Diagnostic and prognostic value of serum interleukin‑16 in patients with gastric cancer

  • Authors:
    • Hongyun Yang
    • Yanyan Han
    • Lele Wu
    • Chaojun Wu
  • View Affiliations

  • Published online on: October 2, 2017     https://doi.org/10.3892/mmr.2017.7688
  • Pages: 9143-9148
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Abstract

Gastric cancer (GC) is one of the major leading causes of cancer‑associated mortality worldwide. Serum biomarkers have a vital role in diagnosis and prognosis of GC, and interleukin (IL)‑16 may serve as a useful biomarker with prognostic value for human cancers. The current study aimed to evaluate the expression level of serum IL‑16 in patients with GC, and evaluate the diagnostic and prognostic value of IL‑16. ELISA was performed determine the serum IL‑16 levels in patients with GC and healthy controls. Receiver operator curve analysis was performed to evaluate the diagnostic and prognostic potential value of serum IL‑16 in GC diagnosis. Migration and invasion assays were performed using cells with IL‑16 small interfering RNA (siRNA) knockdown. The results demonstrated that serum IL‑16 levels were significantly higher in GC samples than in healthy controls, and increased serum IL‑16 levels were significantly associated with tumor recurrence and poor prognosis. Knockdown of IL‑16 significantly suppressed the migration and invasion of GC cells. In conclusion, the current results indicate that serum IL‑16 levels may have diagnostic and prognostic value for patient with GC.

Introduction

Gastric cancer remains the second leading cause of cancer-associated mortality worldwide and is the fourth most common malignancy. East Asian countries account for ~50% of the incidence of gastric cancer (GC), and ~1 million new cases and 0.7 million deaths per year worldwide (1). Due to the limited of techniques for GC screening, the majority of patients with GC are diagnosed at an advanced stage, and the prognosis for patients with advanced GC remains poor.

Patients with GC have considerably lower survival rates than those with other gastroenterological tract cancers, except for cancer of the esophagus, and the 5-year survival rate of patients with localized disease (stages I, II, N0; 63.2%) decreases to 28.4% as the cancer spreads to regional lymph nodes (stages II, III, N1-N3), and to 3.9% following the detection of distant metastases (stage IV) (2).

Current methods for diagnosis and monitoring of GC include invasive tests, such as endoscopy and biopsy; however, such tests are limited due to their high cost and invasiveness (3). Esophagogastroduodenoscopy, one of the most reliable methods for diagnosis of GC, is broadly used in China, South Korea and Japan, where the incidence rates of GC are high, while the effectiveness and feasibility of gastroscopy is questionable for countries with low GC incidence rates (2).

In order to screen for GC at an early stage and reduce the incidence and mortality, it is urgent to develop novel biomarkers for early GC diagnosis and prognosis evaluation. Conventional GC-associated serum markers lack of sufficient sensitivity and specificity to obtain early detection, such as carcinoembryonic antigen (CEA), carbohydrate antibody (CA) 12-5, and CA19-9, as well as CA72-4 (46), and there is a growing need to identify useful biomarkers for early noninvasive diagnosis and monitoring of the progression of GC. Interleukin-16 (IL-16), produced predominantly by CD8(+) cells, induces chemotaxis of CD4(+) T cells, monocytes and eosinophils. IL-16 acts as an immunomodulatory cytokine that contributes to the regulatory process of CD4(+) cell recruitment and activation at sites of inflammation, and has an essential role in initiating and/or sustaining the inflammatory response (7). In addition, IL-16 can promote the secretion of tumor-associated inflammatory cytokines by monocytes, such as IL-1b, IL-6 and IL-15, and has an important role in the carcinogenesis of human cancers (811). However, the diagnostic and prognostic value of serum IL-16 in patients with GC remains unknown.

In the present study, the mRNA and protein levels of IL-6 in GC cell lines were measured, the IL-6 level in serum from patients with GC was analyzed, and the association of the serum IL-6 level with patient clinical outcomes were evaluated to assess whether serum IL-6 is useful as a diagnostic and prognostic biomarker for GC.

Materials and methods

Ethics statement

Informed consent from all patients and healthy controls, and approval from the Affiliated Hospital of Taishan Medical University Ethics Committee was obtained to collect blood samples and review patient medical records.

Sample collection

Patients with GC (n=98; mean age, 61.5±8.1 years; range 41–75 years) based on histological examination, received curative treatment in the Affiliated Hospital of Taishan Medical Hospital (Tai'an, China) between January 2005 and March 2010 were enrolled in current study. Prior to the current study, none of the patients with GC had received any chemotherapy, radiation therapy, surgery, immunotherapy or other treatments, and no metastases were identified prior to surgery. Serum samples were collected at the time of diagnosis, prior to tumor resection, at 3 weeks post-operation and at the moment of recurrence. Healthy donors (n=98) were enrolled as control, and they were matched to the patients with GC in terms of sex and age. Serum was obtained from a 5-ml blood sample following centrifugation for 10 min at 1,006 × g at room temperature and stored at −20°C prior to analysis.

Follow-up data included clinical, laboratory and radiological examination performed every 3 months during the first year, every 6 months during the subsequent 4 years. Overall survival (OS) was assessed from the date of primary diagnosis to death or last follow-up.

Measurement of serum IL-16 levels

Serum IL-16 levels were determined by the Human IL-16 Quantikine ELISA kit (D1600; R&D Systems, Inc., Minneapolis, MN, USA) according to the manufacturer's instructions. Briefly, a human IL-16 monoclonal antibody was pre-coated onto a 96-well plate. Standards and samples were added into each well and allowed to incubate for 2 h at room temperature, and IL-16 was bound by the immobilized antibody. Following washing to remove the unbound substances, an enzyme-linked polyclonal antibody specific for IL-16 was added to each well. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added to the wells and color developed in proportion to the amount of IL-16 bound. The intensity of the colored reaction product was measured using an automated ELISA reader at 450 nm. The results were expressed as ng/ml (7). Serum CEA was measured with ARCHITECT I2000 SR (Abbott Pharmaceutical Co. Ltd., Lake Bluff, IL, USA).

Downregulation of IL-16 mRNA by small interfering RNA (siRNA) transfection

The poorly differentiated human GC cell line MKN45 was obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cells were cultured in RPMI-1640 medium (Thermo Fisher Scientific, Inc., Waltham, MA, USA), supplemented with 10% fetal calf serum (Gibco; Thermo Fisher Scientific, Inc.) at 37°C and 5% CO2 in humidified incubator. The IL-16 gene silencing by transfection with small interfering RNA (siRNA) was performed according to a previous study (12). GC cells (3×105) were washed and resuspended in 100 µl OptiMEM I medium (Gibco; Thermo Fisher Scientific, Inc.) For each condition, 50 pmol siRNA (IL-16-targeting siRNAs; HSS142654 and, for the control group, scrambled, non-targeting control siRNA; D-001206-13-20; Invitrogen; Thermo Fisher Scientific, Inc.) was added into the cells followed by incubation at room temperature for 10 min. Lipofectamine 2000 (Thermo Fisher Scientific, Inc.) was diluted 1:40 in OptiMEM I medium without serum and incubated for 10 min at room temperature, and then the dilution (100 µl) was added to the cells and incubated for 20 min at room temperature. Cell suspensions were placed in a 24-well plate and incubated for 4 h at 37°C. Complete medium (1.5 ml) was added into each well and cells were cultured for another 72 h at 37°C. Green fluorescence protein was used as a reporter for siRNA. Following transfection, ≥5 random fields of transfected cells were selected by using bright-field microscopy and fluorescent microscopy. Transfection efficiency was determined by dividing the number of fluorescent cells in regions of interest by the total cell number in the field.

RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

Total RNA was extracted from MKN45 cell lines using the TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's instruction (13). The first-strand IL-16 cDNA was synthesized using the PrimeScript RT-PCR Kit (Takara Bio, Inc., Otsu, Japan) with total RNA. Reverse transcription reactions were carried out at 42°C for 60 min and terminated by heating to 95°C for 10 min. RT-qPCR was performed with the SYBR Green PCR MasterMix (Applied Biosystems; Thermo Fisher Scientific, Inc.) under the following conditions: 10 min at 95°C, followed by 40 cycles of 15 sec at 95°C and 1 min at 60°C). Each reaction was performed in duplicate. The 2−ΔΔCq method were used to calculate the relative expression levels, gene expression was normalized to the geometric mean using GAPDH as an internal control (14). The primers used in the qPCR reaction were as follows: IL-16, 5′-GCAAGTCTCTCAAGGGGACC-3′ (forward) and 5′-CAGACACACCCCACACCTTT-3′ (reverse); GAPDH, 5′-GACTCATGACCACAGTCCATGC-3′ (forward) and 5′-AGAGGCAGGGATGATGTTCTG-3′ (reverse).

Western blotting

IL-16 protein level was analyzed by western blotting assay according a previous study (13,15). Proteins were extracted in cell lysis buffer (89900; Thermo Fisher Scientific, Inc.) on ice followed by centrifugation at 12,000 × g for 10 min at 4°C, then boiled at 100°C for 10 min. Following extraction, the protein concentration was determined by the BCA Protein Assay (Pierce; Thermo Fisher Scientific, Inc.). Proteins (25 µg per well) were resolved by 10% SDS-PAGE and electro-transferred to nitrocellulose membranes. Each membrane was blocked with 5% non-fat dried milk in Tris buffered saline-Tween-20 for 1 h at room temperature, and subsequently incubated with the primary antibody for 16 h at 4°C. The following antibodies were used: Anti-IL16 monoclonal (ab180792; 1:1,000; Abcam, Cambridge, UK) and anti-β actin (ab8226; 1:1,000; Abcam). Immunoreactivity was detected by sequential incubation with horseradish peroxidase-conjugated secondary antibody (ab97051; 1:1,000; Abcam) for 1 h at room temperature and visualized using an ECL detection kit (Amersham Pharmacia, Uppsala, Sweden). The density of the specific bands was quantified with an ImageJ version 1.46 (National Institutes of Health, Bethesda, MD, USA).

Cell migration and invasion assays

The siRNA transfection cells and scramble control siRNA transfection cells were used in cell migration and invasion assays (16). The transwell chamber assay was used to assess cell migration ability, and BioCoat Matrigel Invasion Chambers (Corning Incorporated, Corning, NY, USA) were used to analyze the cell invasion ability. Briefly, 200 cells were seeded in the chamber, and 10% fetal bovine serum (Gibco; Thermo Fisher Scientific, Inc.) was used as the chemoattractant. After 24 h, cells on the lower surface of the chamber were fixed in 10% paraformaldehyde for 20 min at room temperature and stained with 0.1% crystal violet again for 20 min at room temperature. This was followed by counting under a light microscope. Cells were visualized, and 10 representative fields of view were imaged. Experiments were performed in triplicate at least.

Statistical analysis

Statistical analyses were performed out using SPSS version 17.0 (SPSS, Inc., Chicago, IL, USA) or Prism 6.00 (GraphPad Software, Inc., La Jolla, CA, USA). A receiver-operating characteristic (ROC) curve was obtained and the area under the ROC curve (AUC) was calculated to evaluate the potential diagnosis value of serum IL-16 in GC. The Mann-Whitney U test was used to compare the serum level of IL-16 between patients with GC and healthy volunteers. Wilcoxon signed rank test was used to analyze serum IL-16 levels between pre-operative serum samples and post-operative serum samples. Survival curve data was calculated using the Kaplan-Meier method and compared with log-rank tests. Data were presented as mean ± standard deviation and P<0.05 was considered to indicate a statistically significant difference.

Results

IL-16 is increased in the serum of 98 patients with GC

The levels of total serum IL-16 in the patients with GC (n=98) and healthy controls (n=98) were detected by ELISA. The serum IL-16 level in the patients with GC were significantly higher compared with those in the healthy controls (P<0.05; Fig. 1A), the mean IL-16 level in the GC group was 2.59-fold higher than that in healthy controls.

In order to analyze the diagnostic potential of serum IL-16 for GC, ROC curves were constructed using on the data from 98 patients with GC and 98 healthy controls. The results indicated the serum IL-16 level was able to differentiate patients with GC (n=98) from healthy controls (n=98) with an AUC of 0.882.

The sensitivity of IL-16 reached 79.6%, and the specificity was as high as 78.6%, which indicated that for diagnosis of GC IL-16 as a novel marker is better than the traditional tumor marker, CEA, in terms of the sensitivity and specificity (Table I).

Table I.

Sensitivity and specificity of serum IL-16 and CEA.

Table I.

Sensitivity and specificity of serum IL-16 and CEA.

TestCEA (%)IL-16 (%)P-valuea
Sensitivity68.279.6<0.05
Specificity59.778.6<0.05

a Fisher's exact test. IL-16, interleukin-16; CEA, carcinoembryonic antigen.

Serum IL-16 level is reduced post-operation

In order to evaluate the serum IL-16 level prior to and following operation, serum samples were obtained pre-operative and at 3 weeks post-operation. As presented in Fig. 2, the serum IL-16 level was significantly reduced following tumor resection, compared with the value prior to tumor resection (P<0.05), indicating positive association between tumor presence and the serum IL-16 levels in patients with GC.

Serum IL-16 level is increased in patients with recurrence

Fig. 3 demonstrated that serum IL-16 levels in the recurrence group (n=60) were higher than that in the non-recurrence group (n=38; P<0.05). ROC curve analysis based on the serum IL-16 level confirmed the ability of IL-16 to distinguish between patients with and without recurrence. The AUC of 0.89 (95% confidence interval, 0.84–0.95) indicates good discriminative power (P<0.001).

Low serum IL-16 level predicts good prognosis in patients with GC

The correlations between survival and the serum IL-16 levels in patients were evaluated by the Kaplan-Meier method. Patients with GC (n=98) were followed-up for 60 months after the tumor resection. Based on the data, the appropriate cut-off value of serum IL-16 levels for predicting the presence of GC was 384 pg/ml. The cut-off value was determined by finding the cut-off with highest Youden Index, or equivalently, the highest Sensitivity + Specificity (17). Kaplan-Meier analysis with the log-rank test indicated that patients with GC in the low serum IL-16 level group (<384 pg/ml) had a significantly longer 5-year OS rate compared with the high serum IL-16 level group (>384 pg/ml; P<0.05; Fig. 4).

IL-16 knockdown suppresses the migration and invasion of GC cells

To assess the role of IL-16 in the migration and invasion of GC cells, IL-16 knockdown by siRNA in the GC line MKN45 was performed in the current study. Western blotting assay and RT-qPCR was used to assess IL-16 downregulation in transfected cells, which indicated that siRNA significantly suppressed IL-16 protein levels (Fig. 5A and B).

Transwell assays were performed to evaluate cell migration and invasiveness, and the results revealed that the knockdown of IL-16 suppressed significantly the migration ability and the invasive ability of the GC cells (Fig. 5C and D).

Discussion

GC remains a major public health problem, as it remains the second leading cause of cancer-associated mortality worldwide. An early diagnosis and early treatment strategy can significantly improve the survival rates of patients with GC, and the used of serum biomarkers, including CA 19-9, CEA and CA 72-4, to identify patients with a high risk of GC would improve the early diagnosis rate (1821). However, the sensitivity and specificity of these serum biomarkers used in diagnosis of GC is low (22,23). Currently, the precise mechanisms underlying GC remain unknown.

Inflammatory disease has been reported as a risk factor for cancer, and 25% of all cancer cases worldwide correlate with cases of chronic infection and inflammation. Furthermore, patients with chronic inflammation have a much higher risk of tumor formation and progression (2426). IL-16 is a multifunctional cytokine with a fundamental role in inflammatory diseases, and in the development and progression of tumors (27). Compérat et al (24) reported that IL-16 appears to be a useful prognostic factor in prostate cancer, and its expression in prostate cancer tissue was correlated with tumor aggressiveness and biochemical relapse of the disease. Yellapa et al (25) demonstrated that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression. Regarding GC, a previous study indicated that IL-16 was associated with an increased risk of non-cardia GC in a Chinese population (28).

In the current study, IL-16 expression was decreased in the serum of patients with GC compared with healthy controls, and its expression was associated with diagnostic value and prognosis. IL-16 was useful in the identification of patients with GC from healthy controls, which was superior to the traditional marker, CEA, although the sensitivity of the serum IL-16 as a marker was not particularly high. The IL-16 level in patients with GC was higher than that in healthy controls. Qin et al (27) also reported that the serum IL-16 levels were increased in patients with nasopharyngeal carcinoma compared with controls, which may be because IL-16 is associated with increased susceptibility to nasopharyngeal carcinoma by increasing the production of IL-16. In addition, the serum IL-16 of patients with GC was decreased significantly following tumor resection compared with prior to surgery. As tumor-associated neo-angiogenesis is an early event in tumor development, and IL-16 is a pro-angiogenic cytokine that stimulates production of neoangiogenic factors, decreased serum levels of IL-16 are associated with tumor resection and reduced tumor-associated neo-angiogenesis (29).

Despite improvements in diagnostic procedures and treatment strategies, >70% of recurrences and tumor-associated mortality occur within 2 years post-surgery due to early recurrence originating from minimal residual disease. Tumor recurrence is the leading cause of mortality in patients that undergo curative surgery for GC (30). In current study, the IL-16 levels were determined in patients with and without recurrence, and indicated that IL-16 levels were higher in patients with recurrence than in non-recurrence patients, suggesting an association between the serum IL-16 level and tumor recurrence. In addition, ROC curve analysis revealed that serum IL-16 had a diagnostic value in GC, and discriminated between patients with GC recurrence and those with no recurrence.

The 5-year OS rate was 30.8% in the high IL-16 group, and 65.0% in the low IL-16 group; Kaplan-Meier analysis revealed that the OS was longer for the patients with low serum IL-16 levels than those with high IL-16 levels.

To further examine the role of IL-16 in the migration and invasion of GC cells, IL-16-depletion in MKN45 cells was established using siRNA, and the cell migration and invasion abilities were assessed using Transwell assays. The knockdown of IL-16 significantly reduced the migration and invasive ability of GC cells.

In conclusion, the current study revealed that serum IL-16 level may not only serve as a useful diagnostic biomarker for patients with GC, but also may predict cancer recurrence and patient prognosis. Furthermore, reducing the IL-16 level may be a novel therapeutic option for treatment of GC.

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December-2017
Volume 16 Issue 6

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Yang H, Han Y, Wu L and Wu C: Diagnostic and prognostic value of serum interleukin‑16 in patients with gastric cancer. Mol Med Rep 16: 9143-9148, 2017
APA
Yang, H., Han, Y., Wu, L., & Wu, C. (2017). Diagnostic and prognostic value of serum interleukin‑16 in patients with gastric cancer. Molecular Medicine Reports, 16, 9143-9148. https://doi.org/10.3892/mmr.2017.7688
MLA
Yang, H., Han, Y., Wu, L., Wu, C."Diagnostic and prognostic value of serum interleukin‑16 in patients with gastric cancer". Molecular Medicine Reports 16.6 (2017): 9143-9148.
Chicago
Yang, H., Han, Y., Wu, L., Wu, C."Diagnostic and prognostic value of serum interleukin‑16 in patients with gastric cancer". Molecular Medicine Reports 16, no. 6 (2017): 9143-9148. https://doi.org/10.3892/mmr.2017.7688