Gene Summary

Gene:IL17A; interleukin 17A
Aliases: IL17, CTLA8, IL-17, CTLA-8, IL-17A
Summary:The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO). High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL17A (cancer-related)

Tian CH, Dai J, Zhang W, et al.
Expression of IL-17 and its gene promoter methylation status are associated with the progression of chronic hepatitis B virus infection.
Medicine (Baltimore). 2019; 98(23):e15924 [PubMed] Free Access to Full Article Related Publications
To explore interleukin-17 (IL-17) and its epigenetic regulation during the progression of chronic hepatitis B virus (HBV) infection.A total of 162 patients with chronic HBV infection, including 75 with chronic hepatitis B (CHB), 54 with hepatitis B-associated liver cirrhosis and 33 with hepatitis B-associated hepatocellular carcinoma (HBV-HCC), were enrolled in this study. Thirty healthy adults of the same ethnicity were enrolled in the control group. Whole venous blood was obtained from the patients and normal controls (n = 30). Clinical and laboratory parameters were assessed, and we performed enzyme-linked immunosorbent assay and quantitative real-time PCR to measure the serum levels and relative mRNA expression of IL-17, respectively. IL-17 promoter methylation in peripheral blood mononuclear cells was assessed by methylation-specific PCR. We analyzed the serum and mRNA levels of IL-17 and IL-17 promoter methylation in the 4 groups as well as the effect of methylation on serum IL-17 levels. Correlations between the IL-17 promoter methylation status and clinical parameters were analyzed by Spearman correlation analysis.Compared to the normal control group, the patient groups exhibited significantly higher serum and relative mRNA levels of IL-17. The methylation distribution among the patients was significantly lower than that among the normal controls (P < .05), with the HBV-HCC group showing the lowest IL-17 gene methylation frequency. The average IL-17 promoter CG methylation level was negatively correlated with IL-17 mRNA expression (r = -0.39, P = .03), and negative correlations between IL-17 promoter methylation and prothrombin time activity (r = -0.585, P = .035), alanine aminotransferase (r = -0.522, P < .01), aspartate aminotransferase (r = -0.315, P < .05), and the model for end-stage liver disease score (r = -0.461, P < .05) were observed. IL-17 serum levels in the methylated-promoter groups were significantly lower than those in the unmethylated-promoter groups.IL-17 expression and promoter methylation were associated with chronic HBV infection progression, especially in the HBV-HCC group. The IL-17 promoter status may help clinicians initiate the correct treatment strategy at the CHB stage.

Rudnicka K, Backert S, Chmiela M
Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences.
Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed] Related Publications
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.

Barilla RM, Diskin B, Caso RC, et al.
Specialized dendritic cells induce tumor-promoting IL-10
Nat Commun. 2019; 10(1):1424 [PubMed] Free Access to Full Article Related Publications
The drivers and the specification of CD4

Li T, Li M, Xu C, et al.
miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6.
Oncol Rep. 2019; 41(5):2897-2908 [PubMed] Related Publications
The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

Mohammadipour K, Mansouri R, Salmanpour R, et al.
Investigation of Interleukin-17 Gene Polymorphisms and Serum Levels in Patients with Basal Cell Carcinoma of the Skin.
Iran J Immunol. 2019; 16(1):53-61 [PubMed] Related Publications
BACKGROUND: Interleukin 17 (IL-17) is a pro-inflammatory cytokine that plays an important role in cancer pathogenesis.
OBJECTIVE: To investigate the association of two IL-17 gene polymorphisms (rs2275913 and rs763780), as well as IL-17 serum levels with susceptibility to Basal Cell Carcinoma (BCC) of skin.
METHODS: Two hundred subjects with BCC and 200 healthy controls were recruited. DNA was extracted from peripheral blood leukocytes and genotypes were determined using PCR-RFLP methods. Serum levels were assessed by ELISA.
RESULTS: At position rs2275913 in IL-17A, the frequencies of GG, AG and AA genotypes were 99 (49.5%), 76 (38%) and 25 (12.5%) in patients and 97 (48.5%), 84 (42%) and 19 (9.5%) in the control group. The distribution of AA, GA and GG genotypes at position rs763780 in IL-17F were 166 (83%), 34 (17%) and 0 (0%) in patients and 158 (79%), 40 (20%) and 2 (1%) in the control group. Haplotype analysis by Arlequin software package revealed that GA haplotype was the most frequent haplotype in both groups. No significant differences were found in alleles, genotypes, and haplotypes frequencies between study groups at both positions (P>0.05). While no difference in IL-17 serum levels was observed between individuals with different genotypes, statistical analysis showed higher IL-17A serum levels, but not IL-17F, in patients compared to controls (0.65 ± 0.11 and 0.03 ± 0.02 pg/ml), respectively, (P<0.001).
CONCLUSION: Our findings do not support the association of rs763780 and rs2275913 gene polymorphisms in IL-17gene with susceptibility of Iranians with BCC. Increased IL-17A serum levels may still play a role in pathogenesis of BCC.

Wang JS, Wang YG, Zhong YS, et al.
Identification of co-expression modules and pathways correlated with osteosarcoma and its metastasis.
World J Surg Oncol. 2019; 17(1):46 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma is the most common bone tumor that occurs in children.
METHODS: To identify co-expression modules and pathways correlated with osteosarcoma and its clinical characteristics, we performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data of osteosarcoma with 52 samples. Then we performed pathway enrichment analysis on genes from significant modules.
RESULTS: A total of 5471 genes were included in WGCNA, and 16 modules were identified. Module-trait analysis identified that a module involved in microtubule bundle formation, drug metabolism-cytochrome P450, and IL-17 signaling pathway was negatively correlated with osteosarcoma and positively correlated with metastasis; a module involved in DNA replication was positively correlated with osteosarcoma; a module involved in cell junction was positively correlated with metastasis; and a module involved in heparin binding negatively correlated with osteosarcoma. Moreover, expression levels in four of the top ten differentially expressed genes were validated in another independent dataset.
CONCLUSIONS: Our analysis might provide insight for molecular mechanisms of osteosarcoma.

Duan M, Goswami S, Shi JY, et al.
Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma.
Clin Cancer Res. 2019; 25(11):3304-3316 [PubMed] Related Publications
PURPOSE: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).
RESULTS: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7
CONCLUSIONS: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.

Khodabandehlou N, Mostafaei S, Etemadi A, et al.
Human papilloma virus and breast cancer: the role of inflammation and viral expressed proteins.
BMC Cancer. 2019; 19(1):61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is currently the most common neoplasm diagnosed in women globally. There is a growing body of evidence to suggest that human papillomavirus (HPV) infection may play a key role in invasiveness of breast cancer. The aim of this study was to determine the presence of HPV in patients with breast cancer and its possible association with cancer progression.
METHODS: Breast specimens were collected from 72 patients with breast cancer and 31 healthy controls. The presence of HPV was investigated by polymerase chain reaction (PCR) and genotyping was performed for positive cases. We also evaluated the viral factors such as E6, E2, and E7 in HPV positive cases. Enzyme-linked immunosorbent assay (ELISA (and Real-time PCR techniques were used to measure the expression level of anti-carcinogenic genes, such as p53, retinoblastoma (RB), breast and ovarian cancer susceptibility gene (BRCA1, BRCA2) and inflammatory cytokines, including tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), nuclear factor-kB (NF-kB), and different interleukins [ILs] (IL-1,IL6, and IL-17).
RESULTS: The HPV DNA was detected in 48.6% of breast cancer samples, whereas only 16.1% of controls were positive for HPV. We observed statistically significant differences between breast cancer patients and HPV presence (P = 0.003). HPV type 18 was the most prevalent virus genotype in patients. The expression of P53, RB, BRCA1, and BRCA2 were decreased in patients with HPV-positive breast cancer as compared to HPV-negative breast cancer and healthy controls. (All P-values were less than 0.05). The presence of the HPV was associated with increased inflammatory cytokines (IL-1, IL-6, IL-17, TGF-β, TNF-α, and NF-kB) and tumor progression.
CONCLUSION: The present study demonstrated that HPV infection may implicate in the development of some types of breast cancer.

Zheng X, Dong L, Wang K, et al.
MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection.
Ann Surg Oncol. 2019; 26(3):884-893 [PubMed] Related Publications
BACKGROUND: The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4
METHODS: In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured.
RESULTS: In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells.
CONCLUSIONS: Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.

Li N, Wang J, Yu W, et al.
MicroRNA‑146a inhibits the inflammatory responses induced by interleukin‑17A during the infection of Helicobacter pylori.
Mol Med Rep. 2019; 19(2):1388-1395 [PubMed] Related Publications
Helicobacter pylori (H. pylori) infection is the major cause of chronic active gastritis and peptic ulcer disease. Upregulation of IL‑17A is associated with H. pylori infection in the gastric mucosa; however, the factors involved in the regulation of interleukin (IL)‑17A‑induced inflammatory responses in H. pylori‑associated gastritis remain unknown. MicroRNAs (miRNAs) serve as key post‑transcriptional regulators of gene expression and are associated with the H. pylori infection. The present study aimed to analyze the effects of IL‑17A on the expression of miR‑146a upon infection with H. pylori, as well as to identify the possible impact of miR‑146a dysregulation on the inflammatory response in vivo and in vitro. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression levels of miR‑146a in gastric epithelial cells upon IL‑17A stimulation. The effects of miR‑146a mimics on IL‑17A‑induced inflammatory responses in SGC‑7901 cells were evaluated. The effects of miR‑146a mimics on the expression levels of IL‑1 receptor‑associated kinase 1 (IRAK1) and tumor necrosis factor receptor‑associated factor 6 (TRAF6) upon IL‑17A treatment were analyzed, and the IL‑17A‑stimulated inflammation following the silencing of IRAK1 and TRAF6 was observed. In addition, the correlation between miR‑146a and IL‑17A in human gastric mucosa with H. pylori was examined. The results indicated that IL‑17A‑induced miR‑146a may regulate the inflammatory response during the infection of H. pylori in a nuclear factor‑κB‑dependent manner. Furthermore, the expression of miR‑146a and IL‑17A are positively correlated in human gastric mucosa infected with H. pylori. These data suggested that miR‑146a may serve as a biomarker or therapeutic target in gastritis therapy.

Orciani M, Caffarini M, Torresetti M, et al.
Breast Implant Texturization Does Not Affect the Crosstalk Between MSC and ALCL Cells.
Inflammation. 2019; 42(2):721-730 [PubMed] Related Publications
In the last decade, there has been a growing interest about the possible association between anaplastic large cell lymphoma (ALCL) and breast implants (BIA-ALCL). Many variables, such as breast implants texturization, have been investigated. Breast implants often lead to the formation of a periprosthetic capsule, characterized by inflammation. The presence of the inflamed capsule has been found in the majority of patients with BIA-ALCL. Inflammation may be sustained or counteracted by mesenchymal stem cells (MSCs) by the secretion of pro- or anti-inflammatory cytokines. MSCs were isolated from three capsules surrounding micro-textured (micro-MSCs) and from three capsules surrounding macro-textured (macro-MSCs) implants; after characterization, MSCs were co-cultured with KI-JK cells (a cell line derived from the cutaneous form of ALCL). The secretion of cytokines related to inflammation, the proliferation rate, and the expression of genes referred to pro-tumoral mechanisms were evaluated. Co-cultures of KI-JK cells with micro- or macro-MSCs gave the same results about the secretion of cytokines (increase of IL10, G-CSF, and TGF-β1 and decrease of IL4, IL5, IL12, IL13, IL17A, IFN-γ (p < 0.05) with respect to mock sample), expression of selected genes (increase for ACVR1, VEGF, TGF-βR2, CXCL12, and MKi67 (p < 0.05) with respect to control sample), and the proliferation rate (no variation between mock and co-cultured samples). Our results suggest that MSCs derived from capsules surrounding micro- and macro-textured implants display the same effects on the ALCL cells.

Zeng C, Chen L, Chen B, et al.
Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(12):1266-1273 [PubMed] Related Publications
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1β, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis.

Khatoon J, Prasad KN, Rai RP, et al.
Expression levels of A disintegrin and metalloproteases (ADAMs), and Th17-related cytokines and their association with Helicobacter pylori infection in patients with gastroduodenal diseases.
Pathog Dis. 2018; 76(8) [PubMed] Related Publications
Expression levels of A disintegrin and metalloproteases (ADAMs) (10 and 17) and Th17-related cytokines [interleukin (IL) 17A, IL-17F, IL-33, IL-23, IL-23R] were investigated by quantitative real time polymerase chain reaction in gastric biopsies of patients with different gastroduodenal pathologies in the presence and absence of Helicobacter pylori infection. Patients with gastric cancer (GC) (n = 70, intestinal-type 38 and diffuse type 32), peptic ulcer disease [n = 50, duodenal ulcer (DU) 16 and gastric ulcer (GU) 34] and functional dyspepsia (n = 120) were included in the study. Further, the expression levels of ADAMs and Th17 cytokines were correlated with H. pylori cytotoxin-associated genes pathogenicity island (cagPAI) status. Expression levels of ADAMs (10 and 17) and Th17-related cytokines (IL-17A, IL-23, IL-23R) were significantly higher in H. pylori-positive than in H. pylori-negative gastric biopsies. Significant increase in ADAM17 and Th17 cytokines (IL-17A and IL-23) expressions was observed in patients with GU and intestinal-type GC in the presence of H. pylori infection and in strains harbouring intact cagPAI. Expression levels of IL-17A, IL-23 and ADAM17 were strongly correlated with GU and intestinal-type GC and weakly with DU and diffuse-type GC in the presence of H. pylori infection. Higher expression levels of ADAM17 and Th17 cytokines (IL-17A and IL-23), and their strong correlation with GU and intestinal-type GC patients in the presence of H. pylori and its intact cagPAI status, suggest a possible role of strain specificity in the pathogenesis of these diseases.

Hao S, Chen X, Wang F, et al.
Breast cancer cell-derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells.
Carcinogenesis. 2018; 39(12):1488-1496 [PubMed] Related Publications
Interleukin 35 (IL-35) is a potent immunosuppressive cytokine, consisting of an Epstein-Barr virus-induced gene 3 (EBI3) subunit and a p35 subunit. IL-35 is mainly produced by regulatory T and regulatory B cells, and plays a crucial role in the development and prevention of infectious and autoimmune diseases. However, the effect of IL-35 in malignant disease is not well understood. In this study, we demonstrated that breast cancer cells (BCCs) also expressed and secreted IL-35 and higher level of IL-35 in BCCs was closely associated with poor prognosis of patients and was an independent unfavorable prognostic factor for breast cancer. Subsequent study revealed that BCC-derived IL-35 inhibited conventional T (Tconv) cell proliferation and further induced suppressed Tconv cells into IL-35-producing induced regulatory T (iTr35) cells. Furthermore, BCC-derived IL-35 promoted the secretion of inhibitory cytokine IL-10 and obviously decreased the secretion of Th1-type cytokine IFN-γ and Th17-type cytokine IL-17 in Tconv cells. Meanwhile, the expression of inhibitory receptor CD73 was also elevated on the surface of Tconv cells following the BCCs' supernatant treatment. Mechanistically, BCC-derived IL-35 exhausted Tconv cells and induced iTr35 by activating transcription factor STAT1/STAT3. Hence, our results indicate functions of BCC-derived IL-35 in promoting tumor progression through proliferation inhibition of tumor-infiltrating Tconv cells and induction of iTr35 cells in tumor microenvironment. This study highlights that IL-35 produced by BCCs are a potential therapeutic target for breast cancer.

Subramanian K, Dierckx T, Khouri R, et al.
Decreased RORC expression and downstream signaling in HTLV-1-associated adult T-cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?
Int J Cancer. 2019; 144(7):1664-1675 [PubMed] Free Access to Full Article Related Publications
Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in HTLV-1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4

Gonzalez-Hormazabal P, Romero S, Musleh M, et al.
Anticancer Res. 2018; 38(10):5703-5708 [PubMed] Related Publications
BACKGROUND/AIM: Inflammation is a key process in gastric carcinogenesis. Cytokines are mediators of inflammation and are involved in metastasis and tumorigenicity. We previously assessed the role of cytokine gene polymorphisms in gastric cancer risk in Chile. In the present study, we aimed to analyze whether these polymorphisms are associated with overall survival (OS) in gastric cancer (GC) patients.
PATIENTS AND METHODS: A total of 153 individuals with GC diagnosis were followed-up for at least 2 years. Hazard ratios (HR) were estimated from Cox regression models using SNPs as predictor variables. The following SNPs were genotyped for study using a TaqMan assay: rs16944 (IL1B -511C>T); rs4073 (IL8 -251 T>A); rs2275913 (IL-17 -197G>A); rs1800872 (IL10 -592 C>A); rs1800896 (IL10 -1082A>G); rs28372698 (IL32).
RESULTS: Interleukin-8 rs4073 (IL-8 -251T>A) showed association with OS under the dominant model (TA + AA) only when adjusted by clinicopathological variables (HR=1.64, 95%CI=1.05-2.55, p=0.030, q-value=0.18), but not with the univariate model (HR=1.51, 95%CI=0.98-2.31, p=0.062, q-value=0.37). No significant differences were observed after adjusting for population stratification (PC1 and PC2 from Principal Component Analysis using genotypes from Infinium Global Screening Array). After stratification by clinicopathological variables, the association with shorter overall survival was higher among patients with diffuse-type tumors (HR=2.24, 95%CI=1.16-4.45) and patients with tumor size >5 cm (HR=1.79, 95%CI=1.08-2.97).
CONCLUSION: These results suggest a role of IL-8 rs4073 in cancer prognosis. Its use as a prognostic marker of GC survival warrants further investigation.

Ye F, Song J, Wang Y, et al.
Proliferation Potential-Related Protein Promotes the Esophageal Cancer Cell Proliferation, Migration and Suppresses Apoptosis by Mediating the Expression of p53 and Interleukin-17.
Pathobiology. 2018; 85(5-6):322-331 [PubMed] Related Publications
OBJECTIVE: This study aims to investigate the mechanism of proliferation potential-related protein (PP-RP) in influencing the proliferation, migration, and apoptosis of esophageal cancer cells.
METHODS: Quantitative real-time PCR and western blotting were performed to analyze the expression of PP-RP gene, p53, and interleukin (IL)-17 in human normal tissues and tumor tissues, as well as the expression of p53 and IL-17 in Eca109 and TE3 cells. The esophageal cancer cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell apoptosis was detected by flow cytometry, and cell migration was detected by transwell migration.
RESULTS: PP-RP expressed highly in tumor tissue and Eca109 and TE3 cells, PP-RP overexpression inhibited the expression of p53 and promoted the expression of IL-17 in Eca109 and TE3 cells. PP-RP overexpression increased the expression of F-actin, promoted cell proliferation, and migration and suppressed cell apoptosis. Cell proliferation ability and cell migration ability were significantly strengthened while apoptosis was suppressed by PP-RP + pyruvate carboxylase deoxyribonucleic acid (PCDNA)-p53 group and PP-RP + IL-17 siRNA group in TE3 cells.
CONCLUSION: Our data suggest that PP-RP promotes esophageal cancer cell proliferation and migration, and suppresses apoptosis by mediating the expression of p53 and IL-17.

Meng S, Li L, Zhou M, et al.
Distribution and prognostic value of tumor‑infiltrating T cells in breast cancer.
Mol Med Rep. 2018; 18(5):4247-4258 [PubMed] Free Access to Full Article Related Publications
Tumor-infiltrating lymphocytes are associated with the response to neoadjuvent chemotherapy and prognosis in breast cancer. However, the distribution, interaction and prognostic value of tumor‑infiltrating T cells, the main component of the tumor microenvironment, have seldom been reported. In the present study, surgical specimens of 72 breast cancer patients were analyzed. Tumor‑infiltrating T cell subsets [cluster of differentiation (CD)4+T, CD8+T and regulatory T cells] and expression of their cytokines [interferon‑γ, interleukin (IL)‑4, and IL‑17] were evaluated by flow cytometry. These parameters together with The Cancer Genome Atlas database were used to demonstrate the distribution, interaction and prognostic value of tumor‑infiltrating T cells in breast cancer. Tumor‑infiltrating lymphocytes were closely associated with histological grade (P=0.03), estrogen receptor status (P=0.006), human epidermal growth factor receptor 2 status (P=0.047) and molecular subtype in breast cancer (P=0.012). The gene expression of CD4, CD8A and forkhead box protein P3 in the tumor was increased compared with healthy breast tissue, and was positively associated with the prognosis of breast cancer patients. HER2+ and triple‑negative breast cancer exhibited a significantly increased percentage of CD4+T cells (P=0.01) and regulatory T cells (P=0.035), and a decreased percentage of CD8+T cells (P=0.006) compared with the luminal subtype. Furthermore, the regulatory T cell number was positively correlated with CD8+T cell number in tumors (R=0.7, P=1.5x10‑162) and significantly inhibited the cytokine secretion of T cells. These results reveal the distribution and interaction of tumor‑infiltrating T cell subsets, and indicate that CD8+T cells and regulatory T cells may be used as reliable predictors of prognosis in breast cancer.

Fredericks E, Dealtry G, Roux S
Can J Gastroenterol Hepatol. 2018; 2018:4379673 [PubMed] Free Access to Full Article Related Publications
Background: The wnt/APC/
Methods: Using qPCR and IHC, we compared

Murakami I, Wada N, Nakashima J, et al.
Merkel cell polyomavirus and Langerhans cell neoplasm.
Cell Commun Signal. 2018; 16(1):49 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.
METHODS: We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.
RESULTS: We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.
CONCLUSION: We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.

Lv Q, Wu K, Liu F, et al.
Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer.
Int J Oncol. 2018; 53(4):1809-1817 [PubMed] Related Publications
Interleukin‑17A (IL‑17A) is a CD4 T-cell-derived pro-inflammatory cytokine that is involved in human cervical tumorigenesis. Heparanase (HPSE) is an endo-glycosidase expressed in mammals, which has been confirmed to be associated with cervical cancer invasion. In the present study, it was hypothesized that IL‑17A and HPSE are key proteins promoting tumor angiogenesis and cell proliferation and invasion in cervical cancer. The expression of IL‑17A and HPSE in cervical cancer tissues was detected by immunohistochemical staining. In addition, the expression of IL‑17A and HPSE was down- and upregulated via RNAi and human recombinant proteins, and MTT and Transwell assays were performed to examine cervical cancer cell proliferation and invasion, respectively. Flow cytometry analysis was also performed to detect cell cycle distribution, and the levels of target mRNA and protein were evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. IL‑17A and HPSE were highly expressed in cervical cancer tissues, and microvessel density was notably higher in the IL‑17A-positive group. IL‑17A and/or HPSE recombinant protein promoted the proliferation and invasion of cervical cancer cells, increased the proportion of cells in the G2/M phase, and enhanced the mRNA and protein expression of human papillomavirus E6, P53, vascular endothelial growth factor and CD31, whereas downregulation of IL‑17A and/or HPSE exerted the opposite effects. Furthermore, downregulation of IL‑17A and/or HPSE was found to inhibit the expression of nuclear factor (NF)-κB P65. In summary, IL‑17A and HPSE may promote tumor angiogenesis and cell proliferation and invasion in cervical cancer, possibly via the NF-κB signaling pathway. These findings may lead to the identification of new diagnostic markers and therapeutic targets.

Zhenjiang L, Rao M, Luo X, et al.
Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses Predict Improved Survival in Patients With Glioblastoma Multiforme.
EBioMedicine. 2018; 33:49-56 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM).
PATIENTS AND METHODS: Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics.
RESULTS: Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a 'partial' combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p < .0001) as well as T-cell responses to the survivin
CONCLUSION: Serum cytokine patterns and lymphocyte reactivity to survivin

Bhat AA, Lu H, Soutto M, et al.
Exposure of Barrett's and esophageal adenocarcinoma cells to bile acids activates EGFR-STAT3 signaling axis via induction of APE1.
Oncogene. 2018; 37(46):6011-6024 [PubMed] Free Access to Full Article Related Publications
The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL-17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis.

De Matteis S, Molinari C, Abbati G, et al.
Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients.
J Transl Med. 2018; 16(1):172 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4
METHODS: Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n = 25) and healthy volunteers (n = 25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT
RESULTS: In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4
CONCLUSIONS: Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.

Guan X, Liu Z, Zhang J, Jin X
Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors.
Adv Clin Exp Med. 2018; 27(7):947-953 [PubMed] Related Publications
BACKGROUND: Myeloid-derived suppressor cells (MDSC) play an important role in tumor-mediated immune evasion. Levels of MDSC in peripheral blood are increased in patients with cancer, correlating with cancer stage and outcome. Studies have confirmed the associations between MDSC and various cytokines in the peripheral blood of murine and human cancer hosts. However, little is known about the association between parenchymal MDSC subsets and cytokines, or the mechanism drawing MDSC into tumor parenchyma.
OBJECTIVES: The aim of this study was to analyze the correlation between MDSC subsets and tumor grade as well as stage in renal cell carcinoma (RCC) patients. The expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin 17 (IL-17) and interleukin 18 (IL-18) in the peripheral blood and parenchyma of RCC patients was also detected to explore its correlation with MDSC accumulation.
MATERIAL AND METHODS: Total MDSC, granulocytic MDSC (G-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the blood and parenchyma were isolated and analyzed by flow cytometry. Cytokines were detected by the enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR) and western blot in blood and tumors.
RESULTS: Parenchymal levels of MDSC had a positive correlation with levels of CCL2, IL-17, and IL-18, suggesting these cytokines may attract MDSC into the parenchyma. Moreover, peripheral total MDSC, G-MDSC and I-MDSC were shown to correlate with tumor grade and stage. Gene and protein expression of CCL2, IL-17, and IL-18 was significantly increased in blood and tumors of RCC patients.
CONCLUSIONS: Our study has provided potential new targets for the risk stratification of patients with limited stages of renal carcinoma, in addition to elucidating a possible association between MDSC subsets and cytokine-induced migration into the tumor tissue.

Elshazli RM, Salman DO, Kamel MM, et al.
Genetic polymorphisms of IL-17A rs2275913, rs3748067 and IL-17F rs763780 in gastric cancer risk: evidence from 8124 cases and 9873 controls.
Mol Biol Rep. 2018; 45(5):1421-1444 [PubMed] Related Publications
Interleukin-17 (IL-17) is a critical cytokine involved in inflammation-associated cancers. Single nucleotide polymorphisms (SNPs) might promote carcinogenesis. In this current meta-analysis, we investigated the association of IL-17A and IL-17F gene polymorphisms with gastric cancer (GC) risk. Eligible genetic association studies were retrieved from PubMed, Web of Science and Scopus database sources. Two reviewers independently assessed methodological quality and extracted data from eligible articles. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Quantitative data synthesis was conducted using comprehensive meta-analysis v2. Subgroup analysis and heterogeneity analysis were performed. Begg's funnel plot and Egger's regression tests were used to judge publication bias. In silico data analysis was executed to analyze the functional and structural impact of the SNPs. A total of 21 case-control studies for rs2275913 c.-197G > A (7660 patients and 9409 controls), 9 studies for rs3748067 c.*1249C > T (3378 patients and 4120 controls), and 14 studies for rs763780 c.482A > G (4481 patients and 5354 controls) were included. The pooled estimate revealed an association between IL-17A rs2275913 polymorphism and the risk of GC under all genetic models (A vs. G, OR 1.187, 95% CI 1.086-1.297, P < 0.001; GA vs. GG, OR 1.108, 95% CI 1.008-1.218, P = 0.033; AA vs. GG, OR 1.484, 95% CI 1.236-1.781, P < 0.001), while no evidence of association was found with IL-17A rs3748067 or IL-17F rs763780 polymorphisms. Our results showed that IL-17A promoter rs2275913 variant might represent a potential risk factor for gastric cancer susceptibility.

Crespo J, Wu K, Li W, et al.
Human Naive T Cells Express Functional CXCL8 and Promote Tumorigenesis.
J Immunol. 2018; 201(2):814-820 [PubMed] Free Access to Full Article Related Publications
Naive T cells are thought to be functionally quiescent. In this study, we studied and compared the phenotype, cytokine profile, and potential function of human naive CD4

Dong Z, Zhu X, Li Y, et al.
Oncogenomic analysis identifies novel biomarkers for tumor stage mycosis fungoides.
Medicine (Baltimore). 2018; 97(21):e10871 [PubMed] Free Access to Full Article Related Publications
Patients with mycosis fungoides (MF) developing tumors or extracutaneous lesions usually have a poor prognosis with no cure has so far been available. To identify potential novel biomarkers for MF at the tumor stage, a genomic mapping of 41 cutaneous lymphoma biopsies was used to explore for significant genes.The gene expression profiling datasets of MF were obtained from Gene Expression Omnibus database (GEO). Gene modules were simulated using Weighted Gene Co-expression Network Analysis (WGCNA) and the top soft-connected genes (hub genes) were filtrated with a threshold (0.5). Subsequently, module eigengenes were calculated and significant biological pathways were enriched based on the KEGG database.Four genetic modules were simulated with 3263 genes collected from the whole genomic profile based on cutoff values. Significant diseases genetic terminologies associated with tumor stage MF were found in black module. Subsequently, 13 hub genes including CFLAR, GCNT2, IFNG, IL17A, IL22, MIP, PLCG1, PTH, PTPN6, REG1A, SNAP25, SUPT7L, and TP63 were shown to be related to cutaneous T-cell lymphoma (CTCL) and adult T-cell lymphoma/leukemia (ATLL).In summary, in addition to the reported genes (IL17F, PLCG1, IFNG, and PTH) in CTCL/ATLL, the other high instable genes may serve as novel biomarkers for the regulation of the biological processes and molecular mechanisms of CTLT (MF/SS).

Khosravi N, Caetano MS, Cumpian AM, et al.
IL22 Promotes
Cancer Immunol Res. 2018; 6(7):788-797 [PubMed] Free Access to Full Article Related Publications

Wang LX, Kang ZP, Yang ZC, et al.
MicroRNA-135a Inhibits Nasopharyngeal Carcinoma Cell Proliferation Through Targeting Interleukin-17.
Cell Physiol Biochem. 2018; 46(6):2232-2238 [PubMed] Related Publications
BACKGROUND/AIMS: The objective of this study was to investigate the potential role of IL-17 in the development of nasopharyngeal carcinoma (NPC) and to screen microRNAs (miRNAs) that potentially target IL-17 in NPC cells.
METHODS: Blood was collected from NPC patients and normal subjects, and plasma IL-17 concentration was quantified by enzyme-linked immunosorbent assay. An immortalized normal human nasopharyngeal epithelial cell line, NP69, was treated with or without human IL-17 (15 ng/mL) for various times, and expression of IL-1ß, IL-6, IL-12, and TNF-α mRNA was assessed by real-time reverse transcription PCR. The candidate miRNAs that potentially target IL-17 were predicted by a bioinformatics strategy. The selected miR-135a mimic was transfected into primary NPC cells, and cell proliferation was assessed by MTT assay.
RESULTS: The concentration of plasma IL-17 was significantly higher in the NPC patients (92.5 ± 7.3 pg/mL) than in the control subjects (56.8 ± 2.9 pg/mL). In response to IL-17 treatment, the mRNA expression of IL-1ß and IL-6 was significantly upregulated and reached a peak at 12 h, followed by a slight decrease at 24 h, while the mRNA expression of IL-12 and TNF-α was significantly upregulated at 12 h and remained high even at 48 h after exposure to IL-17. Moreover, miR-135a specifically targets IL-17 and was dramatically downregulated in NPC cells compared with NP69 cells. Transfection of exogenous miR-135a mimic resulted in significant suppression of IL-17 secretion and subsequent inhibition of NPC cell proliferation.
CONCLUSIONS: Blood IL-17 was significantly higher in NPC patients compared with normal subjects. Expression of miR-135a in the cancer cells isolated from nasopharyngeal tumors was significantly lower than that in NP69 cells, and suppression of IL-17 by miR-135a mimic resulted in significant inhibition of NPC cell proliferation. These findings suggested that downregulation of miR-135a may contribute to the development of NPC via the mechanism of IL-17 stimulation of proinflammatory cytokine expression.

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