 (44.4%) 30 (55.6%) nology Company, Shanghai, China). Tumor size (cm)* Complementary DNA was synthe- < 2.8 14 10 (71.4%) 4 (28.6%) 3.995 0.0456 sized with cDNA synthesis kit (Fer- ≥ 2.8 71 30 (42.3%) 41 (57.7%) mantas, Vilnius, Lithuania), according Tumor invasion depth (T)* to the manufacturer’s instructions. The primers of CXCR5 and GAPDH T1+T2 11 7 (63.6%) 4 (36.4%) 1.200 0.2733 T +T 74 34 (45.9%) 40 (54.1%) were designed according to the 3 4 National Center for Biotechnology Nodal metastasis (N)* Information (NCBI) database, and Yes 22 10 (45.5%) 12 (54.5%) 0.0132 0.9083 then synthesized by Sangon Biotech No 64 30 (46.9%) 34 (53.1%) (Shanghai, China). The sequences of * Distant metastasis (M) all primers used in this study are as No 76 35 (46.1%) 41 (53.9%) 0.6891 0.4065 follows: CXCR5-F: GGTCACCCTACC- Yes 10 6 (60%) 4 (40%) ACATCGTC, CXCR5-R: GCCATTCAGC- TNM stage* TTGCAGGTATTG, GAPDH-F: ACAACTT- I+II 35 15 (42.9%) 20 (57.1%) 0.6893 0.4064 TGGTATCGTGGAAGG, GAPDH-R: GC- III+IV 50 26 (52%) 24 (48%) CATCACGCCACAGTTTC. The mRNA Values in bold were defined asP < 0.05. *Note: partial clinical data loss. level of CXCR5 was measured by real- time PCR using SYBR Green method on the Applied Biosystems 7500 present study was to detect the expression of real-time PCR system (Applied Biosystem, USA). CXCR5 in gastric cancer tissues and to analyze All experiments were performed in triplicate. its clinical significance. Data were normalized to the housekeeping gene GAPDH, and the relative abundance of Materials and methods transcripts was calculated by the comparative ΔΔCT method. Patients and tissue microarray Immunohistochemistry Tissue microarray for human gastric cancer (HStm-Ade180Sur-05) was purchased from Immunohistochemical staining was performed Shanghai Outdo Biotech Co., LTD (Shanghai, using the EnVisionTM method according to the China). The tissue microarray included 90 manufacturer’s instructions. The tissue micro- cases of gastric cancer and adjacent normal array section was dewaxed in xylene, rehydrat- tissues. All patients including 60 male and 30 ed and graded ethanol solutions. Antigen female patients underwent surgical stomach retrieval was conducted by heating tissue sec- resection between July 2006 and April 2007. tions at 100°C for 30 min in EDTA (pH 9.0) solu- The median age of these patients was 65 years tion. Then, the sections were immersed in a 3% and survival data were available, with follow-up hydrogen peroxide solution for 30 min to block to 2013 August. In addition, the gastric cancer endogenous peroxidase activity, rinsed in phos- tissues and adjacent normal tissues from 14 phate buffered saline (PBS) for 5 min, blocked cases during the surgical resection were col- with 3% BSA at room temperature for 30 min, lected to determine the expression of CXCR5 andincubated with purified rabbit anti-human mRNA. No patients received pre-operative che- CXCR5 antibody (Millipore, USA) at 4°C over- 7203 Int J Clin Exp Pathol 2016;9(7):7202-7208 CXCR5 expression in gastric cancer Intracellular staining and flow cytometry analy- sis The expression of CXCR5 in cells was examined by flow cytometry using IntraPrepPermeabili- zation Reagent. Human gastric cancer cells such as BGC-823, SGC-7901 and HGC-27 cells were cultured in a standard condition (5% CO2, 37°C). Harvested cells and dispersed cells (5 × 105~1 × 106) were washed with PBS and ali- quoted into 100 mL of IntraPreppermeabilization reagent 1 (Immunotech, Marseille, France) for 15 min at room temperature. After washing once with 1 mL of Hanks’ buffered saline solu- tion (HBSS) with 2% FBS, the cells were perme- Figure 1. CXCR5 mRNA expression in gastric tissues. abilized for 5 min with IntraPreppermeabiliza- The expression level of CXCR5 mRNA in gastric can- tion reagent 2. The cytoplasmic expression cer tissues was significantly higher than that in adja- of CXCR5 was detected by flow cytometry cent gastric tissues (P = 0.0047). (FACSCanto II, BD, USA), and the data were ana- lyzed by using FlowJo10.0.6. night. The section omitting primary antibody was used as the negative control. The horse- Statistical analysis radish peroxidase (HRP)-labeled goat anti- mouse/rabbit secondary antibody used in All statistical analyses were performed using immunohistochemical staining was purchased GraphPad Prism 5.0. The T-test was used to from Dako (Glostrup, Denmark). Diaminoben- analyze the difference in the expression of zene was used as the chromogen and hema- CXCR5 protein between cancer tissues and toxylin as the nuclear counterstain. Sections adjacent normal tissues. The χ2 tests were were dehydrated, cleared and mounted. used to analyze the relationship between CXCR5 expression and pathological parame- Evaluation of CXCR5 immunostaining ters. Overall survival rate of patients with differ- Immunohistochemical staining was assessed ent clinic-pathological parameters was com- using the H-score method as described in our pared by log-rank survival analysis. A statisti- previous study [7]. H-score = (% tumor cells cally significant difference was considered at P unstained × 0) + (% tumor cells stained weak × < 0.05. 1) + (% tumor cells stained moderate × 2) + (% tumor cells stained strong × 3). The H-scores Results ranged from 0 (100% negative tumor cells) to 300 (100% strong staining tumor cells). Results Expression of CXCR5 mRNA in gastric tissues from two pathologists were averaged and used in the statistical analysis.
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