IL16

Gene Summary

Gene:IL16; interleukin 16
Aliases: LCF, NIL16, PRIL16, prIL-16
Location:15q25.1
Summary:The protein encoded by this gene is a pleiotropic cytokine that functions as a chemoattractant, a modulator of T cell activation, and an inhibitor of HIV replication. The signaling process of this cytokine is mediated by CD4. The product of this gene undergoes proteolytic processing, which is found to yield two functional proteins. The cytokine function is exclusively attributed to the secreted C-terminal peptide, while the N-terminal product may play a role in cell cycle control. Caspase 3 is reported to be involved in the proteolytic processing of this protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pro-interleukin-16
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: IL16 (cancer-related)

Liu FT, Zhu PQ, Ou YX, et al.
Positive association between IL-16 rs1131445 polymorphism and cancer risk: a meta-analysis.
Minerva Med. 2016; 107(2):84-91 [PubMed] Related Publications
INTRODUCTION: The association between IL-16 rs1131445 polymorphism and cancer risk is not consistent or even contradictory, this meta-analysis aims to investigate the role of IL-16 gene rs1131445 polymorphisms in the risk of cancer.
EVIDENCE ACQUISITION: A comprehensive online search was conducted in PubMed, EMBASE and CNKI databases to identify eligible studies. The case-control studies related IL-16 rs1131445 C/T polymorphism with the cancer susceptibility were selected according to the inclusion and exclusion criteria. After extracting the basic data information and quality of literature evaluation, the meta-analysis was performed by using STATA 12.0 software, with calculating odds ratio and 95% confidence interval, and further subgroup analysis, literature publication bias test and sensitivity analysis.
EVIDENCE SYNTHESIS: There are totally 1677 cases and 1989 non-tumor controls finally involved. Meta-analysis showed that there are statistical correlations between the IL-16 rs1131445 C/T polymorphism and the cancer risk in Asian populations (TS vs. C, OR=0.80, 95%CI: 0.73-0.88; TT vs. TC, OR=0.75, 95%CI: 0.65-0.87; TT vs. CC, OR=0.69, 95% CI: 0.56-0.84; CC+TC vs. TT, OR=1.36, 95%CI: 1.19-1.55; CC vs. TC+TT, OR=1.27, 95%CI: 1.05-1.53) (all P<0.05).
CONCLUSIONS: IL-16 rs1131445 C/T polymorphism is related to the susceptibility to cancer in Asians, suggesting that the C allelic gene of rs1131445 is significantly associated with an increasing cancer risk.

Robles AI, Traverso G, Zhang M, et al.
Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers.
Gastroenterology. 2016; 150(4):931-43 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors.
METHODS: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies.
RESULTS: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD.
CONCLUSIONS: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.

Kashfi SM, Behboudi Farahbakhsh F, Nazemalhosseini Mojarad E, et al.
Interleukin-16 polymorphisms as new promising biomarkers for risk of gastric cancer.
Tumour Biol. 2016; 37(2):2119-26 [PubMed] Related Publications
Gastric cancer (GC) is the second cause of cancer-related death worldwide. Interleukin (IL)-16 has a vital role in the development and homeostasis of the immune system. In the present study, we evaluated an exon variant rs4072111 C/T polymorphism and 3' UTR variant rs1131445 C/T within the miRNA binding with gastric cancer susceptibility in Iranian population. Genomic DNA was isolated from peripheral blood samples according to phenol chloroform extraction. The genotypes of IL-16 polymorphisms rs1131445 T/C and rs4072111 T/C were determined by polymerase chain reaction-restriction fragment length polymorphism method. In this case control study, a total of 256 patients with gastric cancer (238 cases (92.9 %) non-cardia and 18 cases (7.1 %) cardia) and 300 healthy control subjects were evaluated. In the present study, we found a significant association between rs4072111 of IL-16 gene and risk of GC in Iranian population. Individuals with CT genotype showed a significant association with 1.79-fold increased risk of GC (P = 0.008; adjusted OR 1.792; 95 % CI 1.164-2.759). The significant association was also detected for T allele of rs4072111 and increased risk of GC (P < 0.001; adjusted OR 1.981; 95 % CI 1.354-2.900). We also observed statistically a significant relationship between rs1131445 of IL-16 CT genotype and GC risk. Carriers of IL-16 CT genotype compared with TT genotype had 1.44 times higher increased likelihood of GC (P = 0.048; adjusted OR 1.445; 95 % CI 1.003-2.084). After stratification according to gender, we observed that in rs1131445, CT and CC male carriers had a higher risk of GC than females (P = 0.08; adjusted OR 1.608; 95 % CI 0.945-2.737 and P = 0.08; adjusted OR 2.186; 95 % CI 0.897-5.325, respectively). We also observed that for male carriers with C allele in rs1131445, there was a 1.53-fold higher risk of GC risk than female subjects (P = 0.029; adjusted OR 1.53; 95 % CI 1.04.4-2.248). We found that the rs1131445 T/C and rs4072111 T/C variants of IL-16 were significantly associated with increased risk of GC in Iranian population.

Liu Y, Zhou R, Sulman EP, et al.
Genetic Modulation of Neurocognitive Function in Glioma Patients.
Clin Cancer Res. 2015; 21(14):3340-6 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Accumulating evidence supports the contention that genetic variation is associated with neurocognitive function in healthy individuals and increased risk for neurocognitive decline in a variety of patient populations, including cancer patients. However, this has rarely been studied in glioma patients.
EXPERIMENTAL DESIGN: To identify the effect of genetic variants on neurocognitive function, we examined the relationship between the genotype frequencies of 10,967 single-nucleotide polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase) and neurocognitive function in 233 newly diagnosed glioma patients before surgical resection. Four neuropsychologic tests that measured memory (Hopkins Verbal Learning Test-Revised), processing speed (Trail Making Test A), and executive function (Trail Making Test B, Controlled Oral Word Association) were examined.
RESULTS: Eighteen polymorphisms were associated with processing speed and 12 polymorphisms with executive function. For processing speed, the strongest signals were in IRS1 rs6725330 in the inflammation pathway (P = 2.5 × 10(-10)), ERCC4 rs1573638 in the DNA repair pathway (P = 3.4 × 10(-7)), and ABCC1 rs8187858 in metabolism pathway (P = 6.6 × 10(-7)). For executive function, the strongest associations were in NOS1 rs11611788 (P = 1.8 × 10(-8)) and IL16 rs1912124 (P = 6.0 × 10(-7)) in the inflammation pathway, and POLE rs5744761 (P = 6.0 × 10(-7)) in the DNA repair pathway. Joint effect analysis found significant gene polymorphism-dosage effects for processing speed (Ptrend = 9.4 × 10(-16)) and executive function (Ptrend = 6.6 × 10(-15)).
CONCLUSIONS: Polymorphisms in inflammation, DNA repair, and metabolism pathways are associated with neurocognitive function in glioma patients and may affect clinical outcomes.

Nan H, Hutter CM, Lin Y, et al.
Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
JAMA. 2015; 313(11):1133-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.
OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.
DESIGN, SETTING, AND PARTICIPANTS: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.
EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.
MAIN OUTCOMES AND MEASURES: Colorectal cancer.
RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).
CONCLUSIONS AND RELEVANCE: In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

Woods NT, Monteiro AN, Thompson ZJ, et al.
Interleukin polymorphisms associated with overall survival, disease-free survival, and recurrence in non-small cell lung cancer patients.
Mol Carcinog. 2015; 54 Suppl 1:E172-84 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Biomarkers based on germline DNA variations could have translational implications by identifying prognostic factors and sub-classifying patients to tailored, patient-specific treatment. To investigate the association between germline variations in interleukin (IL) genes and lung cancer outcomes, we genotyped 251 single nucleotide polymorphisms (SNPs) from 33 different IL genes in 651 non-small cell lung cancer (NSCLC) patients. Analyses were performed to investigate overall survival, disease-free survival, and recurrence. Our analyses revealed 24 different IL SNPs significantly associated with one or more of the lung cancer outcomes of interest. The GG genotype of IL16:rs7170924 was significantly associated with disease-free survival (HR = 0.65; 95% CI 0.50-0.83) and was the only SNP that produced a false discovery rate (FDR) of modest confidence that the association is unlikely to represent a false-positive result (FDR = 0.142). Classification and regression tree (CART) analyses were used to identify potential higher-order interactions. We restricted the CART analyses to the five SNPs that were significantly associated with multiple endpoints (IL1A:rs1800587, IL1B:rs1143634, IL8:s12506479, IL12A:rs662959, and IL13:rs1881457) and IL16:rs7170924 which had the lowest FDR. CART analyses did not yield a tree structure for overall survival; separate CART tree structures were identified for recurrence, based on three SNPs (IL13:rs1881457, IL1B:rs1143634, and IL12A:rs662959), and for disease-free survival, based on two SNPs (IL12A:rs662959 and IL16:rs7170924), which may suggest that these candidate IL SNPs have a specific impact on lung cancer progression and recurrence. These data suggest that germline variations in IL genes are associated with clinical outcomes in NSCLC patients.

Luo QS, Wang JL, Deng YY, et al.
Interleukin-16 polymorphism is associated with an increased risk of glioma.
Genet Test Mol Biomarkers. 2014; 18(10):711-4 [PubMed] Related Publications
OBJECTIVE: Previous studies have shown that interleukin (IL)-16 is overexpressed in human and rat gliomas. Potential links between IL-16 polymorphisms and glioma risk are currently unclear. The aim of this study was to investigate the association between IL-16 polymorphisms and glioma risk.
METHODS: We examined IL-16 gene polymorphisms (i.e., rs 4778889, rs 11556218, and rs 4072111) in 216 patients with glioma and 275 controls in a Chinese population. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk.
RESULTS: The rs 11556218TG genotype is associated with an increased risk of glioma compared with the TT genotype (OR=1.76; 95% CI, 1.22-2.54; p=0.002). Similarly, the rs 11556218G allele is associated with an increased risk of glioma compared with the T allele (OR=1.41; 95% CI, 1.06-1.87; p=0.017). However, no significant association was observed between the IL-16 rs 4778889 and rs 4072111 polymorphisms and the risk of glioma.
CONCLUSION: These findings suggest that the IL-16 rs 11556218 polymorphism may be used as a susceptibility marker for glioma.

Kushlinskii NE, Timofeev YS, Solov'ev YN, et al.
Components of the RANK/RANKL/OPG system, IL-6, IL-8, IL-16, MMP-2, and calcitonin in the sera of patients with bone tumors.
Bull Exp Biol Med. 2014; 157(4):520-3 [PubMed] Related Publications
Serum levels of sRANKL, RANK, OPG, IL-8, IL-6, IL-16, MMP-2, and calcitonin were measured by ELISA in patients with malignant, borderline, and benign bone tumors and in healthy individuals (control). Serum levels of RANK, OPG, IL-8, IL-6, and the OPG/sRANKL ratio were significantly higher, while the level of MMP-2 was significantly lower in patients with bone tumors than in controls. Serum concentration of IL-16 in osteosarcoma patients was significantly lower than in chondrosarcoma patients. No significant differences between bone sarcomas of different differentiation were detected for any of the studied markers. Calcitonin level depended on the tumor location and type.

Mi Y, Wang L, Zong L, et al.
Genetic variants in microRNA target sites of 37 selected cancer-related genes and the risk of cervical cancer.
PLoS One. 2014; 9(1):e86061 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
OBJECTIVES: Single nucleotide polymorphisms (SNPs) in putative microRNA binding sites (miRSNPs) modulate cancer susceptibility via affecting miRNA binding. Here, we sought to investigate the association between miRSNPs and cervical cancer risk.
METHODS: We first genotyped 41 miRSNPs of 37 cancer-related genes in 338 patients and 334 controls (Study 1), and replicated the significant associations in 502 patients and 600 controls (Study 2). We tested the effects of miRSNPs on microRNA-mRNA interaction by luciferase reporter assay.
RESULTS: Five SNPs displayed notable association with cervical cancer risk in Study 1. Only IL-16 rs1131445 maintained a significant association with cervical cancer (CT/CC vs. TT, adjusted OR = 1.51, P = 0.001) in Study 2. This association was more evident in the combined data of two studies (adjusted OR = 1.49, P = 0.00007). We also found that miR-135b mimics interacted with IL-16 3'-UTR to reduce gene expression and that the rs1131445 T to C substitution within the putative binding site impaired the interaction of miR-135b with IL-16 3'-UTR. An ELISA indicated that the serum IL-16 of patients with cervical cancer was elevated (vs. controls, P = 0.001) and correlated with the rs1131445 genotype. Patients who carried the rs1131445 C allele had higher serum IL-16 than non-carriers (P<0.001).
CONCLUSIONS: These results support our hypothesis that miRSNPs constitute a susceptibility factor for cervical cancers. rs1131445 affects IL-16 expression by interfering with the suppressive function of miR135b and this variant is significantly associated with cervical cancer risk.

Yellapa A, Bitterman P, Sharma S, et al.
Interleukin 16 expression changes in association with ovarian malignant transformation.
Am J Obstet Gynecol. 2014; 210(3):272.e1-10 [PubMed] Related Publications
OBJECTIVE: Long-term unresolved inflammation has been suggested as a risk factor for the development of various malignancies. The goal of this study was to examine whether the expression of interleukin (IL)-16, a proinflammatory cytokine, changes in association with ovarian cancer (OVCA) development.
STUDY DESIGN: In an exploratory study, changes in IL-16 expression in association with OVCA development and progression were determined using ovarian tissues and serum samples from healthy subjects (n = 10) and patients with benign (n = 10) and malignant ovarian tumors at early (n = 8) and late (n = 20) stages. In the prospective study, laying hens, a preclinical model of spontaneous OVCA, were monitored (n = 200) for 45 weeks with serum samples collected at 15-week interval. Changes in serum levels of IL-16 relative to OVCA development were examined.
RESULTS: The frequency of IL-16-expressing cells increased significantly in patients with OVCA (P < .001) compared to healthy subjects and patients with benign ovarian tumors. The concentration of serum IL-16 was higher in patients with benign tumors (P < .05) than in healthy subjects and increased further in patients with early-stage (P < .05) and late-stage (P < .03) OVCA. Increase in tissue expression and serum levels of IL-16 in patients with early and late stages of OVCA were positively correlated with the increase in ovarian tumor-associated microvessels. Prospective monitoring showed that serum levels of IL-16 increase significantly (P < .002) even before ovarian tumors become grossly detectable in hens.
CONCLUSION: This study showed that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression.

Zhao Y, Tao L, Wang B, et al.
Interleukin-16 gene polymorphisms rs4778889, rs4072111, rs11556218, and cancer risk in Asian populations: a meta-analysis.
Genet Test Mol Biomarkers. 2014; 18(3):174-82 [PubMed] Related Publications
OBJECTIVES: Some polymorphisms of the interleukin-16 (IL-16) gene are associated with various cancers. To resolve inconsistencies in published data, we performed a meta-analysis of studies of IL-16 polymorphisms and cancer risk.
MATERIALS AND METHODS: Seven eligible studies pooling 1678 cases and 1937 controls were quantitatively analyzed to evaluate three IL-16 polymorphisms (rs4778889, rs4072111, rs11556218) and cancer risk. Hardy-Weinberg equilibrium (HWE) for controls was evaluated by goodness-of-fit chi-squared tests. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated for each genetic model and allelic comparison. Data were pooled using fixed- or random-effects models depending on heterogeneity across studies.
RESULTS: Our meta-analysis demonstrated that the IL-16 polymorphism rs11556218 was significantly associated with increased susceptibility to cancer in several models, including allelic contrast (OR=1.307; 95% CI, 1.108-1.541), heterozygote contrast (OR=1.650; 95% CI, 1.424-1.911), and dominant model (OR=1.605; 95% CI, 1.391-1.845). The result remained consistent after adjustment for age and gender. No significant association was found between IL-16 polymorphisms rs4778889 rs4072111 and cancer risk.
CONCLUSIONS: The rs11556218 T/G polymorphism of the IL-16 gene was significantly associated with elevated cancer risk in Asian populations. Our results warrant larger, better-designed studies, including a greater ethnic variety.

Zhang T, Wang H
Variants of interleukin-16 associated with gastric cancer risk.
Asian Pac J Cancer Prev. 2013; 14(9):5269-73 [PubMed] Related Publications
AIM: We conducted a case-control matched study to investigate the role of IL-16 gene polymorphisms, rs4072111, rs1131445, rs4778889 and rs11556218, in the risk of gastric cancer in a Chinese population, also performing subgroup analysis by subsites.
METHODS: To test the hypothesis of involvement, we analyzed the four SNPs of IL16 in 347 cancer patients and 368 controls. Demographic data and other information were collected using a newly designed questionnaire. Genotyping of IL16 (rs4072111, rs1131445, rs4778889 and rs11556218) was performed in a 384-well plate format on the MassARRAY® platform.
RESULTS: In our study, we found the gastric cancer patients were more likely to be male and have a family history of cancer (P < 0.05). We found the rs4778889 CC and rs11556218 GG genotype was significantly associated with 1.97 and 1.84-fold increased risk of non-cardia gastric cancer, while we did not find significant association between the four IL-16 SNPs and cardia gastric cancer.
CONCLUSIONS: In conclusion, our study indicated that IL-16 rs4778889 CC and rs11556218 GG genotypes are associated with an increased risk of non-cardia gastric cancer in a Chinese population. Our results offer insights into the influence of IL-16 on development of gastric cancer.

Qin X, Peng Q, Lao X, et al.
The association of interleukin-16 gene polymorphisms with IL-16 serum levels and risk of nasopharyngeal carcinoma in a Chinese population.
Tumour Biol. 2014; 35(3):1917-24 [PubMed] Related Publications
Interleukin (IL)-16 plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. Genetic variation in DNA sequence of IL16 gene may lead to altered cytokine production and/or activity, and this variation may modulate an individual's susceptibility to nasopharyngeal carcinoma (NPC). To test this hypothesis, we investigated the association of IL16 gene polymorphisms and serum IL-16 levels with NPC risk in a Chinese population. We analyzed IL16 gene rs11556218 T/G, rs4778889 T/C, and rs4072111 C/T polymorphisms using PCR-RFLP and DNA sequencing, and serum IL-16 levels were measured by ELISA. The IL16 rs11556218 T/G polymorphism was significantly associated with the susceptibility to NPC patients. The TG genotype was associated with a significantly higher risk of NPC as compared with the TT genotype (OR = 2.05, 95% CI 1.04-4.01; p = 0.037). Patients carrying the G allele had a significantly higher risk for developing NPC compared with individuals carrying the T allele (OR = 1.79, 95% CI 1.07-3.01; p = 0.027). The serum IL-16 levels were increased in NPC patients compared with controls (p < 0.01); the genotypes carrying the IL16 rs11556218 G variant allele were associated with increased serum IL-16 levels compared with the homozygous wild-type genotype in NPC patients (all p values <0.01). Our data suggested that IL16 rs11556218 T/G polymorphism was associated with increased susceptibility to NPC through increasing the production of serum IL-16 levels.

Hughes L, Ruth K, Rebbeck TR, Giri VN
Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men.
Prostate Cancer Prostatic Dis. 2013; 16(4):308-14 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening.
METHODS: The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with 1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype.
RESULTS: Among 256 African Americans with one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26-7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes.
CONCLUSIONS: Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future.

Richmond J, Tuzova M, Cruikshank W, Center D
Regulation of cellular processes by interleukin-16 in homeostasis and cancer.
J Cell Physiol. 2014; 229(2):139-47 [PubMed] Related Publications
Interleukin-16 (IL-16) is generated as a precursor molecule that is cleaved by caspase-3 to produce a pro-IL-16 molecule that functions as a regulator of T cell growth, and a secreted peptide that functions as a CD4 and/or CD9 ligand for induction of cell motility and activation. IL-16 has been predominantly studied as a contributing factor in the orchestration of an immune response; however, more recently IL-16 bioactivity has been closely associated with the progression of a number of different cancers. While the association between IL-16 plasma levels and tumor progression has been reported for many types of cancer, the mechanism for IL-16 involvement has been partially elucidated for three of the cancer types, cutaneous T cell lymphoma (CTCL), multiple myeloma (MM), and breast cancer. The mechanism for promoting cell growth is different in each of these cancers and involves a sequence mutation in the pro-molecule facilitating decreased p27(KIP1) levels in CTCL; over expression of the secreted IL-16 molecule to induce proliferation in CTCL T cells, and plasma cells in MM; and increased secreted IL-16 acting to recruit CD4+ pro-tumor macrophages in breast cancer. This article will review the cellular process for generating IL-16, the biological activities for both the pro- and secreted forms of the protein, and then the mechanism by which these forms contribute to cancer progression. As a soluble cytokine the ability to reduce or eliminate IL-16 synthesis through siRNA approaches or bioactivity through the use of neutralizing antibody treatment may represent a novel therapeutic approach.

Milke L, Schulz K, Weigert A, et al.
Depletion of tristetraprolin in breast cancer cells increases interleukin-16 expression and promotes tumor infiltration with monocytes/macrophages.
Carcinogenesis. 2013; 34(4):850-7 [PubMed] Related Publications
The RNA-binding protein tristetraprolin (TTP) destabilizes target messenger RNAs (mRNAs) containing AU-rich elements within their 3' untranslated region. Thereby, it controls the expression of multiple inflammatory and tumor-associated transcripts. Moreover, a loss of TTP in tumors predicts disease-associated survival. Although tumor intrinsic functions of TTP have previously been studied, the impact of TTP on the interaction of tumors with their microenvironment remains elusive. As immune cell infiltration into tumors is a critical determinant for tumor progression, this study aimed at determining the influence of tumor cell TTP on the interaction between tumor and immune cells, specifically monocytes (MO)/macrophages (MΦ). Knockdown (k/d) of TTP in T47D breast cancer cells enhanced tumor growth both in vitro and in vivo and increased infiltration of MO into 3D tumor spheroids in vitro and of MΦ into tumor xenografts in vivo. Enhanced migration of MO toward supernatants of TTP-deficient tumor spheroids was determined as the underlying principle. Interestingly, we noticed interleukin-16 (IL-16) mRNA stabilization when TTP was depleted. In line, IL-16 protein levels were elevated in TTP-deficient spheroids and their supernatants as well as in TTP k/d tumor xenografts and critically contributed to the enhanced chemotactic behavior. In summary, we show that the loss of TTP in tumors not only affects tumor cell proliferation and survival but also enhances infiltration of MO/MΦ into the tumors, which is typically associated with poor prognosis. Moreover, we identified IL-16 as a critical TTP-regulated chemotactic factor that contributes to MO/MΦ migration.

Azimzadeh P, Romani S, Mohebbi SR, et al.
Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population.
Cancer Genet. 2012; 205(10):501-7 [PubMed] Related Publications
MicroRNAs (miRNAs) are agents of post-transcriptional gene expression, and they can affect many functions of an individual cell or tissue from extracellular matrix production to inflammatory processes and tumor development. We aimed to determine the possible role of miRNA-binding site polymorphisms located in five cancer-related genes: IL-16, CDKN2A (p16), RAF1, PTGER4, and ITGB4 in colorectal cancer (CRC) risk modification in an Iranian population. This study was performed on 643 individuals (249 CRC cases and 394 healthy controls). We selected five cancer-related genes (IL-16, CDKN2A (p16), RAF1, PTGER4, and ITGB4) and investigated the genotypes of the 3' untranslated region miRNA-binding site polymorphisms in these genes in our study population. The restriction fragment length polymorphism results were confirmed by a direct sequencing method. We found a statistically significant difference between the rs1131445 polymorphism of the IL-16 gene and CRC. The frequencies of the genotypes TT, CT, and CC in controls were 51%, 40.4%, and 8.6%, respectively, and in cases were 41.4%, 44.1%, and 14.5%, respectively, which shows a significant association between the CC genotype of the rs1131445 polymorphism and CRC (P = 0.004). The frequency of the C allele in the CRC group was higher than in the controls, and the C allele of the rs1131445 polymorphism was found to be in association with CRC (P = 0.009). These associations remained significant after Bonferroni's correction for multiple testing. We found that the AA genotype of the rs743554 polymorphism in the ITGB4 gene and the T allele of the rs1051208 polymorphism of the RAF1 gene were associated with the risk of CRC in females; however, after Bonferroni's correction we found that they were non-significant. Finally, we can conclude that a significant relationship exists between the miRNA-binding site polymorphism of the IL-16 gene and CRC risk in the Iranian population.

Batai K, Shah E, Murphy AB, et al.
Fine-mapping of IL16 gene and prostate cancer risk in African Americans.
Cancer Epidemiol Biomarkers Prev. 2012; 21(11):2059-68 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer.
METHODS: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry.
RESULTS: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10(-8)). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes.
CONCLUSION: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs.
IMPACT: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs.

Atanackovic D, Hildebrandt Y, Templin J, et al.
Role of interleukin 16 in multiple myeloma.
J Natl Cancer Inst. 2012; 104(13):1005-20 [PubMed] Related Publications
BACKGROUND: Multiple myeloma is a malignancy characterized by the expansion of a plasma cell clone that localizes to the human bone marrow. Myeloma cells and bone marrow stromal cells produce soluble factors that promote the survival and progression of multiple myeloma. Interleukin 16 (IL-16) is involved in regulating the migration and proliferation of normal leukocytes. However, the role of IL-16 in human cancers, including multiple myeloma, is unclear.
METHODS: We investigated IL-16 expression in cell lines (n = 10) and in the bone marrow of myeloma patients (n = 62) and healthy bone marrow donors (n = 12) by quantitative reverse transcription-polymerase chain reaction, immunoblot analysis, enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry. Transfection of two human multiple myeloma cell lines with small interfering RNAs was used to examine the effect of IL-16 gene silencing on apoptosis by flow cytometry, on proliferation by bromodeoxyuridine incorporation, and on colony formation. Protein neutralization assays were performed by treating multiple myeloma cells with a monoclonal antibody against the carboxyl-terminal fragment of IL-16. All statistical tests were two-sided.
RESULTS: IL-16 was strongly overexpressed in the bone marrow of myeloma patients compared with healthy donors. Myeloma cell lines as well as primary tumor cells from myeloma patients constitutively expressed IL-16 and its receptors CD4 and/or CD9 and spontaneously secreted soluble IL-16. Silencing of IL-16 reduced the proliferative activity of myeloma cells by approximately 80% compared with untreated cells (mean relative proliferative activity IL-16 siRNA vs untransfected cells, EJM cells: 20.1%, 95% confidence interval [CI] = 14.3% to 26.0%, P = .03; KMS-12-BM cells: 22.8%, 95% CI = 5.5% to 40.0%, P = .04), and addition of a recombinant carboxyl-terminal IL-16 peptide reversed that effect. A monoclonal antibody directed against IL-16 or its receptors had a comparably strong growth-inhibiting effect on the tumor cells.
CONCLUSIONS: IL-16 is an important growth-promoting factor in multiple myeloma and a candidate for novel diagnostic, prognostic, and therapeutic applications for this incurable human malignancy.

Azimzadeh P, Romani S, Mohebbi SR, et al.
Interleukin-16 (IL-16) gene polymorphisms in Iranian patients with colorectal cancer.
J Gastrointestin Liver Dis. 2011; 20(4):371-6 [PubMed] Related Publications
BACKGROUND AND AIMS: A number of theories have been put forward to clarify the etiology of colorectal cancer (CRC), such as genetic alterations and cytokine production. A combination of inflammatory cytokines has an important role in cancer development. The aim of our study was to screen for alterations located in promoter and exons of IL-16 gene sequence, to determine the distribution of genotypes in individuals with CRC and healthy controls in a sample of Iranian population.
METHODS: The case group consisted of 260 individuals with colorectal cancer and the control group included 405 healthy individuals. Three IL-16 gene polymorphisms (rs4072111, rs11556218, rs4778889) were genotyped using PCR-RFLP method. RFLP results were confirmed by direct sequencing.
RESULTS: A significant association between rs11556218 SNP in the IL-16 gene and the risk of CRC was found. The TG genotype of rs11556218 T/G polymorphism showed significant association with a 1.75 fold increased risk of CRC (P=0.005; adjusted OR: 1.759; 95% CI: 1.191-2.598). In addition a significant association between CC genotype of rs4778889 T/C polymorphism and decreased risk of CRC in male subjects (P=0.045; adjusted OR: 0.192; 95% CI: 0.038-0.967) was determined.
CONCLUSION: This study is the first report of IL-16 gene polymorphisms among CRC patients from Iran. Our results suggest an influence of rs11556218 T > G and rs4778889 T/C polymorphisms on the altered risk of CRC.

Curiel-Lewandrowski C, Yamasaki H, Si CP, et al.
Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma.
J Clin Invest. 2011; 121(12):4838-49 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro-IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent-kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro-IL-16. T cells isolated from 11 patients with advanced CTCL, but not those from healthy controls or patients with T cell acute lymphocytic leukemia (T-ALL), demonstrated reduction in nuclear pro-IL-16 levels. Sequence analysis identified the presence of mutations in the 5' end of the PDZ1 region of pro-IL-16, a domain required for association of pro-IL-16 with the nuclear chaperone HSC70 (also known as HSPA8). HSC70 knockdown led to loss of nuclear translocation by pro-IL-16 and subsequent increases in Skp2 levels and decreases in p27Kip1 levels, which ultimately enhanced T cell proliferation. Thus, our data indicate that advanced CTCL cell growth is facilitated, at least in part, by mutations in the scaffold protein pro-IL-16, which directly regulates Skp2 synthesis.

Li S, Deng Y, Chen ZP, et al.
Genetic polymorphism of interleukin-16 influences susceptibility to HBV-related hepatocellular carcinoma in a Chinese population.
Infect Genet Evol. 2011; 11(8):2083-8 [PubMed] Related Publications
AIM: Interleukin-16 (IL16) as a multifunctional cytokine, plays a key role in inflammatory and autoimmune diseases as well as tumour growth and progression. Recently, genetic polymorphisms of IL16 have been reported to be associated with susceptibility to a range of cancers. This study was undertaken to investigate the IL16 gene polymorphisms and determine whether these genetic factors are related to the occurrence of hepatocellular carcinoma (HCC) in a Chinese population.
METHODS: We analyzed three polymorphisms of the IL16 gene (rs11556218T/G, rs4072111C/T and rs4778889T/C) in 206 patients with HBV-related HCC, 270 chronic hepatitis B patients and 264 healthy controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and DNA sequencing technology.
RESULTS: IL16 polymorphisms were not associated with risk of HCC when compared with healthy controls. However, IL16 polymorphisms were significantly associated with susceptibility to HBV-related HCC when using chronic hepatitis B patients as controls. The rs11556218T/G TG and GG genotypes were associated with significantly increased risk of HBV-related HCC compared with the TT genotype (OR = 1.96 and OR = 3.33). The data also revealed that subjects with the G allele appeared to have higher susceptibility to HBV-related HCC than those with the T allele (OR = 2.10). Under the dominant model genotype TG+GG appeared to be associated with an increased risk of HBV-related HCC (OR = 2.18). The rs4072111C/T TT genotype was associated with a significantly increased risk of HBV-related HCC compared with the CC genotype (OR = 6.67). Polymorphisms of the IL16 gene were significantly associated with susceptibility to chronic hepatitis B when using healthy subjects as controls. The rs11556218T/G TG and GG genotypes were associated with significantly decreased risk of chronic hepatitis B compared with the TT genotype (OR = 0.49 and OR = 0.29). The data also revealed that subjects with the G allele appeared to have lower susceptibility to chronic hepatitis B than those with the T allele (OR = 0.46). Under the dominant model genotype TG + GG appeared to have lower susceptibility to chronic hepatitis B (OR = 0.44).
CONCLUSIONS: This study showed that the genotypes and allele of IL16 SNPs were associated with chronic HBV infection and HCC. However, further investigation with a larger sample size and haplotype analysis with other SNPs may be required to validate the genetic effects of the IL16 polymorphisms on chronic HBV infection and HCC.

de Chaisemartin L, Goc J, Damotte D, et al.
Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer.
Cancer Res. 2011; 71(20):6391-9 [PubMed] Related Publications
De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies.

Compérat E, Rouprêt M, Drouin SJ, et al.
Tissue expression of IL16 in prostate cancer and its association with recurrence after radical prostatectomy.
Prostate. 2010; 70(15):1622-7 [PubMed] Related Publications
BACKGROUND: Genetic polymorphism located within the IL16 gene has been reported to be associated with aggressive prostate cancer (PCa). Our aim was to establish whether the tissue expression of IL16 is a prognostic factor of survival in PCa.
METHODS: The files of patients who underwent radical prostatectomy (RP) between 1995 and 2001 were reviewed. The cases were selected and classified according to the D'Amico classification for risk of recurrence (intermediate or high). The value of IL16 and its receptor CCR5 (chemokine (C-C motif) receptor 5) expression levels were determined as witness of aggressiveness patterns and markers of biological relapse in patients with PCa treated by RP. A tissue microarray of 304 cases was constructed. IL16 and CCR5 expression levels were characterized by immunohistochemistry.
RESULTS: IL16 expression was correlated with high Gleason score (i.e., >7) (P < 0.01). It was not significant for CCR5. IL16 and CCR5 were not associated with prostate-specific antigen (PSA) or capsular extension of the disease. The accurate prediction of disease outcome, using stratification of cases, according to negative margins and D'Amico classification was significantly enhanced by status of IL16 expression (P ≤ 0.01). In univariate analyses, Gleason score, PSA level, stage and loss of IL16 expression were related to better biological-free survival (P < 0.05) but not CCR5. In a multivariate analysis, IL16 expression, Gleason score, and tumor stage were independent factors for biochemical-free survival (P = 0.001).
CONCLUSIONS: IL16 appears to be a useful prognostic factor in PCa. Its expression in PCa tissue was correlated to tumor aggressiveness and biochemical relapse of the disease.

Zhu J, Qin C, Yan F, et al.
IL-16 polymorphism and risk of renal cell carcinoma: association in a Chinese population.
Int J Urol. 2010; 17(8):700-7 [PubMed] Related Publications
OBJECTIVES: Interleukin-16 (IL-16) plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. A T-to-C polymorphism at the -295 position in the promoter region of the IL-16 gene has been described. This variation might lead to altered IL-16 expression, and might modulate an individual's susceptibility to cancer. The objective of the present study was to determine if IL-16 polymorphism is associated with risk of renal cell carcinoma (RCC).
METHODS: A case-control study including 335 RCC cases and 340 cancer-free controls was carried out. All subjects were genetically unrelated ethnic Han Chinese recruited from a single institution between July 2006 and July 2009. The IL-16 -295 T>C polymorphism was determined by using the polymerase chain reaction-restriction fragment length polymorphism method. Serum samples were available for 70 RCC cases and 96 controls to detect IL-16 concentration.
RESULTS: Compared with the IL-16 -295 TT genotype, the CC genotype had a significantly decreased RCC risk (adjusted odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.18-0.66). Furthermore, a significant decreased risk of RCC was found in the combined variant genotypes CT + CC compared with the TT genotype (adjusted OR = 0.68, 95% CI = 0.50-0.93). In addition, the serum IL-16 levels in RCC patients were significantly lower than those in controls (P < 0.001). Furthermore, patients carrying CC genotype or CT genotype had higher serum IL-16 levels than TT carriers.
CONCLUSION: IL-16 -295 T>C polymorphism is significantly associated with a higher risk of developing RCC in Chinese population.

Gao LB, Liang WB, Xue H, et al.
Genetic polymorphism of interleukin-16 and risk of nasopharyngeal carcinoma.
Clin Chim Acta. 2009; 409(1-2):132-5 [PubMed] Related Publications
BACKGROUND: Common genetic variants in inflammatory cytokine genes can affect the risk of developing nasopharyngeal carcinoma (NPC). Interleukin-16 (IL-16), a pro-inflammatory cytokine, plays a pivotal role in inflammatory diseases as well as in the pathogenesis of tumors.
METHODS: We analyzed rs4778889 T/C, rs11556218 T/G, and rs4072111 C/T polymorphisms of IL-16 in 206 patients with NPC and 373 healthy controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and DNA sequencing methods.
RESULTS: The rs11556218 T/G polymorphism of IL-16 gene was significantly associated with the susceptibility to NPC. The TG genotype was associated with a significantly higher risk of NPC as compared with the TT genotype (OR=1.67; 95% CI, 1.18-2.36). Patients carrying the G allele had a significantly higher risk for developing NPC compared to individuals carrying the T allele (OR=1.36; 95% CI, 1.03-1.78).
CONCLUSIONS: This study shows an association between IL-16 gene polymorphisms and the risk of NPC, and our data suggests that IL-16 gene polymorphisms may be useful as genetic susceptibility markers for NPC.

Enjuanes A, Benavente Y, Bosch F, et al.
Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia.
Cancer Res. 2008; 68(24):10178-86 [PubMed] Related Publications
To identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), we performed a case-control study genotyping 768 single-nucleotide polymorphisms (SNP) in 692 cases of CLL and 738 controls. We investigated nonsynonymous SNPs, SNPs with potential functional effect, and tag SNPs in regulatory gene regions in a total of 172 genes involved in cancer biology. After adjustment for multiple testing, we found a strong association between CLL risk and six genetic variants: CCNH (rs2266690, V270A), APAF1 (rs17028658, 3'region), IL16 (rs4505265, first intron), CASP8 (rs1045485, D302H), NOS2A (rs2779251, promoter), and CCR7 (rs3136687, intron 1). We found association with CLL susceptibility and 22 haplotypes in APAF1, IL6, TNFRSF13B, IL16, CASP3, CCR7, LTA/TNF, BAX, BCL2, CXCL12, CASP10/CASP8, CASP1, CCL2, BAK1, and IL1A candidate genes. Finally, we evaluated using public data sets the potential functional effect on gene expression levels of the CLL associated genetic variants detected in regulatory regions. Minor alleles for APAF1 and IL16 were associated with lower mRNA levels; no expression differences were observed for CCR7, whereas NOS2A could not be assessed. This study suggests that common genetic variation in apoptosis- and immunoregulation-related genes is associated with the CLL risk.

Gao LB, Rao L, Wang YY, et al.
The association of interleukin-16 polymorphisms with IL-16 serum levels and risk of colorectal and gastric cancer.
Carcinogenesis. 2009; 30(2):295-9 [PubMed] Related Publications
Interleukin (IL)-16, a multifunctional cytokine, plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. Genetic variation in the DNA sequence of the IL-16 gene may lead to altered cytokine production and/or activity, and this variation may modulate an individual's susceptibility to both colorectal cancer (CRC) and gastric cancer (GC). To test this hypothesis, we investigated the association of IL-16 gene polymorphisms with serum levels of IL-16 and the risk of CRC and GC in a Chinese population. We analyzed single-nucleotide polymorphisms of the IL-16 gene in 596 cancer patients (376 patients with CRC and 220 patients with GC), and also in 480 age- and sex-matched controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Serum IL-16 levels were measured by enzyme-linked immunosorbent assay. The rs11556218 T/G polymorphism of the IL-16 gene was significantly associated with the susceptibility to CRC and GC patients. Both male and female patients carrying the G allele had a significantly higher risk for developing CRC and GC compared with individuals carrying the T allele. Alternatively, women carrying the T allele (rs4072111 C/T) showed a decreased risk for CRC and GC compared with individuals carrying the C allele. In patients with CRC or GC, IL-16 serum levels were significantly higher than those in the healthy controls, although no significant association between IL-16 polymorphisms and serum levels of IL-16 was observed. Our data indicate that IL-16 polymorphisms may contribute to CRC and GC susceptibility.

Colt JS, Rothman N, Severson RK, et al.
Organochlorine exposure, immune gene variation, and risk of non-Hodgkin lymphoma.
Blood. 2009; 113(9):1899-905 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Organochlorine exposure was linked to non-Hodgkin lymphoma (NHL) risk. To determine whether this relation is modified by immune gene variation, we genotyped 61 polymorphisms in 36 immune genes in 1172 NHL cases and 982 controls from the National Cancer Institute-Surveillance, Epidemiology, and End Results (NCI-SEER) study. We examined 3 exposures with elevated risk in this study: PCB180 (plasma, dust measurements), the toxic equivalency quotient (an integrated functional measure of several organochlorines) in plasma, and alpha-chlordane (dust measurements, self-reported termiticide use). Plasma (100 cases, 100 controls) and dust (682 cases, 513 controls) levels were treated as natural log-transformed continuous variables. Unconditional logistic regression was used to calculate beta coefficients and odds ratios, stratified by genotype. Associations between all 3 exposures and NHL risk were limited to the same genotypes for IFNG (C-1615T) TT and IL4 (5'-UTR, Ex1-168C>T) CC. Associations between PCB180 in plasma and dust and NHL risk were limited to the same genotypes for IL16 (3'-UTR, Ex22+871A>G) AA, IL8 (T-251A) TT, and IL10 (A-1082G) AG/GG. This shows that the relation between organochlorine exposure and NHL risk may be modified by particular variants in immune genes and provides one of the first examples of a potential gene-environment interaction for NHL.

Yang EV, Kim SJ, Donovan EL, et al.
Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression.
Brain Behav Immun. 2009; 23(2):267-75 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Studies suggest that stress can be a co-factor for the initiation and progression of cancer. The catecholamine stress hormone, norepinephrine (NE), may influence tumor progression by modulating the expression of factors implicated in angiogenesis and metastasis. The goal of this study was to examine the influence of NE on the expression of VEGF, IL-8, and IL-6 by the human melanoma cell lines, C8161, 1174MEL, and Me18105. Cells were treated with NE and levels of VEGF, IL-8, and IL-6 were measured using ELISA and real-time PCR. The expression of beta-adrenergic receptors (beta-ARs) mRNA and protein were also assessed. Finally, immunohistochemistry was utilized to examine the presence of beta1- and beta2-AR in primary and metastatic human melanoma biopsies. We show that NE treatment upregulated production of VEGF, IL-8, and IL-6 in C8161 cells and to a lesser extent 1174MEL and Me18105 cells. The upregulation was associated with induced gene expression. The effect on C8161 cells was mediated by both beta1- and beta2-ARs. Furthermore, 18 of 20 melanoma biopsies examined expressed beta2-AR while 14 of 20 melanoma biopsies expressed beta1-AR. Our data support the hypothesis that NE can stimulate the aggressive potential of melanoma tumor cells, in part, by inducing the production VEGF, IL-8, and IL-6. This line of research further suggests that interventions targeting components of the activated sympathetic-adrenal medullary (SAM) axis, or the utilization of beta-AR blocking agents, may represent new strategies for slowing down the progression of malignant disease and improving cancer patients' quality of life.

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