Gene Summary

Gene:IL2; interleukin 2
Aliases: IL-2, TCGF, lymphokine
Summary:The protein encoded by this gene is a secreted cytokine that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine is a heterotrimeric protein complex whose gamma chain is also shared by interleukin 4 (IL4) and interleukin 7 (IL7). The expression of this gene in mature thymocytes is monoallelic, which represents an unusual regulatory mode for controlling the precise expression of a single gene. The targeted disruption of a similar gene in mice leads to ulcerative colitis-like disease, which suggests an essential role of this gene in the immune response to antigenic stimuli. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (36)
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

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chronic Lymphocytic Leukemia
  • Cell Proliferation
  • Breast Cancer
  • Polymorphism
  • Risk Factors
  • Up-Regulation
  • Genetic Predisposition
  • Single Nucleotide Polymorphism
  • Mutation
  • Cancer Gene Expression Regulation
  • T-Lymphocytes, Regulatory
  • Immunotherapy
  • T-Lymphocytopenia, Idiopathic CD4-Positive
  • Molecular Sequence Data
  • Gene Expression
  • Chromosome 4
  • Case-Control Studies
  • Oligonucleotides
  • Cytokines, Interleukin-2
  • Melanoma
  • Interferon-gamma
  • Cytokines
  • Ovarian Cancer
  • FISH
  • Lymphocyte Activation
  • Base Sequence
  • Cytotoxicity, Immunologic
  • Phenotype
  • Receptors, Interleukin-2
  • Karyotyping
  • Chromosome Aberrations
  • Childhood Cancer
  • Genotype
  • Natural Killer Cells
  • Transfection
  • Transduction
  • Polymerase Chain Reaction
  • Tandem Repeat Sequences
  • Adolescents
  • T-Lymphocytes
  • Messenger RNA
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: IL2 (cancer-related)

Gutiérrez-Rodríguez A, Hansberg-Pastor V, Camacho-Arroyo I
Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells.
Biomed Res Int. 2017; 2017:1295087 [PubMed] Free Access to Full Article Related Publications
Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM) from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12-48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.

Lin CF, Lin CM, Lee KY, et al.
Escape from IFN-γ-dependent immunosurveillance in tumorigenesis.
J Biomed Sci. 2017; 24(1):10 [PubMed] Free Access to Full Article Related Publications
Immune interferon (IFN), also known as IFN-γ, promotes not only immunomodulation but also antimicrobial and anticancer activity. After IFN-γ binds to the complex of IFN-γ receptor (IFNGR) 1-IFNGR2 and subsequently activates its downstream signaling pathways, IFN-γ immediately causes transcriptional stimulation of a variety of genes that are principally involved in its biological activities. Regarding IFN-γ-dependent immunosurveillance, IFN-γ can directly suppress tumorigenesis and infection and/or can modulate the immunological status in both cancer cells and infected cells. Regarding the anticancer effects of IFN-γ, cancer cells develop strategies to escape from IFN-γ-dependent cancer immunosurveillance. Immune evasion, including the recruitment of immunosuppressive cells, secretion of immunosuppressive factors, and suppression of cytotoxic T lymphocyte responses, is speculated to be elicited by the oncogenic microenvironment. All of these events effectively downregulate IFN-γ-expressing cells and IFN-γ production. In addition to these extrinsic pathways, cancer cells may develop cellular tolerance that manifests as hyporesponsiveness to IFN-γ stimulation. This review discusses the potential escape mechanisms from IFN-γ-dependent immunosurveillance in tumorigenesis.

Liu W, Liu SY, He YB, et al.
MiR-451 suppresses proliferation, migration and promotes apoptosis of the human osteosarcoma by targeting macrophage migration inhibitory factor.
Biomed Pharmacother. 2017; 87:621-627 [PubMed] Related Publications
Previous studies have shown that MiR-451 plays an important role in human osteosarcoma carcinogenesis, but the underlying mechanism by which MiR-451 affects the osteosarcoma has not been fully understood. This study intends to uncover the mechanism by which MiR-451 functions as a tumor suppressor. The expression of MiR-451 in osteosarcoma tissues and osteosarcoma cell lines was monitored by real-time PCR. The proliferation ability was examined by MTT and cell cycle assay. The migration and apoptosis of cells were monitored by migration assay and flow cytometry, respectively. Moreover, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was examined by tube formation assay. The effect of MiR-451 on MIF was determined by luciferase assays and Western blot assay. The results showed that MiR-451 expression level was significantly reduced in the osteosarcoma compared with normal bone tissues. Overexpression of MiR-451 significantly attenuated the proliferation and migration, and induced the apoptosis of osteosarcoma cells. Furthermore, the angiogenesis of HUVEC cells transfected with MiR-451 mimics was assayed and the decreased angiogenic ability was detected compared to the controls. Finally, we demonstrated that MiR-451 overexpression inhibited the malignant behavior of osteosarcoma by downregulating MIF. These findings suggest that MiR-451 may act as a tumor suppressor in osteosarcoma. MiR-451 inhibited cell proliferation, migration and angiogenesis and promoted apoptosis of human osteosarcoma cells, at least partially, by inhibiting the expression of MIF. MiR-451/MIF may be a novel therapeutic target in treatment of osteosarcoma.

Gan WY, Li HM, Zhang YG, et al.
Association between IL18-607C/A and -137G/C polymorphisms and susceptibility to non-small cell lung cancer in a Chinese population.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Lung cancer is one of the main causes of cancer-related mortality in males and females worldwide. A pleiotropic effect has been observed in the interleukin 18 gene (IL18); its effects include the activation of natural killer cell cytotoxicity and the promotion of the Th1 immune response through the alteration of the expression of interferon-γ and TNF-α in humans. IL18 is therefore involved in the elimination of tumor cells in the human body. We recruited 357 patients with non-small cell lung cancer (NSCLC) and 414 controls to evaluate the correlation between two genetic variations (IL18-607C/A and IL18-137G/C) and the pathogenesis of NSCLC. We used polymerase chain reaction-restriction fragment length polymorphism to genotype IL18-607C/A and IL18-137G/C. Statistical analysis revealed that individuals harboring the AA genotype of IL18-607C/A had an increased risk of NSCLC compared to those harboring the CC genotype (OR = 2.20, 95%CI = 1.30-3.74). Individuals expressing the A allele of IL18-607C/A had an elevated risk of developing NSCLC compared to those expressing the C allele (OR = 1.31, 95%CI = 1.06-1.62). In summary, our analysis shows that the IL18-607C/A genetic variation is related to the risk of NSCLC, whereas the IL18-137G/C variation is not. Therefore, the IL18-607C/A variation is related to the pathogenesis of NSCLC in the Chinese population studied.

Hayashi T, Kawano M, Ichimura T, et al.
Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma.
Anticancer Res. 2016; 36(10):4997-5007 [PubMed] Related Publications
Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Wang K, Vella AT
Regulatory T Cells and Cancer: A Two-Sided Story.
Immunol Invest. 2016; 45(8):797-812 [PubMed] Related Publications
Regulatory T cells (Tregs) play pivotal roles in limiting the duration and magnitude of immune response against infectious agents and self-antigens. This is accomplished through contact-dependent and -independent mechanisms that involve crosstalk between Treg cells and other immune and tissue-specific cell types. The same machinery is employed by Tregs to regulate immune responses to cancer, limiting both pro-tumor inflammation and anti-tumor immunity. Factors produced by Treg cells also act directly on transformed epithelial cells and exert opposing effects during different stages of cancer development. Therefore, the immune regulatory cell population serves as a double-edged sword for the development, progression, and treatment of cancers. In this review, we summarize current knowledge on the roles of Treg lymphocytes during cancer development, as well as the underlying cellular and molecular mechanism.

Moeini S, Saeidi M, Fotouhi F, et al.
Synergistic effect of programmed cell death protein 1 blockade and secondary lymphoid tissue chemokine in the induction of anti-tumor immunity by a therapeutic cancer vaccine.
Arch Virol. 2017; 162(2):333-346 [PubMed] Related Publications
The use of DNA vaccines has become an attractive approach for generating antigen-specific cytotoxic CD8(+) T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be improved by using an adjuvant injected together with checkpoint antibodies. In the current study, we evaluated whether the therapeutic effects of a DNA vaccine encoding human papilloma virus type 16 (HPV-16) E7 can be enhanced by combined application of an immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway and secondary lymphoid tissue chemokine (SLC) also known as CCL21 adjuvant, in a mouse cervical cancer model. The therapeutic effects of the DNA vaccine in combination with CCL21 adjuvant plus PD-1 blockade was evaluated using a tumor growth curve. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using non-radioactive cytotoxicity and MTT assays, respectively. Vascular endothelial growth factor (VEGF) and IL-10 expression in the tumor and the levels of IFN-γ and IL-4 in supernatants of spleno-lymphocyte cultures were measured using ELISA. The immune efficacy was evaluated by in vivo tumor regression assay. The results showed that vaccination with a DNA vaccine in combination with the CCL21 adjuvant plus PD-1 blockade greatly enhanced cytotoxic T lymphocyte production and lymphocyte proliferation rates and greatly inhibited tumor progression. Moreover, the vaccine in combination with adjuvant and blockade significantly reduced intratumoral VEGF, IL-10 and splenic IL-4 but induced the expression of splenic IFN-γ. This formulation could be an effective candidate for a vaccine against cervical cancers and merits further investigation.

Gao J, Shi LZ, Zhao H, et al.
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.
Cell. 2016; 167(2):397-404.e9 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

Haydaroglu H, Oguzkan Balcı S, Pehlıvan S, et al.
Effect of Cytokine Genes in the Pathogenesis and on the Clinical Parameters for the Treatment of Multiple Myeloma.
Immunol Invest. 2017; 46(1):10-21 [PubMed] Related Publications
In this study, we aimed to explore the association among gene variants of five cytokines, tumor necrosis factor alpha (TNF-α), transforming growth factor beta-1 (TGF-β1), interferon gamma (IFN-γ), interleukin-6 (IL-6), and interleukin-10 (IL-10), and clinical parameters and prognosis in patients with multiple myeloma (MM) treated with novel therapeutic drugs in Turkish population for the first time except TNF-α. We analyzed five cytokine genes in 113 cases with MM and 113 healthy controls. Cytokine genotyping was performed by the polymerase chain reaction-sequence-specific primer method (PCR-SSP). AG genotype associated with high expression in TNF-α gene (-308) variant was found to be significantly higher (p = 0.019), and GG genotype associated with low expression in TNF-α gene (-308) variant was significantly lower in MM group as compared with controls (p = 0.012). IFN-γ (+874) variant TT genotype was increased (p = 0.037), and AA genotype was decreased (p = 0.002) in MM group in contrast to controls. IFN-γ (+874) T allele was higher in MM patients compared with controls (OR = 1.985, p = 0.000), while A allele was significantly lower (OR = 0.5037, p = 0.0005). Multivariate analysis revealed that factors associated with 5-year overall survival (OS) were only IPI III (RR = 1.630, p = 0.018) and thrombocytopenia (RR = 2.207, Cox p = 0.021), while 5-year event-free survival (EFS) was associated with IPI III (RR = 1.524, p = 0.022), thrombocytopenia (RR = 2.902, p = 0.002), APSCT treatment (RR = 1.729, p = 0.035), and female gender (RR = 0.435, p = 0.002) with negative prognostic values. Our results suggested that TNF-α gene (-308) AG genotype and IFN-γ (+874) TT genotype and T allele may have a role on MM, while other cytokines were not associated with the risk of MM.

Mashimo M, Yurie Y, Kawashima K, Fujii T
CRAC channels are required for [Ca(2+)]i oscillations and c-fos gene expression after muscarinic acetylcholine receptor activation in leukemic T cells.
Life Sci. 2016; 161:45-50 [PubMed] Related Publications
AIMS: T lymphocytes express muscarinic acetylcholine receptors (mAChRs) involved in regulating their proliferation, differentiation and cytokine release. Activation of M1, M3 or M5 mAChRs increases the intracellular Ca(2+) concentration ([Ca(2+)]i) through inositol-1,4,5-phosphate (IP3)-mediated Ca(2+) release from endoplasmic reticulum Ca(2+) stores. In addition, T lymphocytes express Ca(2+)-release activated Ca(2+) (CRAC) channels to induce Ca(2+) influx and to regulate diverse immune functions. Our aim in the present study was to assess the role of CRAC channels during mAChR activation in the Ca(2+)-dependent transduction that contributes to the regulation of T cell function.
MAIN METHODS: Changes in [Ca(2+)]i following mAChR activation on human leukemic T cells, CCRF-CEM (CEM), were monitored using fura-2, based on the ratio of 510nm fluorescences elicited by excitation at 340nm and 380nm (R340/380).
KEY FINDINGS: We demonstrate that CEM cells express mainly M3 and M5 mAChRs, but little the M1 subtype, and that oxotremorine-M (Oxo-M), an mAChR agonist, induces an initial transient increase in [Ca(2+)]i followed by repetitive [Ca(2+)]i oscillations. Removing extracellular Ca(2+) or pharmacological blockade of CRAC channels abolished the [Ca(2+)]i oscillations without affecting the initial [Ca(2+)]i transient induced by Oxo-M. Moreover, CRAC channel blockade also suppressed Oxo-M-induced c-fos and interleukin-2 expression.
SIGNIFICANCE: These results suggest that upon M3 or M5 mAChR activation, IP3-mediated Ca(2+) release induces extracellular Ca(2+) influx through CRAC channels, which generates repetitive [Ca(2+)]i oscillations and, in turn, enhances c-fos gene expression in T lymphocytes.

Djaafar S, Dunand-Sautier I, Gonelle-Gispert C, et al.
Enoxaparin Attenuates Mouse Colon Cancer Liver Metastases by Inhibiting Heparanase and Interferon-γ-inducible Chemokines.
Anticancer Res. 2016; 36(8):4019-32 [PubMed] Related Publications
BACKGROUND/AIM: Low-molecular-weight heparin (LMWH) has been suggested to reduce the risk of cancer progression in both preclinical and clinical studies but the underlying mechanisms remain poorly explored. The aim of the study was to investigate the anti-metastatic role of enoxaparin, a clinically-used LMWH, in a murine model of colon cancer and to explore its underlying mechanisms.
MATERIALS AND METHODS: Using a reproducible mouse model of colon carcinomas, we assessed the capacity of enoxaparin, a LMWH, to affect tumor metastasis of colon carcinoma cell lines in mice.
RESULTS: The hepatic growth of colon carcinoma metastases was strongly inhibited by enoxaparin compared to (Ctrl) group (p=0.001). This effect was associated to an inhibition of heparanase mRNA expression and protein production both in vivo and in vitro. In addition, enoxaparin inhibited the liver and serum production of interferon gamma (Ifnγ)-inducible chemokine receptor ligands. Overexpression of heparanase prompted proliferation, migration and growth of colon carcinoma in vitro and in vivo to a point that was not affected by enoxaparin in vivo anymore.
CONCLUSION: Enoxaparin decreased liver metastases in a mouse model of colon carcinoma. These results suggest that enoxaparin may benefit patients with cancer and deserves further laboratory and clinical investigations.

Zaretsky JM, Garcia-Diaz A, Shin DS, et al.
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
N Engl J Med. 2016; 375(9):819-29 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

Tang T, Eldabaje R, Yang L
Current Status of Biological Therapies for the Treatment of Metastatic Melanoma.
Anticancer Res. 2016; 36(7):3229-41 [PubMed] Related Publications
Compared to early-stage melanoma when surgical excision is possible, metastatic disease continues to offer a much grimmer prognosis as traditional chemotherapy treatment regimens offer relatively little survival benefit. This has led to changes in treatment approaches over the preceding two decades as contemporary methods for the treatment of advanced or metastatic melanoma now involve a number of biological modalities, which include immunotherapeutic approaches, targeted therapies and epigenetic modification therapies. Clinically available immunotherapeutic agents include interleukin 2 (IL-2), as well as drugs targeting the important immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The targeted therapeutic agents modulate specific pro-oncogenic mutations such as v-Raf murine sarcoma viral oncogene homolog B (BRAF), receptor tyrosine kinases, MEK inhibitors and potential future therapeutic targets, such as the CDK4/CDK6, PTEN and GNAQ/GNA11 genes. Additionally, an increasing understanding of the role of epigenetic alterations in the development and progression of melanoma now offers a new potential drug target. Several of these agents have shown promising results; however, in many investigations, combinations of different therapeutic approaches, each with different mechanisms of action, have yielded improved outcomes as treatment regimens continue to be further optimized by active research and patient disease sub-group analyses. This review summarizes the novel biological agents and new treatments, directly contributing to the significant improvement of biological therapies and markedly advancing knowledge of clinical application of newly approved and developed therapies in treatment of patients with metastatic melanoma.

Peddireddy V, Badabagni SP, Sulthana S, et al.
Association of TNFα(-308), IFNγ(+874), and IL10(-1082) gene polymorphisms and the risk of non-small cell lung cancer in the population of the South Indian state of Telangana.
Int J Clin Oncol. 2016; 21(5):843-852 [PubMed] Related Publications
BACKGROUND: Cytokine-mediated inflammation is important in the pathogenesis of non-small cell lung cancer (NSCLC). Genetic polymorphisms in cytokine genes and their association with lung cancer in the Indian population have not been reported.
METHODS: For the first time, we analyzed genetic polymorphisms of TNFα (-308), IFNγ (+874), and IL10 (-1082) genes in 246 NSCLC patients and 250 healthy controls in the South Indian population from Telangana using ARMS PCR.
RESULTS: IFNγ(+874) A/T and IL10(-1082) G/G gene polymorphisms were found to be significantly associated with NSCLC with 1.56- and 1.68-fold disease risk, respectively. There was no association between the risk of NSCLC and TNFα(-308) polymorphism. Gene polymorphisms stratified according to smoking revealed that IFNγ(+874) A/T polymorphisms in smokers increased the disease risk by 2.91 fold. IL10(-1082) G/G polymorphisms showed 2-fold increased risk among patients who were smokers when compared to the controls. However, there was no association between TNFα(-308), IFNγ(+874), and IL10(-1082) gene polymorphism and the stage of the NSCLC patients. The overall risk associated with the combination of these polymorphisms indicated that the TNFα(-308) G/A + IFNγ(+874) A/T + IL10(-1082) G/G genotype increased the risk by 1.5 fold.
CONCLUSIONS: The results of our study indicate an association between cytokine gene polymorphisms and the risk of NSCLC in an Indian population.

Yan Y, Liang Z, Du Q, et al.
MicroRNA-23a downregulates the expression of interferon regulatory factor-1 in hepatocellular carcinoma cells.
Oncol Rep. 2016; 36(2):633-40 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Interferon regulatory factor-1 (IRF-1) is a tumor-suppressor gene induced by interferon-γ (IFNγ) and plays an important role in the cell death of hepatocellular carcinoma (HCC). HCC tumors evade death in part by downregulating IRF-1 expression, yet the molecular mechanisms accounting for IRF-1 suppression in HCC have not yet been characterized. Previous studies have shown that microRNA-23a (miR-23a) can suppress apoptosis by targeting IRF-1. Therefore, we hypothesized that miR-23a promotes HCC growth by downregulating IRF-1. For the in vivo studies, 7 cases of resected HCC and adjacent liver samples were analyzed. For the in vitro studies, IRF-1 mRNA and protein were examined in HepG2 and Huh-7 HCC cells after IFNγ stimulation by real-time PCR and western blotting, respectively. To determine the role of miR-23a in regulating IRF-1, HepG2 cells were transfected with an miR-23a mimic or inhibitor, and IRF-1 expression was examined. Binding of miR-23a was assessed by cloning the 528-bp human IRF-1 3'-untranslated region (3'UTR) into luciferase reporter plasmid pMIR-IRF-1-3'UTR. The results showed that IRF-1 mRNA expression was downregulated in the human HCC tumor tissues compared to that in the adjacent background liver tissues. IFNγ-induced IRF-1 protein was less in the HepG2 tumor cells compared to that in the primary human hepatocytes. miR-23a expression was inversely correlated with IRF-1, and addition of the miR-23a inhibitor increased basal IRF-1 mRNA and protein. Likewise, the miR-23a mimic downregulated IFNγ-induced IRF-1 protein expression, while the miR-23a inhibitor increased IRF-1. Furthermore, the miR-23a mimic repressed IRF-1-3'UTR reporter activity, while the miR-23a inhibitor increased the reporter activity. These results demonstrated that IRF-1 expression is downregulated in human HCC tumors compared to that noted in the background liver. miR-23a downregulates the expression of IRF-1 in HCC cells, and the IRF-1 3'UTR has an miR‑23a binding site that binds miR-23a and decreases reporter activity. These findings suggest that the targeting of IRF-1 by miR-23a may be the molecular basis for IRF-1 downregulation in HCC and provide new insight into the regulation of HCC by miRNAs.

Yeh CH, Bellon M, Pancewicz-Wojtkiewicz J, Nicot C
Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients.
Proc Natl Acad Sci U S A. 2016; 113(24):6731-6 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2-independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.

Liu R, Luo F, Liu X, et al.
Biological Response Modifier in Cancer Immunotherapy.
Adv Exp Med Biol. 2016; 909:69-138 [PubMed] Related Publications
Biological response modifiers (BRMs) emerge as a lay of new compounds or approaches used in improving cancer immunotherapy. Evidences highlight that cytokines, Toll-like receptor (TLR) signaling, and noncoding RNAs are of crucial roles in modulating antitumor immune response and cancer-related chronic inflammation, and BRMs based on them have been explored. In particular, besides some cytokines like IFN-α and IL-2, several Toll-like receptor (TLR) agonists like BCG, MPL, and imiquimod are also licensed to be used in patients with several malignancies nowadays, and the first artificial small noncoding RNA (microRNA) mimic, MXR34, has entered phase I clinical study against liver cancer, implying their potential application in cancer therapy. According to amounts of original data, this chapter will review the regulatory roles of TLR signaling, some noncoding RNAs, and several key cytokines in cancer and cancer-related immune response, as well as the clinical cases in cancer therapy based on them.

Kivrak Salim D, Sahin M, Köksoy S, et al.
Local Immune Response in Helicobacter pylori Infection.
Medicine (Baltimore). 2016; 95(20):e3713 [PubMed] Article available free on PMC after 01/04/2017 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.

Yassin AM, Elnouby M, El-Deeb NM, Hafez EE
Tungsten Oxide Nanoplates; the Novelty in Targeting Metalloproteinase-7 Gene in Both Cervix and Colon Cancer Cells.
Appl Biochem Biotechnol. 2016; 180(4):623-637 [PubMed] Related Publications
In this study, we synthesized tungsten oxide (WO3) nanoplates, both crystallographic phases and the morphology of the samples were determined by powder x-ray diffraction and the scanning electron microscopy, respectively. The obtained data clarified that, the all prepared WO3·H2O samples were composed of large quantity of nanoplates. The cytotoxicity patterns of nanoplates were checked on both normal and cancer mammalian cell lines. Both nanoplates cytotoxicity did not exceed the 50 % inhibitory concentration (IC50) on the all normal tested cells even by using concentrations up to 1 mg/ml. In addition, orthorhombic tungsten oxide nanoplate was more potent against both Caco2 and Hela cells by showing inhibition percentages in cellular viability 64.749 and 72.27, respectively, and with cancer selectivity index reached 3.2 and 2.6 on both colon and cervix cancer, respectively. The anticancer effects of nanoplates were translated to alteration in both pro-apoptotic and anti-apoptotic genes expressions. Tungsten oxide nanoplates down regulated the expression of B cell lymphoma 2 (Bcl-2) and metalloproteinase-7 (MMP7) genes. In addition, orthorhombic tungsten oxide nanoplates showed more potentiation in IL2 and IL8 induction (40.43 pg/ml) and upregulation of TNF-α gene expression but with lower folds than Escherichia coli lipopolysaccharide (LPS) induction.

Kroon P, Gadiot J, Peeters M, et al.
Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma.
Cancer Immunol Immunother. 2016; 65(6):753-63 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.

El-Shemi AG, Ashshi AM, Na Y, et al.
Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model.
J Exp Clin Cancer Res. 2016; 35:74 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Gene-based virotherapy mediated by oncolytic viruses is currently experiencing a renaissance in cancer therapy. However, relatively little attention has been given to the potentiality of dual gene virotherapy strategy as a novel therapeutic approach to mediate triplex anticancer combination effects, particularly if the two suitable genes are well chosen. Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-12 (IL-12) have been emerged as promising pharmacological candidates in cancer therapy; however, the combined efficacy of TRAIL and IL-12 genes for treatment of human hepatocellular carcinoma (HCC) remains to be determined.
METHODS: Herein, we investigated the therapeutic efficacy of concurrent therapy with two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-ΔB/TRAIL) and IL-12 gene (Ad-ΔB/IL-12), respectively, on preclinical models of human HCC, and also elucidated the possible underlying mechanisms. The effects of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy were assessed both in vitro on Hep3B and HuH7 human HCC cell lines and in vivo on HCC-orthotopic model established in the livers of athymic nude mice by intrahepatic implantation of human Hep3B cells.
RESULTS: Compared to therapy with non-armed control Ad-ΔB, combined therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 elicited profound anti-HCC killing effects on Hep3B and HuH7 cells and on the transplanted Hep3B-orthotopic model. Efficient viral replication and TRAIL and IL-12 expression were also confirmed in HCC cells and the harvested tumor tissues treated with this combination therapy. Mechanistically, co-therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 exhibited an enhanced effect on apoptosis promotion, activation of caspase-3 and-8, generation of anti-tumor immune response evidenced by upregulation of interferon gamma (IFN-γ) production and infiltration of natural killer-and antigen presenting cells, and remarkable repression of intratumor vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) expression and tumor microvessel density.
CONCLUSIONS: Overall, our data showed a favorable therapeutic effect of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy against human HCC, and may therefore constitute a promising and effective therapeutic strategy for treating human HCC. However, further studies are warranted for its reliable clinical translation.

Chaurasiya S, Hew P, Crosley P, et al.
Breast cancer gene therapy using an adenovirus encoding human IL-2 under control of mammaglobin promoter/enhancer sequences.
Cancer Gene Ther. 2016; 23(6):178-87 [PubMed] Related Publications
Interleukin-2 (IL-2) has been used clinically for the treatment of some malignancies, but the toxicities associated with systemic IL-2 therapy are a major challenge. Here we have determined whether transcriptional targeting of IL-2 to breast cancer (BrCa) using an engineered human mammaglobin promoter/enhancer (MPE2) is a feasible option for reducing IL-2-associated toxicities while still achieving a meaningful antitumor effect. We have constructed nonreplicating adenovirus vectors encoding either a reporter gene (luciferase) or human IL-2 (hIL-2) complementary DNA under control of the MPE2 sequence, the murine cytomegalovirus immediate early (MCMV) promoter or the human telomerase reverse transcriptase (hTERT) promoter. Luciferase and hIL-2 complementary DNAs under the control of the MPE2 sequence in adenovirus vectors were expressed at high levels in BrCa cells and at lower levels in normal cells of human and murine origin. Cancer specificity of the hTERT promoter was found to be similar to that of the MPE2 promoter in cells of human origin, but reduced specificity in murine cells. The MPE2 regulatory sequence demonstrated excellent tissue specificity in a mouse tumor model. Whereas the MCMV promoter-controlled IL-2 vector generated high liver toxicity in mice, the MPE2-controlled IL-2 vector generated little or no liver toxicity. Both IL-2 vectors exerted significant tumor growth delay; however, attempts to further enhance antitumor activity of the IL-2 vectors by combining with the proapoptotic drug procaspase activating compound 1 (PAC1) were unsuccessful.

Mognol GP, Carneiro FR, Robbs BK, et al.
Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player.
Cell Death Dis. 2016; 7:e2199 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The NFAT (nuclear factor of activated T cells) family of transcription factors consists of four Ca(2+)-regulated members (NFAT1-NFAT4), which were first described in T lymphocytes. In addition to their well-documented role in T lymphocytes, where they control gene expression during cell activation and differentiation, NFAT proteins are also expressed in a wide range of cells and tissue types and regulate genes involved in cell cycle, apoptosis, angiogenesis and metastasis. The NFAT proteins share a highly conserved DNA-binding domain (DBD), which allows all NFAT members to bind to the same DNA sequence in enhancers or promoter regions. The same DNA-binding specificity suggests redundant roles for the NFAT proteins, which is true during the regulation of some genes such as IL-2 and p21. However, it has become increasingly clear that different NFAT proteins and even isoforms can have unique functions. In this review, we address the possible reasons for these distinct roles, particularly regarding N- and C-terminal transactivation regions (TADs) and the partner proteins that interact with these TADs. We also discuss the genes regulated by NFAT during cell cycle regulation and apoptosis and the role of NFAT during tumorigenesis.

Zhang H, Liang C, Hou X, et al.
Study of the combined treatment of lung cancer using gene-loaded immunomagnetic albumin nanospheres in vitro and in vivo.
Int J Nanomedicine. 2016; 11:1039-50 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Combination therapy for lung cancer has garnered widespread attention. Radiation therapy, gene therapy, and molecular targeted therapy for lung cancer have certain effects, but the disadvantages of these treatment methods are evident. Combining these methods can decrease their side effects and increase their curative effects. In this study, we constructed a pYr-ads-8-5HRE-cfosp-iNOS-IFNG plasmid (a gene circuit that can express IFNγ), which is a gene circuit, and used that plasmid together with C225 (cetuximab) to prepare gene-loaded immunomagnetic albumin nanospheres (IMANS). Moreover, we investigated the therapeutic effects of gene-loaded IMANS in combination with radiation therapy on human lung cancer in vitro and in vivo. The results showed that this gene circuit was successively constructed and confirmed that the expression of INFγ was increased due to the gene circuit. Gene-loaded IMANS combined with radiation therapy demonstrated improved results in vitro and in vivo. In conclusion, gene-loaded IMANS enhanced the efficacy of combination therapy, solved problems related to gene transfer, and specifically targeted lung cancer cells.

Wang YZ, Qiu SC
Prediction of key genes in ovarian cancer treated with decitabine based on network strategy.
Oncol Rep. 2016; 35(6):3548-58 [PubMed] Related Publications
The objective of the present study was to predict key genes in ovarian cancer before and after treatment with decitabine utilizing a network approach and to reveal the molecular mechanism. Pathogenic networks of ovarian cancer before and after treatment were identified based on known pathogenic genes (seed genes) and differentially expressed genes (DEGs) detected by Significance Analysis of Microarrays (SAM) method. A weight was assigned to each gene in the pathogenic network and then candidate genes were evaluated. Topological properties (degree, betweenness, closeness and stress) of candidate genes were analyzed to investigate more confident pathogenic genes. Pathway enrichment analysis for candidate and seed genes were conducted. Validation of candidate gene expression in ovarian cancer was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) assays. There were 73 nodes and 147 interactions in the pathogenic network before treatment, while 47 nodes and 66 interactions after treatment. A total of 32 candidate genes were identified in the before treatment group of ovarian cancer, of which 16 were rightly candidate genes after treatment and the others were silenced. We obtained 5 key genes (PIK3R2, CCNB1, IL2, IL1B and CDC6) for decitabine treatment that were validated by RT-PCR. In conclusion, we successfully identified 5 key genes (PIK3R2, CCNB1, IL2, IL1B and CDC6) and validated them, which provides insight into the molecular mechanisms of decitabine treatment and may be potential pathogenic biomarkers for the therapy of ovarian cancer.

Sun L, Xia WY, Zhao SH, et al.
An asymmetrically dimethylarginated nuclear 90 kDa protein (p90aDMA) induced by interleukin (IL)-2, IL-4 or IL-6 in the tumor microenvironment is selectively degraded by autophagy.
Int J Oncol. 2016; 48(6):2461-71 [PubMed] Related Publications
Protein arginine methylation is a common posttranslational modification resulting in the generation of asymmetric dimethylarginine (aDMA) and symmetric dimethylarginine (sDMA). Currently, the regulation of aDMA or sDMA by hypoxia, nutrient stavation or cytokines in the tumor microenvironment remains largely unknown. Here we show that p90aDMA, p70aDMA and p90sDMA, endogenous proteins containing aDMA or sDMA with mass 70 or 90 kDa, were widely and dominantly expressed in breast cancer cell lines. Notably, it was p90aDMA rather than p90sDMA that accumulated in the nucleus upon stimulation of cancer cells with interleukin (IL)-2, IL-4, IL-6 but not IL-8. In addition, the p90aDMA accumulation could be inhibited after treatment with a global methyltrasferase inhibitor, adenosine-2',3'-dialdehyde (AdOx). It seemed that some endogenous proteins in cancer cells were asymmetrically arginine-methylated upon exposure to some cytokines.. Furthermore, endogenous proteins of aDMA, such as p90aDMA and p70aDMA, were degraded in response to hypoxia, nutrient starvation and rapamycin treatment in breast and cervical cancer cells. IL-2/4/6 slightly increased basal autophagy but slightly decreased the rapamycin‑induced autophagy in cancer cells, suggesting that IL-2/4/6 and autophagy inducers play distinct roles in the regulation of aDMA of proteins. Conversely, rapamycin accumulated p90sDMA in MDA-MB‑231 and MCF-7 cells. Taken together, our results add a new dimension to the complexity of arginine methylated regulation in response to various stimuli and provide the first evidence that aDMA serves as one specific degradation signal of selective autophagy.

Wu Z, Sun Y, Zhu S, et al.
Association of Interferon Gamma +874T/A Polymorphism and Leukemia Risk: A Meta-Analysis.
Medicine (Baltimore). 2016; 95(12):e3129 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Interferon gamma (IFN-γ) has antitumor and antiproliferative effects, and previous studies indicated IFN-γ +874T/A (rs2430561) polymorphism were related to the risk of many types of cancer. However, the association between IFN-γ +874T/A polymorphism and leukemia risk remained controversial.We performed a comprehensive meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA). Electronic database of Embase, Pubmed, and the Cochrane Library were searched for eligible articles published up to December 13, 2015. The association between genetic polymorphisms and leukemia risk was measured by odds ratios (ORs) and its corresponding 95% confidence intervals (CIs).A total of 8 studies amounting to 420 patients and 767 control subjects were retrieved for this study. Although associations between IFN-γ +874T/A polymorphism and overall leukemia risks were lacking, decreased chronic lymphocytic leukemia (CLL) risk was detected in the allelic model (T vs A, OR=0.660, 95%CI = 0.483-0.902, P = 0.009, I = 0.0% and P = 0.863 for heterogeneity), the codominant model (TT vs AA, OR = 0.472, 95%CI = 0.247-0.902, P = 0.023, I = 0.0% and P = 0.994 for heterogeneity), and dominant model (TT + TA vs AA, OR = 0.457, 95%CI = 0.285-0.734, P = 0.001, I = 40.3% and P = 0.195 for heterogeneity) by using fixed-effect model separately. On the contrary, results indicated T carries have an increased chronic myelogenous leukemia (CML) risk in dominant model (TT + TA vs AA, OR = 1.783, 95%CI = 1.236-2.573, P = 0.002, I = 19.0% and P = 0.295 for heterogeneity).This study suggests IFN-γ +874T/A polymorphism are related to CML and CLL risk. In addition, our work also points out IFN-γ +874T/A polymorphism may play dual contrasting role in leukemia risk.

Xiao W, Dong X, Zhao H, et al.
Expression of MIF and c-erbB-2 in endometrial cancer.
Mol Med Rep. 2016; 13(5):3828-34 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The aim of the present study was to investigate the expression of c-erbB-2 and macrophage migration inhibitory factor (MIF) in endometrial cancer and to elucidate the significance of the early diagnosis and prognosis of endometrial cancer. The gene copy number of c‑erbB‑2 and MIF was characterized by reverse transcription quantitative polymerase chain reaction and the reactivity was assessed by immunohistochemistry in 70 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. A correlation between age, tumor stage, grade, myometrial invasion and lymph node metastasis was observed. The mRNA expression of c‑erbB‑2 and MIF was high in endometrial carcinoma. The positive expression rate of MIF protein in normal endometrium, atypical hyperplasia and endometrial carcinoma significantly increased along with the degree of aggravation of the disease by 20 (3/15), 45 (9/20) and 70% (35/50), respectively. The positive expression of MIF and c‑erbB‑2 was highest in endometrial cancer and a significantly higher level of protein was observed in tumors at stage I, stage G1, with a depth of myometrial invasion <0.4 cm and no lymph node metastasis. The protein expression of c‑erbB‑2 in endometrial cancer was higher in tumors at the G2‑3 phase, clinical stage III‑IV, lymph node metastasis, and had no association with the depth of myometrial invasion and age. MIF and c‑erbB‑2 were correlated with the occurrence and the development of endometrial cancer, and thus can be used for the early diagnosis and prognosis of endometrial cancer. The present study laid the foundation for identifying new treatments for endometrial cancer.

Lv W, Chen N, Lin Y, et al.
Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis.
Cancer Lett. 2016; 375(2):245-55 [PubMed] Related Publications
Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-κB phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1-dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer.

Kawaguchi K, Suzuki E, Yamaguchi A, et al.
Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer.
Breast Cancer. 2017; 24(1):111-120 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients.
METHODS: The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD-L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC).
RESULTS: We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-γ production.
CONCLUSION: Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy.

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