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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2017


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 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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)

Eiro N, Fernandez-Gomez J, Sacristán R, et al.
Stromal factors involved in human prostate cancer development, progression and castration resistance.
J Cancer Res Clin Oncol. 2017; 143(2):351-359 [PubMed] Related Publications
PURPOSE: To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
RESULTS: Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat-shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
CONCLUSIONS: These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).

Alinejad V, Hossein Somi M, Baradaran B, et al.
Co-delivery of IL17RB siRNA and doxorubicin by chitosan-based nanoparticles for enhanced anticancer efficacy in breast cancer cells.
Biomed Pharmacother. 2016; 83:229-240 [PubMed] Related Publications
Overexpression of IL17RB is associated with poor prognosis and short survival of the breast cancer patients.IL17RB/IL17B signaling triggers a substantial increase in the cell growth, proliferation and migration through the activation of NF-κB as well as the up-regulation of the Bcl-2. In this study we designed carboxymethyl dextran (CMD) Chitosan nanoparticles (ChNPs) to encapsulated IL17RB siRNA and doxorubicin (DOX) as an anticancer drug. Then we investigated the efficiency of the simultaneous delivery of drug/siRNA on viability and gene expression of MDA-MB361 cell lines. Furthermore the efficacy of dual agent nanoparticles to induce apoptosis and inhibit migration of breast cancer cells was assessed by Annexin-V and wound healing assays respectively. Our results showed that DOX-siRNA-CMD-ChNPs had about 114nm size; with polydispersity index and zeta potential about 0.3 and 10.1mV respectively. Fourier transform infrared spectroscopy (FTIR) confirmed the formation of DOX-siRNA-CMD-ChNPs complex. In addition IL17RB siRNA had significant effect on DOX-induced cytotoxicity in MDA-MB361 cells. Furthermore treatment with dual agent nanoparticles resulted in a significant silencing of NF-κB and Bcl-2 relative gene expression, apoptosis induction and migration inhibition in MDA-MB361 cells. In conclusion, co-delivery of IL17RB siRNA and DOX can be considered as an effective system for the treatment of breast cancer.

Fan LL, Xue XZ, Jiao N
In vitro effect of IL-17D on human ovarian carcinoma cells and inherent immunity.
J Biol Regul Homeost Agents. 2016 Jul-Sep; 30(3):815-820 [PubMed] Related Publications
This study explored the expression of interleukin 17D (IL-17D) secreted by human ovariancarcinoma cells and the effect of exogenous IL-17D transfection on MICA, which is the ligand of NKG2D, on the surface of ovary carcinoma cells. Human ovarian papillary serous adenocarcinoma cell line SKOV3, empty vector control cell line SKOV3/vector, exogenous human IL-17D stable-transfected cell line SKOV3/IL-17D, as well as cisplatin (CDDP)-resistant cell SKOV/CDDP were cultured; ovarian adenocarcinoma cell line OVCAR-3, empty vector control cell line OVCAR3/vector and OVCAE3/IL- 17D were observed under a microscope. In the study, methyl-thiazolyl-tetrazolium (MTT) method was used to detect the inhibition rate, resistance index and proliferation of SKOV3 and SKOV3/CDDP. It was found that the expression of IL-17 D in SKOV3/CDDP was much higher than that of its parent cell line SKOV3; IL-17D might be correlated to the drug resistance of cells; the proliferation of SKOV3 transfected with IL-17D was significantly accelerated, indicating IL-17D may be effective in promoting the growth of oncocyte.

Xu BL, Li YT, Dong SX, et al.
IL-17 rs2275913 genetic variation contributes to the development of gastric cancer in a Chinese population.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
The purpose of this hospital-based case-control study was to assess whether the interleukin (IL)-17 rs2275913 genetic variation can influence susceptibility to gastric cancer. Samples from a total of 202 gastric cancer patients and 237 controls were collected from the Linyi People's Hospital between March 2013 and March 2015. The IL-17 rs2275913 gene polymorphism was identified by polymerase chain reaction and restriction fragment length polymorphism. When compared with control subjects, gastric cancer patients were older in age (OR = 3.89, 95%CI = 2.55-5.95), male (OR = 2.08, 95%CI = 1.39-3.10), had a habit of alcohol consumption (OR = 1.71, 95%CI = 1.15-2.55), and were more likely to be infected with Helicobacter pylori (OR = 2.76, 95%CI = 1.83-4.16). We observed that the AA genotype of the IL-17 rs2275913 polymorphism resulted in a 2.32-fold risk of gastric cancer compared to the GG genotype (OR = 2.32, 95%CI = 1.20-4.54; P = 0.01). The AG combined with AA genotype of the IL-17 rs2275913 polymorphism had more risk of developing gastric cancer than the GG genotype (OR = 1.50, 95%CI = 1.01-2.23; P = 0.04). Moreover, the AA genotype of the IL-17 rs2275913 polymorphism was correlated with a higher risk of developing gastric cancer than the GG and AG genotypes combined (OR = 2.01, 95%CI = 1.08-3.79; P = 0.02). In conclusion, the results of our study suggest that the IL-17 rs2275913 polymorphism could contribute to the risk of gastric cancer.

Kivrak Salim D, Sahin M, Köksoy S, et al.
Local Immune Response in Helicobacter pylori Infection.
Medicine (Baltimore). 2016; 95(20):e3713 [PubMed] Free Access to Full Article Related Publications
There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.

Yang LJ, Gao W, Bai JY, et al.
Correlation between Interleukin-17 gene polymorphism and gastric cancer susceptibility in Han Chinese population.
Eur Rev Med Pharmacol Sci. 2016; 20(7):1271-82 [PubMed] Related Publications
OBJECTIVE: The present study aims to investigate the correlation between Interleukin (IL)-17 gene polymorphism with gastric cancer susceptibility in Han Chinese population.
PATIENTS AND METHODS: Between November 2013 and October 2014, 386 patients with gastric cancer who had undergone surgeries at our institution and 374 age- and sex-matched healthy controls were included in this study. Single nucleotide polymorphisms (SNPs) of IL-17 gene (rs2275913, rs3748067, rs4711998 and rs763780) in patients and health controls were studied by using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) and DNA sequencing technology. The correlation between IL-17 polymorphism and gastric cancer susceptibility was analyzed using logistic regression analysis.
RESULTS: For IL17 rs2275913, no significant differences were observed in the frequencies of AA genotype and A allele between patients and controls (c2 = 0.870 p > 0.05; c2 = 0.814 p > 0.05). In IL17 rs3748067, the frequencies of TT genotype and T allele were significantly higher in patients than in controls (c2 = 12.82 p < 0.01; c2 = 12.805 p < 0.01). For IL17A rs4711998, no significant differences were observed in the frequencies of AA genotype and A allele between patients and controls (c2 = 2.636, p > 0.05; c2 = 1.462, p > 0.05). As for ILl7F rs763780, the frequencies of GG genotype and G allele in patients were significantly different from those in controls (c2 = 16.534, p < 0.01; c2 = 16.399, p < 0.01).
CONCLUSIONS: Polymorphism of IL-17 rs3748067 and rs763780 is closely associated with gastric cancer development. Polymorphism of L-17 rs2275913 and rs4711998 may be correlated with the risk for gastric cancer.

Wang XT, Lv M, Guo HY
Effects of epidural block combined with general anesthesia on antitumor characteristics of T helper cells in hepatocellular carcinoma patients.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):67-77 [PubMed] Related Publications
This study discusses the changes of T helper cells (Th cells) of patients who received different anesthesia methods in liver cancer resection. We selected 122 patients who were diagnosed with hepatocellular carcinoma and underwent liver cancer resection and divided them into a general anesthesia combined with epidural anesthesia group (group A) and general anesthesia group (group B). Peripheral blood was collected to detect Th cells on the day of surgery, and on the second and seventh days after surgery. Th1 and Th2 cell frequency and mRNA expression of interferon-γ (IFN-γ) of all patients significantly rose on the second day but recovered to the previous level on the seventh day. Th1/Th2 increased remarkably on the seventh day compared to the second day. Compared to the day of surgery, Th17, regulatory T (Treg)cells as well as mRNA expression of interleukin-17 (IL-17) and FoxP3 had no obvious changes on the second day, but dramatically declined on the seventh day. Compared to group B, Th1 cell frequency and Th1/Th2 in group A had a slight increase on the second day, and a remarkable increase on the seventh day; but Th2, Th17 and Treg cell frequency in group A slightly decreased on the second day and remarkably decreased on the seventh day. mRNA of IFN-γ, cytokine levels and IFN-γ/IL-4 of group A were all higher than group B on the seventh day, while mRNA of IL-17, concentration of IL-17 as well as concentration of transforming growth factor-β1 (TGF-β1) in group A were much lower than group B. These findings suggest that improving antitumor activity of Th cells can benefit patients who receive liver cancer resection.

Luo Y, Yang Z, Su L, et al.
Non-CSCs nourish CSCs through interleukin-17E-mediated activation of NF-κB and JAK/STAT3 signaling in human hepatocellular carcinoma.
Cancer Lett. 2016; 375(2):390-9 [PubMed] Related Publications
Within the cancer stem cell (CSC) niche, non-CSCs play an indispensable role in facilitating a microenvironment capable of maintaining CSC properties. Non-CSCs contribute to not only the structure and topology of the tumor microenvironment but also the maintenance of the dynamic state of CSCs. Interleukin-17E (IL-17E/IL-25) is important in allergic inflammation and protection against parasitic infection. Moreover, it has also been demonstrated that IL-17E takes part in different cancers recently. Here, for the first time we demonstrate that discrepant expression of IL-17E and the IL-17 receptor B (IL-17RB) exists in Nanog positive (Nanog(Pos)) CSCs and Nanog negative (Nanog(Neg)) non-CSCs in hepatocellular carcinoma (HCC). Moreover, we further demonstrate that IL-17E binding to IL-17RB activates NF-κB and JAK/Stat3 pathways to promote proliferation and sustain self-renewal of CSCs in HCC. Meanwhile, the beneficial effect of IL-17E on Nanog(Pos) CSCs could be blocked by specific inhibitors of JAK and NF-κB signaling. All the findings indicated that non-CSC-derived secreted IL-17E binds IL-17RB on CSCs to signal via JAK/Stat3 and NF-κB pathways to mediate crosstalk between CSCs and non-CSCs. Therefore, IL-17E/IL-17RB signaling represents a potential therapeutic target for treatment of HCC.

Teng DC, Sun J, An YQ, et al.
Role of PHLPP1 in inflammation response: Its loss contributes to gliomas development and progression.
Int Immunopharmacol. 2016; 34:229-34 [PubMed] Related Publications
PH domain leucine-rich repeats protein phosphatase 1(PHLPP1) belongs to a novel family of Ser/Thr protein phosphatases: PHLPP serves as tumor suppressor in several cancers. However, little knowledge about the expression of PHLPP1 in human glioma tumor tissue and its role in inflammation response in glioma cells was known. Glioma samples were obtained from a total of 37 patients including 16 males and 21 females with surgical removal of the brain tumor. PHLPP1 protein and inflammatory cytokines were measured by Western blot analysis and immunohistochemistry while mRNA was determined by RT-PCR. The levels of inflammatory cytokines including TNF-α, IL-17, IL-1β in U251 glioma cells were evaluated by siRNA PHLPP1 and PHLPP1 addition. The loss of PHLPP1 expression occurs at high frequency in human gliomas. The highest mean values of PHLPP1 mRNA and protein were found in non-glioma brain tissues whereas the lowest mean values were found in those in glioblastoma with an increase of TNF-α, IL-17, IL-1β (p<0.05). PHLPP1 expression in human glioma was associated negatively with the severity of the tumor and inflammatory cytokines. siRNA PHLPP1 could increase the levels of inflammatory cytokines in U251 glioma cells while PHLPP1 addition could inhibit significantly inflammatory cytokines. We concluded that PHLPP1 played a suppression role in inflammatory response of glioma. The present study indicated that PHLPP1 could be used as a predictor for the prediction of the patients or as a therapeutic target for the treatment of human glioma.

Li L, Han C, Chen FX, et al.
Expression of CD27, CD28 and IL-17A in peripheral blood from patients with colorectal carcinoma.
Eur Rev Med Pharmacol Sci. 2016; 20(4):642-51 [PubMed] Related Publications
OBJECTIVE: To compare the different expressions of CD27, CD28, IL-17A, IFN-γ and TNF-α in the peripheral blood sampled from patients with colorectal carcinoma and healthy volunteers.
PATIENTS AND METHODS: Vδ2 T cells were isolated from the peripheral blood mononuclear cells (PBMCs) of patients with the colorectal carcinoma (CRC, n = 30) and healthy controls (HC, n = 21). The proportion of CD27, CD28, IL-17A, IFN-γ and TNF-α of Vδ2 T cells was detected by the flow cytometry.
RESULTS: We found that the proportion of IL-17A of Vδ2 T cells in PBMCs was higher in the CRC vs. the HC group (p < 0.05). A significant positive correlation was observed between the expression of IFN-γ and TNF-α of Vδ2 T cells. In the CRC patients, the proportions of IL-17A of CD27- Vδ2 T cells and CD28+ Vδ2 T cells were higher than those of CD27+ Vδ2 T cells and CD28- Vδ2 T cells, whereas the expression of IFN-γ and TNF-α of CD27-Vδ2 T cells was lower than that of CD27+ Vδ2 T cells.
CONCLUSIONS: Vδ2 T cells from PBMCs had higher expression of IL-17A in CRC patients than that in the HC group. The expression of IFN-γ and TNF-α of Vδ2 T cells from PBMCs was positively correlated. The cytokine profiles of peripheral Vδ2 T cells were likely determined by a CD27 and CD28 involving mechanism.

Zhou Y, Wu PW, Yuan XW, et al.
Interleukin-17A inhibits cell autophagy under starvation and promotes cell migration via TAB2/TAB3-p38 mitogen-activated protein kinase pathways in hepatocellular carcinoma.
Eur Rev Med Pharmacol Sci. 2016; 20(2):250-63 [PubMed] Related Publications
OBJECTIVE: Hepatocellular carcinoma (HCC) is characterized by progressive development and poor prognosis against a background of chronic inflammation. Interleukin (IL)-17A is an important proinflammatory cytokine that contributes to inflammatory pathology and tumor microenvironment. Research on autophagy has increasingly focused on its role in inflammation. Thus, we investigated the effect of IL-17A on the progression of HCC through the autophagic pathway.
MATERIALS AND METHODS: The expression and prognostic values of IL-17A and autophagic gene Beclin-1 were determined using immunohistochemistry in 83 HCC patients after resection. The effects and underlying molecular mechanisms of IL-17A on human HCC were explored in vitro using recombinant human IL-17A.
RESULTS: High expression of IL-17A and low expression of Beclin-1 were associated with worse TNM stage in HCC patients. And the level of autophagy was lower in tumor tissues compared with tumor-adjacent tissues. In vitro, recombinant human IL-17A inhibited starvation-induced autophagy and maintained cell viability through activating TAK1-binding protein 2 (TAB2 and TAK1-binding protein 3 (TAB3)-inducing p38 mitogen-activated protein kinase (MAPK) in Huh7 and HepG2 HCC cells. IL-17A promoted migration of HCC cells through the TAB2/p38 MAPK and TAB3/p38 MAPK pathways.
CONCLUSIONS: IL-17A promotes migration of HCC cells and prevents autophagic cell death from starvation by activating TAB2/p38 MAPK and TAB3/p38 MAPK.

Dai ZM, Zhang TS, Lin S, et al.
Role of IL-17A rs2275913 and IL-17F rs763780 polymorphisms in risk of cancer development: an updated meta-analysis.
Sci Rep. 2016; 6:20439 [PubMed] Free Access to Full Article Related Publications
Single nucleotide polymorphisms (SNPs) in the interleukin-17 (IL-17) gene have been shown to be correlated with susceptibility to cancer. However, various studies report different results of this association. The aim of the present work was to clarify the effects of IL-17A G197A (rs2275913) and IL-17F T7488C (rs763780) polymorphisms on cancer risk. We performed systematic searches of the PubMed and CNKI databases to obtain relevant publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the association of rs2275913 and rs763780 polymorphisms with cancer risk. Data were extracted from the selected studies, and statistical analysis was conducted using the STATA software. Our results indicated that rs2275913 and rs763780 polymorphisms significantly increase cancer risk, especially in gastric cancers. Subgroup analysis suggested the existence of a significant correlation between rs763780 polymorphism and cancer susceptibility in Caucasian populations. This updated meta-analysis confirms that rs2275913 and rs763780 polymorphisms are highly associated with increased risk for multiple forms of cancer.

Parodi A, Traverso P, Kalli F, et al.
Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence.
Oncotarget. 2016; 7(6):6424-35 [PubMed] Free Access to Full Article Related Publications
Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFNγ+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently <1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always >1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio.

Ning C, Xie B, Zhang L, et al.
Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen.
Cancer Res. 2016; 76(6):1354-66 [PubMed] Related Publications
Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68(+)CD163(+) macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68(+)CD163(+) macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting.

Willerslev-Olsen A, Krejsgaard T, Lindahl LM, et al.
Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma.
Blood. 2016; 127(10):1287-96 [PubMed] Free Access to Full Article Related Publications
Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.

Zhou P, Zhang Q, Zhao Y, et al.
IL-17 promoted the inhibition of medulloblastoma in mice by splenocyte injection.
Eur J Med Res. 2015; 20:98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interleukin 17 (IL-17) is a proinflammatory cytokine produced by a new subset of activated CD4+ T cells, Th17 cells. We previously showed that increased Th17 cell populations were presented in human medulloblastoma-infiltrating T cells and peripheral blood. In this study, we attempted to address the possible role of Th17 cells in the biologic activity of IL-17 for tumor control.
METHODS: We grafted fresh surgically obtained medulloblastoma into syngeneic athymic nude/nude mice. We intrapertonially injected splenocyte and murine IL-17 in mice on the second day. The tumor volume and the life spans of the mice were measured. Meanwhile, the IL-17, IL-6, IL-23, Ccl2, Ccl20 and IFN-gamma expression in the tumors was also examined by real-time PCR, Western blot and enzyme-linked immunosorbent assay.
RESULTS: We found that medulloblastoma growth in IL-17-injected mice was significantly inhibited compared to the non-IL-17 treated mice. In contrast to the IL-17 antitumor activity observed in mice injected with splenocytes, we observed that IFN-gamma, IL-6, IL-23, Ccl2, and Ccl20 proteins were significantly increased in tumor tissues of mice injected with IL-17.
CONCLUSIONS: These experiments suggest that IL-17 may promote splenocyte antitumor activity in medulloblastoma. We postulate that IL-17's antitumor activity may be related to the increased protein levels of IFN-gamma, IL-6, IL-23, Ccl2, and Ccl20.

Wang Q, Luan W, Warren L, et al.
Prognostic Role of Immune Cells in Hepatitis B-associated Hepatocellular Carcinoma Following Surgical Resection Depends on Their Localization and Tumor Size.
J Immunother. 2016; 39(1):36-44 [PubMed] Related Publications
This study aims to evaluate localized expression of CD4, interleukin (IL)-17, Foxp3, and CD8 in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) and to explore their potential effects on outcome following surgical resection. This prospective study includes 66 HBV-HCC surgical resection patients enrolled from 2008 to 2013. CD4, IL-17, Foxp3, and CD8 mRNA in 4 regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated using real-time polymerase chain reaction. The tumoral regions had lower CD4 and CD8 expression as compared with paired non-neoplastic regions, whereas the expression of IL-17 and Foxp3 did not differ. High Foxp3 in all regions except non-neoplastic liver distant from tumor was associated with poor overall survival, whereas low CD8 expression in distant non-neoplastic liver may be associated with high HCC recurrence rate. Although the expression of almost all molecules did not differ between small (≤3 cm) and large HCC (>3 cm), high IL-17 in periphery of tumor, high CD8 in center of tumor, or low CD8 in distant non-neoplastic liver was associated with high HCC recurrence rate in patients with small HCC, but not in those with large HCC. The effect of immune cells on HCC progression therefore depends on the expression level, localization, and tumor size, and an imbalance toward regulatory T cells is associated with poor outcome.

Lu Y, Gu J, Lu H, et al.
Association Between IL-17A +197 G/A Polymorphism and Cancer Risk: A Meta-analysis.
Genet Test Mol Biomarkers. 2016; 20(1):24-30 [PubMed] Related Publications
AIMS: The association between interleukin-17 (IL-17) gene polymorphism and cancer is controversial. Thus, we performed a meta-analysis to evaluate the correlation between this gene variant and cancer risk.
MATERIALS AND METHODS: We retrieved the available data from EMBASE and PUBMED through June, 2015, and evaluated the effect of the rs2273913 polymorphism in different ethnicities and cancer types. A meta-analysis was performed after data sorting.
RESULTS: Significant associations were confirmed among Asians by the allelic model (T allele vs. G allele, 95% confidence interval [95% CI] 1.304-2.120), homozygote comparison (AA vs. GG, 95% CI 1.073-1.615), and the recessive model (AA vs. AG/GG, 95% CI 1.128-1.778). We also demonstrated that rs2273913 confers a high risk of nongastrointestinal cancer based on the allelic model (T allele vs. G allele, 95% CI 2.288-3.442), homozygote comparison (AA vs. GG, 95% CI 1.312-1.925), and recessive model (AA vs. AG/GG, 95% CI 1.259-1.689).
CONCLUSIONS: Our present study indicates that the IL-17A +197 G/A/T polymorphism (rs2275913) is associated with the risk of cancer in Asian populations and nongastrointestinal cancers. Hence, rs2275913 might be useful as a diagnostic biomarker of cancer in these populations.

Kopp S, Warnke E, Wehland M, et al.
Mechanisms of three-dimensional growth of thyroid cells during long-term simulated microgravity.
Sci Rep. 2015; 5:16691 [PubMed] Free Access to Full Article Related Publications
Three-dimensional multicellular spheroids (MCS) of human cells are important in cancer research. We investigated possible mechanisms of MCS formation of thyroid cells. Both, normal Nthy-ori 3-1 thyroid cells and the poorly differentiated follicular thyroid cancer cells FTC-133 formed MCS within 7 and 14 days of culturing on a Random Positioning Machine (RPM), while a part of the cells continued to grow adherently in each culture. The FTC-133 cancer cells formed larger and numerous MCS than the normal cells. In order to explain the different behaviour, we analyzed the gene expression of IL6, IL7, IL8, IL17, OPN, NGAL, VEGFA and enzymes associated cytoskeletal or membrane proteins (ACTB, TUBB, PFN1, CPNE1, TGM2, CD44, FLT1, FLK1, PKB, PKC, ERK1/2, Casp9, Col1A1) as well as the amount of secreted proteins (IL-6, IL-7, IL-8, IL-17, OPN, NGAL, VEGFA). Several of these components changed during RPM-exposure in each cell line. Striking differences between normal and malignant cells were observed in regards to the expression of genes of NGAL, VEGFA, OPN, IL6 and IL17 and to the secretion of VEGFA, IL-17, and IL-6. These results suggest several gravi-sensitive growth or angiogenesis factors being involved in 3D formation of thyroid cells cultured under simulated microgravity.

Wu X, Yang T, Liu X, et al.
IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer.
Tumour Biol. 2016; 37(4):5493-501 [PubMed] Related Publications
Gastric cancer is the world's second most common malignancy and is a major threat to global health. IL-17, a CD4 T cell-derived mediator of angiogenesis, plays a major role in stimulating angiogenesis by regulating the production of a variety of proangiogenic factors, including the vascular endothelial growth factor (VEGF). The level of VEGF expression correlates with tumor progression and metastasis in gastric cancer tissues. Abnormal activation of signal transducer and activator of transcription 3 (Stat3) rendered the tumor cells highly angiogenic, which is manifested by an increased microvascular density (MVD) and considered it as a potential molecular marker for poor prognosis in gastric cancer angiogenesis. We determined that IL-17A-induced VEGF upregulation and neovascularization through a Stat3-mediated signaling pathway and hypothesized that blocking the Stat3 activation by using JSI-124, an inhibitor of phosphorylated Stat3, could significantly reduce the VEGF expression and can thus prevent angiogenesis. We showed an inhibition of angiogenesis and tumor progression when JSI-124 was treated with IL-17A in the cells and xenografts in an animal model and suggested that targeting the Stat pathway with JSI-124 could derive an effective therapeutic target for gastric cancers and could be a promising drug in gastric cancer treatment.

Hojjat-Farsangi M, Jeddi-Tehrani M, Daneshmanesh AH, et al.
Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia.
PLoS One. 2015; 10(11):e0142310 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.
MATERIALS AND METHODS: Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.
RESULTS: The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05).
CONCLUSION: ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.

Sun LX, Wang XB, Huang XJ
Association analysis of rs2275913G>A and rs763780T>C interleukin 17 polymorphisms in Chinese women with cervical cancer.
Genet Mol Res. 2015; 14(4):13612-7 [PubMed] Related Publications
We conducted a case-control study with a relatively large sample size, and investigated the association between rs2275913G>A and rs763780T>C and the risk of cervical cancer. Three hundred and six newly diagnosed patients with histologically confirmed cervical cancer and 354 cancer-free control subjects were recruited from the Forestry General Hospital between May 2011 and May 2014. The gene polymorphisms rs2275913G>A and rs763780T>C were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. By unconditional logistic regression analysis, our study found that the AA genotype and the A allele of rs2275913 were associated with a higher risk of cervical cancer compared with the wild-type genotype, and the ORs (95%CIs) were 2.84 (1.57-5.23) and 1.55 (1.22-1.97), respectively. Compared with the G allele, the A allele of rs699947 was associated with a significantly increased risk of cervical cancer in subjects above 20 years and who were positive for human papillomavirus 16 (HPV-16) or HPV-18 infection. Patients with the A allele of rs2275913 had increased risk of cervical cancer, regardless of the number of births they had experienced or their smoking habits. We suggest that rs2275913 may play a role in the etiology of cervical cancer, although further large-sample studies are needed to confirm these observations.

Qi WT, Gao JL, Zhang SS
Role of IL-17 gene polymorphisms in the susceptibility to gastric cancer.
Genet Mol Res. 2015; 14(4):13364-9 [PubMed] Related Publications
We conducted a study to investigate the role of three IL-17 gene single nucleotide polymorphisms (SNP) (rs2275913G>A, rs3748067C>T, and rs763780 T>C) in the development of gastric cancer. A total of 252 patients with gastric cancer and 252 control subjects were collected between May 2012 and May 2014. The SNP genotyping of IL-17A rs2275913G>A and rs3748067C>T and IL-17F rs763780 T>C was performed using the Sequenom MassARRAY platform (Sequenom, San Diego, CA, USA) according to the manufacturer instructions. By conditional regression analysis, individuals carrying the AA and the GA+AA genotypes of rs2275913G>A were correlated with an elevated risk of gastric cancer when compared with those carrying the GG genotype, and the adjusted ORs (95%CIs) were 2.05 (1.13-3.76) for the AA genotype and 1.45 (1.03-2.08) for the GA+AA genotype. In conclusion, our results suggest that the IL-17A rs3748067C>T and IL-17F rs763780 T>C polymorphisms play an important role in the risk of gastric cancer in a Chinese population.

Li L, Tian YL, Lv XM, et al.
Association analysis of IL-17A and IL-17F polymorphisms in Chinese women with cervical cancer.
Genet Mol Res. 2015; 14(4):12178-83 [PubMed] Related Publications
We selected six tagged single nucleotide polymorphisms (SNPs) in the interleukin 17A (IL-17A) and IL-17F genes, and evaluated the relationship between the six common SNPs and environmental factors in cervical cancer patients. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the IL-17A (rs2275913, rs3748067, and rs3819025) and IL-17F (rs763780, rs9382084, and rs1266828) SNPs. The associations between IL-17A and IL-17F gene polymorphisms and risk of cervical cancer were estimated by conditional logistic regression. Compared with the control subjects, the cervical cancer patients had a lower age at first live birth, a habit of smoking, a family history of cancer, and a greater incidence of human papillomavirus-16 or 18 infections. The logistic regression analysis showed that the variant AA genotype of rs2275913 was associated with a significantly higher risk of cervical cancer than the wild-type GG genotype (OR = 1.99, 95%CI = 1.12-3.50). However, no evidence of the association was observed between rs3748067, rs3819025, rs763780, rs9382084, and rs1266828 polymorphisms and the risk of cervical cancer. We suggest that rs2275913 may play a role in the etiology of cervical cancer. These findings could be helpful in identifying individuals at increased risk of developing cervical cancer.

Zhang H, Li ZL, Ye SB, et al.
Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator.
Cancer Immunol Immunother. 2015; 64(12):1587-99 [PubMed] Free Access to Full Article Related Publications
The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR(-)CD33(+)CD11b(+) MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14(+) monocytic (Mo-MDSCs, >60 %) and CD15(+) granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFβ and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFβ secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR(-)CD33(+)CD11b(+) cells and CD14(+) Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.

Zhang W, Tian X, Mumtahana F, et al.
The existence of Th22, pure Th17 and Th1 cells in CIN and Cervical Cancer along with their frequency variation in different stages of cervical cancer.
BMC Cancer. 2015; 15:717 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, it is found that T-helper (Th) 22 cells are involved in different types of autoimmune and tumor diseases. But, till now, no study has been carried out to understand the involvement of these cells in cervical cancer (CC).
METHODS: Flow cytometry was used to determine the expression of interferon gamma (IFN-γ), Interleukin-22 (IL-22), IL-17 in the peripheral blood of healthy controls (HC), CIN and cervical cancer patients. From peripheral blood mononuclear cells (PBMCs), mRNA expression levels of Aryl hydrocarbon receptor (AHR), RAR-related orphan receptor C (RORC), TNF-α and IL-6 were respectively determined. Using the method of ELISA, plasma concentrations of IL-22, IL-17 and TNF-α were examined.
RESULTS: Th22 and Th17 cells were elevated in CC and CIN patients. Th1 cells and the plasma concentrations of IL-22 in CC patients were significantly increased compared with HC. In CC patients, an increased prevalence of Th22 cells was associated with lymph node metastases. There was a positive correlation between Th22 and Th17 cells, but an approximately negative correlation between Th22 and Th1 cells in CC patients. The mRNA expression of RORC, TNF-α and IL-6 was significantly high in CC patients.
CONCLUSIONS: Our results indicate that there is a higher circulatory frequency of Th22, Th17 and Th1 cells in CC which may conjointly participate in the pathogenesis and growth of CC.

Cong J, Liu R, Wang X, et al.
Association between interluekin-17 gene polymorphisms and the risk of cervical cancer in a Chinese population.
Int J Clin Exp Pathol. 2015; 8(8):9567-73 [PubMed] Free Access to Full Article Related Publications
We conducted a study to analyze the association of three common SNPs of IL-17A rs2275913 and rs3748067 and IL-17F rs763780 gene polymorphisms with the risk of cervical cancer in a Chinese population. Our study included 352 cervical cancer patients and 352 controls between January 2013 and December 2014. Genotyping of IL-17A rs2275913 and rs3748067 and IL-17F rs763780 genes was performed by multiplex PCR assays using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). By χ(2) test, there was significantly difference in the genotype distribution of IL-17A rs2275913 between cervical cancer patients and control subjects (χ(2)=11.45, P=0.003). By conditional logistic regression analysis, we found that individuals with the GA and AA genotypes were associated with an increased risk of cervical cancer when compared with the GG genotype in codominant model, and the adjusted Ors (95% CI) were 1.57 (1.13-2.18) and 2.01 (1.15-3.49), respectively. In dominant model, we found that the GA+AA genotype of rs2275913 was correlated with a moderate increased risk of cervical cancer compared with the GG genotype (OR=1.64, 95% CI=1.20-2.24). We only found significant interaction between rs2275913 polymorphism and HPV-16 or 18 infection in the risk of cervical cancer (P for interaction <0.05). In conclusion, our study suggests that IL-17A rs2275913 polymorphism may affect the development of cervical cancer in codominant and dominant models, and this gene polymorphism has interaction with HPV-16 or 18 infection.

Wang K, Karin M
The IL-23 to IL-17 cascade inflammation-related cancers.
Clin Exp Rheumatol. 2015 Jul-Aug; 33(4 Suppl 92):S87-90 [PubMed] Related Publications
Two inflammatory cytokines, IL-23 and IL-17A, produced by myeloid cells and different lymphocyte subsets, were found to play important pathogenic functions in several inflammation-related cancers. In colorectal cancer, elevated expression of IL-23, IL-23 receptor and IL-17A has been linked to adverse prognostic outcome and rapid progression to metastatic disease. In mouse models of colorectal tumourigenesis genetic or pharmacological inhibition of these cytokines attenuates tumour development and malignant progression. Collectively, such findings suggest that IL-23 and/or IL-17A inhibitors should be evaluated for their therapeutic and preventative potential in human cancers, especially in colorectal cancer.

Wang H, Zhang Y, Liu Z, et al.
The IL-17A G-197A and IL-17F 7488T/C polymorphisms are associated with increased risk of cancer in Asians: a meta-analysis.
Drug Des Devel Ther. 2015; 9:5159-68 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interleukin-17 (IL-17) is a family of emerged pro-inflammatory cytokines. The IL-17A and IL-17F are two important members of IL-17 family. Previous studies have shown that the functional IL-17A G-197A and IL-17F 7488T/C polymorphisms may contribute to susceptibility to cancer but the results were inconclusive. This meta-analysis was performed to determine the exact association between IL-17 polymorphisms and cancer risk.
METHODS: Online databases were searched to identify eligible case-control studies. Pooled odds ratios (ORs) and confidence intervals (CIs) were calculated by fixed-effect models or random-effect models. Publication bias was detected by Egger's test and Begg's test.
RESULTS: Nine eligible case-control studies of IL-17A G-197A and seven studies of IL-17F 7488T/C, including 3,181 cases and 4,005 controls, were identified. Pooled analysis suggested the variant IL-17A-197A allele was associated with increased risk cancer (GA/AA vs GG, OR =1.27, 95% CI: 1.15, 1.41, P heterogeneity =0.374; and A vs G, OR =1.30, 95% CI: 1.17, 1.45, P heterogeneity =0.021). For IL-17F 7488T/C, the homozygote 7488CC genotype significantly increased risk of cancer (CC vs TC/TT, OR =1.36, 95% CI: 0.97, 1.91, P heterogeneity =0.875; and CC vs TT, OR =1.39, 95% CI: 1.03, 1.88, P heterogeneity =0.979), especially for gastric cancer.
CONCLUSION: The variant IL-17A-197A allele and IL-17F 7488CC genotype were associated with increased risk of cancer, especially for gastric cancer.

Chen X, Wang J, Wang R, et al.
Th1-, Th2-, and Th17-associated cytokine expression in hypopharyngeal carcinoma and clinical significance.
Eur Arch Otorhinolaryngol. 2016; 273(2):431-8 [PubMed] Related Publications
Th0 cells differentiate into Th1 or Th2 depending on multiple transcription factors acting on specific time points to regulate gene expression. Th17 cells, a subset of IL-17-producing T cells distinct from Th1 or Th2 cells, have been described as key players in inflammation and autoimmune diseases as well as cancer development. In the present study, 53 patients with hypopharyngeal cancer were included. The expression levels of Th1-, Th2- and Th17-associated cytokines in hypopharyngeal cancer tissues and pericarcinoma tissues were detected. The relationship between Th1, Th2, or Th17 infiltration and metastasis was studied. Our results showed that the mRNA and protein expressions of Th1 cytokines were lower, while the expressions of Th2 and Th17 cytokines were higher in tumor tissues, and the intensity of expression was strengthened with clinical stage increasing. Cancer tissues had higher level expressions of Th2 and Th17 cytokines than that of pericarcinoma tissues. From the above data, we speculated that high expressions of Th2- and Th17-associated cytokines in hypopharyngeal carcinoma may contribute to cancer development and metastasis.

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