Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IRF2 (cancer-related)
Cancers often evade immune surveillance by adopting peripheral tissue- tolerance mechanisms, such as the expression of programmed cell death ligand 1 (PD-L1), the inhibition of which results in potent antitumor immunity. Here, we show that cyclin-dependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows medulloblastoma (MB) to evade immune elimination. Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
Liu F, Yu X, Huang H, et al.Upregulation of microRNA-450 inhibits the progression of lung cancer in vitro and in vivo by targeting interferon regulatory factor 2.
Int J Mol Med. 2016; 38(1):283-90 [PubMed
] Related Publications
MicroRNAs (miRNAs) are a class of non‑coding RNAs that play pivotal roles in human lung cancer development. The majority of studies have focused on either non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In the present study, we investigated a plausible mechanism of action of miR‑450 in these types of lung cancer. We found that the level of miR‑450 was decreased in lung cancer cell lines, as well as in solid tumors. As exemplified in the H510A (SCLC) and H2291 (NSCLC) cells, transfection with lentivirus carrying miR‑450 upregulated miR‑450 expression and significantly attenuated lung cancer cell proliferation and invasion, as well as the growth of implantated tumors. Interferon regulatory factor 2 (IRF2) was also verified to be a direct target of miR‑450 in lung cancer cells. The overexpression of IRF2 in the H510A and H2291 cells abrogated the inhibitory effects of miR‑450 on lung cancer cell proliferation and invasion. Taken together, in this study, we identified a novel role of miR‑450 in lung cancer. miR-450 targets IRF2 and thus supresses lung cancer cell proliferation and invasion.
Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.
Andres SA, Bickett KE, Alatoum MA, et al.Interaction between smoking history and gene expression levels impacts survival of breast cancer patients.
Breast Cancer Res Treat. 2015; 152(3):545-56 [PubMed
] Related Publications
In contrast to studies focused on cigarette smoking and risk of breast cancer occurrence, this study explored the influence of smoking on breast cancer recurrence and progression. The goal was to evaluate the interaction between smoking history and gene expression levels on recurrence and overall survival of breast cancer patients. Multivariable Cox proportional hazards models were fitted for 48 cigarette smokers, 50 non-smokers, and the total population separately to determine which gene expressions and gene expression/cigarette usage interaction terms were significant in predicting overall and disease-free survival in breast cancer patients. Using methods similar to Andres et al. (BMC Cancer 13:326, 2013a; Horm Cancer 4:208-221, 2013b), multivariable analyses revealed CENPN, CETN1, CYP1A1, IRF2, LECT2, and NCOA1 to be important predictors for both breast carcinoma recurrence and mortality among smokers. Additionally, COMT was important for recurrence, and NAT1 and RIPK1 were important for mortality. In contrast, only IRF2, CETN1, and CYP1A1 were significant for disease recurrence and mortality among non-smokers, with NAT2 additionally significant for survival. Analysis of interaction between smoking status and gene expression values using the combined samples revealed significant interactions between smoking status and CYP1A1, LECT2, and CETN1. Signatures consisting of 7-8 genes were highly predictive for breast cancer recurrence and overall survival among smokers, with median C-index values of 0.8 and 0.73 for overall survival and recurrence, respectively. In contrast, median C-index values for non-smokers was only 0.59. Hence, significant interactions between gene expression and smoking status can play a key role in predicting breast cancer patient outcomes.
Chen YJ, Wu H, Zhu JM, et al.MicroRNA-18a modulates P53 expression by targeting IRF2 in gastric cancer patients.
J Gastroenterol Hepatol. 2016; 31(1):155-63 [PubMed
] Related Publications
BACKGROUND AND AIM: MicroRNA-18a (miR-18a) has been reported to be upregulated in gastric cancer (GC) tissues compared with normal gastric tissues. However, little is known about its prognostic value and biological roles.
METHODS: In this study, miR-18a expression in gastric adenocarcinoma (GAC) tissues and adjacent non-tumor tissues was validated by in situ hybridization, and the predictive values of miR-18a were explored. The biological roles of miR-18a and the underlying signal pathway were investigated in GC cell lines.
RESULTS: Overexpressed intra-tumoral miR-18a was associated with poor survival rate and was an independent prognostic factor for overall survival rate (P < 0.001) in GC patients. Forced expression of miR-18a remarkably enhanced cell proliferation, migration, and invasion in GC cells, while inhibition of miR-18a caused the opposite effects. Further study showed that miR-18a suppressed the expression of interferon regulatory factor 2 (IRF2) by directly binding to its 3'-untranslated region. Moreover, miR-18a expression levels are inversely correlated with IRF2 in human GC tissues. Western blot showed that forced expression of miR-18a could not only downregulate the expression of IRF2, but also inhibit the expression of P53, suggesting that IRF2 might play as a tumor suppressor by regulating P53 signaling in GC.
CONCLUSION: miR-18a modulated P53 expression by directly targeting IRF2 and had a high predictive value for prognosis of GAC patients. These results may lead to identification of therapeutic candidates of GC.
Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors) pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product) to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555) and rectal cancer (n = 754) cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035). Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR) were associated with colon cancer mortality (PARTP < 0.05); JAK2 (PARTP = 0.0086), PIK3CA (PARTP = 0.0098), and SMAD3 (PARTP = 0.0059) had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05). SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002). Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1) were significantly associated with rectal cancer (PARTP < 0.05). The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74) and was 10.99 (95% CI 5.30, 22.78) for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies.
BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features.
METHODS: Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied.
RESULTS: HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1).
CONCLUSIONS: Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.
Sakai T, Mashima H, Yamada Y, et al.The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer.
Pancreas. 2014; 43(6):909-16 [PubMed
] Related Publications
OBJECTIVE: Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer.
METHODS: We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line.
RESULTS: The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2-overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics.
CONCLUSIONS: Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.
Kneitz B, Krebs M, Kalogirou C, et al.Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3.
Cancer Res. 2014; 74(9):2591-603 [PubMed
] Related Publications
A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high-risk prostate cancer, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness, and apoptosis in prostate cancer at least partially via STAT1/STAT3-mediated activation of the JAK/STAT signaling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signaling pathway. miR-221 expression sensitized prostate cancer cells for IFN-γ-mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk prostate cancer.
High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.
Camicia R, Bachmann SB, Winkler HC, et al.BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma.
J Cell Sci. 2013; 126(Pt 9):1969-80 [PubMed
] Related Publications
The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNγ) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1α and STAT1β, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1β. Moreover, BAL1 physically interacts with both STAT1α and STAT1β through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1β, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemo-resistance in DLBCL. As a consequence constitutive IFNγ-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.
Eto M, Kamba T, Miyake H, et al.STAT3 polymorphism can predict the response to interferon-α therapy in patients with metastatic renal cell carcinoma.
Eur Urol. 2013; 63(4):745-52 [PubMed
] Related Publications
BACKGROUND: In our 2007 retrospective study, we reported that single nucleotide polymorphisms (SNPs) in the signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3) gene were significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC).
OBJECTIVE: To prospectively confirm those results, the Japan Immunotherapy SNPs-Study Group for Kidney Cancer conducted this trial.
DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, prospective study, 203 eligible patients were enrolled. We evaluated the correlation between the antitumor effects of IFN-α and 11 SNPs (STAT3-2, STAT3-0, SOCS3-1, IL4R-34, PTGS1-3, PTGS1-4, PTGS1-5, PTGS2-12, IRF2-67, ICSBP-38, and TAP2-5) in eight genes in 180 patients who received IFN-α for >12 wk.
INTERVENTIONS: Patients were treated with three doses per week of IFN-α 5 million IU.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the association of response to IFN-α and overall survival (OS) with genetic polymorphisms using a chi-square test and a logistic regression model.
RESULTS AND LIMITATIONS: The response rate of IFN-α was 13.8% (28 of 203 patients; 9 complete responses [CRs], 19 partial responses [PRs]). The CR rate of 4.4% was higher than we expected. Response to IFN-α was not associated with any of the 11 SNPs examined. However, when we assessed patients with CR, PR, and stable disease >24 wk as a group representing those with clinical response, a significant association was observed between STAT3-2 (rs1905341) and the clinical response of IFN-α (p=0.039). Namely, C/C genotype of STAT3-2 was significantly associated with the clinical response of IFN-α and OS. These results were generated in Japanese patients and should be studied in other ethnic groups.
CONCLUSIONS: This is the first prospective study demonstrating that a STAT3 polymorphism can be a predictive marker for treatment with IFN-α for patients with mRCC.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.
Cui L, Deng Y, Rong Y, et al.IRF-2 is over-expressed in pancreatic cancer and promotes the growth of pancreatic cancer cells.
Tumour Biol. 2012; 33(1):247-55 [PubMed
] Related Publications
Pancreatic cancer is one of the most malignant diseases in the world. Interferon regulator factor 2 (IRF-2), an interferon regulatory factor, has been known to act as an oncogene in distinct types of cancer. In this study, we found that the expression of IRF-2 was up-regulated in primary pancreatic cancer samples and associated with tumor size, differentiation, tumor-node-metastasis stage, and survival of the patients. In pancreatic cancer cells, knockdown on the expression of IRF-2 inhibited cell growth in the liquid culture and on the soft agar. Mechanistically, IRF-2 modulated the growth of pancreatic cancer cells through regulating proliferation and apoptosis effectors, such as cyclin D1 and BAX. Collectively, these results suggest that IRF-2 plays an important role in the tumorigenesis of pancreatic cancer and down-regulation of IRF-2 would be a new treatment target for pancreatic cancer.
Russ AC, Sander S, Lück SC, et al.Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia.
Haematologica. 2011; 96(12):1783-91 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs are regulators of gene expression, which act mainly by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To shed further light on the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation we performed an integrative analysis of microRNA and mRNA expression data sets.
DESIGN AND METHODS: Both microRNA and gene expression profiles were investigated in samples from a cohort of adult cytogenetically normal acute myeloid leukemia patients (n=43; median age 46 years, range 23-60 years) with known NPM1 mutation status (n=23 mutated, n=20 wild-type) and the data were integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative reverse transcriptase polymerase chain reaction, western blotting and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays.
RESULTS: Our integrative approach of analyzing both microRNA- and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA - target mRNA interactions we identified and validated 77 novel candidates with known or potential involvement in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs, such as miR-29a and miR-30c, might contribute to sensitivity to cytarabine, which is observed in NPM1 mutated acute myeloid leukemia.
CONCLUSIONS: Overall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA - target gene interactions of potential relevance for acute myeloid leukemia treatment.
Interferons (IFNs) are proteins involved in many functions including antiviral and antimicrobial response, apoptosis, cell cycle control and mediating other cytokines. IFN gamma (IFNG) is a proinflammatory cytokine that modulates many immune-related genes. In this study we examine genetic variation in IFNG, IFNGR1, IFNGR2 and interferon regulatory factors (IRFs) to determine associations with colon and rectal cancer and survival after diagnosis. We include data from two population-based incident studies of colon cancer (1555 cases and 1956 controls) and rectal cancer (754 cases and 959 controls). Five tagSNPs in IFNG, IRF2 and IRF3 were associated with colon cancer and eight tagSNPs in IFNGR1, IFNGR2, IRF2, IRF4, IRF6 and IRF8 were associated with rectal cancer. IRF3 rs2304204 was associated with the strongest direct association and IRF2 3775554 with the strongest inverse association for colon cancer [odds ratios (ORs) 1.43, 95% confidence interval (CI) 1.12-1.82 for recessive model and 0.52, 95% CI 0.28-0.97 for unrestricted model]. For rectal cancer, IFNGR1 rs3799488 was directly associated with risk (OR 2.30, 95% CI 1.04-5.09 for recessive model), whereas IRF6 rs861020 was inversely associated with risk (OR 0.57, 95% CI 0.34-0.95). Several single-nucleotide polymorphisms interacted significant with both NF-κB1 and IL6 and with aspirin/non-steroidal anti-inflammatory drugs and cigarette smoking. Using a summary score to estimate mutational load, we observed a hazard rate ratio (HRR) close to 5.00 (95% CI 2.73-8.99) for both colon and rectal (HRR 4.83, 95% CI 2.34-10.05) cancer for those in the category having the most at-risk genotypes. These data suggest the importance of IFN-signaling pathway on colon and rectal cancer risk and survival after diagnosis.
Zhang H, Ma H, Wang Q, et al.Analysis of loss of heterozygosity on chromosome 4q in hepatocellular carcinoma using high-throughput SNP array.
Oncol Rep. 2010; 23(2):445-55 [PubMed
] Related Publications
To identify tumour suppressor genes (TSGs) associated with hepatocellular carcinoma (HCC) on chromosome 4q using a high-throughput single nucleotide polymorphism (SNP) array, we first scanned for loss of heterozygosity (LOH) of 40 SNPs on chromosome 4q and discovered 2 hot regions: 4q24-26 and 4q34.3-35. We then further scanned for LOH of 338 SNPs in genes around 4q34.3-35 and discovered 3 genes with the most frequent LOH: nei endonuclease VIII-like 3 (NEIL3), interferon regulatory factor 2 (IRF2) and inhibitor of growth family member 2 (ING2). A review of the literature indicates only ING2 might be a TSG associated with HCC.
Masumi A, Ito M, Mochida K, et al.Enhanced RIG-I expression is mediated by interferon regulatory factor-2 in peripheral blood B cells from hepatitis C virus-infected patients.
Biochem Biophys Res Commun. 2010; 391(4):1623-8 [PubMed
] Related Publications
Chronic hepatitis C patients carry the risk of developing into B-cell non-Hodgkin's lymphoma (B-NHL). To clarify the mechanisms underlying this association, we first investigated the molecular markers of B cells from hepatitis C virus (HCV)-infected patients. CD19-positive cells were isolated as B cells from the peripheral blood mononuclear cells of patients infected with the hepatitis C virus and IFN-related gene expression was analyzed. We found that RIG-I and IRF-2 expression were up-regulated in CD19-positive cells from the infected patients. In vitro luciferase reporter analysis using human cell lines indicated that IRF-2 activates the human RIG-I promoter. IRF-2 expression levels were enhanced by HCV cDNA transfection in Huh7 cells. In addition, we observed much less induction in the interferon stimulated gene 15 (ISG15) after Sendai virus (SenV) stimulation of CD19-positive cells from infected patients versus healthy controls, thereby suggesting an impairment of RIG-I downstream signaling in HCV-infected patients. Hence, we found that the failure of the anti-viral response with enhanced IRF-2 oncogenic protein expression in blood B cells from HCV-infected patients. Our results provide important information to better understand the role of IRFs in the cause of HCV chronic infection.
Choo A, Palladinetti P, Holmes T, et al.siRNA targeting the IRF2 transcription factor inhibits leukaemic cell growth.
Int J Oncol. 2008; 33(1):175-83 [PubMed
] Related Publications
Interferon regulatory factor (IRF) 1 and its functional antagonist IRF2 were originally discovered as transcription factors that regulate the interferon-beta gene. Control of cell growth has led to the definition of IRF1 as a tumour suppressor gene and IRF2 as an oncogene. Clinically, approximately 70% of cases of acute myeloid leukaemia demonstrate dysregulated expression of IRF1 and/or IRF2. Our previous studies have shown that human leukaemic TF-1 cells exhibit abnormally high expression of both IRF1 and IRF2, the latter acting to abrogate IRF1 tumour suppression, making these cells ideal for analysis of down-regulation of IRF2 expression. A novel G418 screening protocol was developed and used for identifying effective siRNA that targets IRF2 (siIRF2). Using optimized siIRF2 in leukaemic TF-1 cells, IRF2 was down-regulated by approximately 70% at both mRNA and protein levels. Phenotypically, this resulted in growth inhibition associated with G2/M arrest as well as induction of polyploidy, differentiation and apoptosis. In contrast to these results, siIRF2 targeting did not affect normal haematopoietic stem/progenitor cell growth. These results indicate the potential utility of IRF2 inhibition as a therapeutic approach to cancer.
Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN-alpha) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN (IFN-gamma), on the other hand, supports melanoma cell survival, possibly through constitutive activation of iNOS expression. We therefore conducted this study to explore the molecular pathways of MDA7/IL-24 regulation of apoptosis via the intracellular induction of IFNs in melanoma. We hypothesized that the restoration of the MDA7/IL-24 axis leads to upregulation of class I IFNs and induction of the apoptotic cascade. We found that MDA7/IL-24 induces the secretion of endogenous IFN-beta, another class I IFN, leading to the arrest of melanoma cell growth and apoptosis. We also identified a series of apoptotic markers that play a role in this pathway, including the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-FasL. In summary, we described a novel pathway of MDA7/IL-24 regulation of apoptosis in melanoma tumors via endogenous IFN-beta induction followed by IRF regulation and TRAIL/FasL system activation.
Wang Y, Liu D, Chen P, et al.Negative feedback regulation of IFN-gamma pathway by IFN regulatory factor 2 in esophageal cancers.
Cancer Res. 2008; 68(4):1136-43 [PubMed
] Related Publications
IFN-gamma is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-gamma receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-gamma by repressing transcription of IFN-gamma-induced genes. Thus far, few studies have explored the influences of IFN-gamma on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-gamma in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-gamma was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-gamma induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-gamma. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-gamma-induced pathway in esophageal cancer cells: IFN-gamma induced IRF-2 up-regulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-gamma. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-gamma and IFNGR1 in human esophageal cancers.
Wang Y, Liu DP, Chen PP, et al.Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers.
Cancer Res. 2007; 67(6):2535-43 [PubMed
] Related Publications
IFN regulatory factor (IRF)-1 and IRF-2 are generally regarded as a tumor suppressor and an oncoprotein, respectively. However, little is known about their expression and function in esophageal squamous cell carcinomas (ESCC). In our present work, IRF-1 expression was decreased and IRF-2 expression was increased in ESCCs compared with matched normal esophageal tissues. Moreover, statistical data indicated that IRF-2 expression was tightly correlated with progression of ESCCs. As expected, overexpression of either IRF-1 or IRF-2 in an ESCC cell line resulted in either suppression or enhancement of cell growth, respectively. Also, proliferation- and apoptosis-related molecules (p21(WAF1/CIP1), cyclin-D1, Bcl-2, and histone H4) were regulated by IRF-1 and IRF-2. Additionally, high levels of IRF-2 blocked the function of IRF-1 by preventing the latter from translocating into the nucleus; in contrast, knock down of IRF-2 by small interfering RNA permitted nuclear localization and activity of IRF-1. In vivo assay using nude mice indicated that the tumorigenicity of ESCC cells was enhanced with IRF-2 overexpression but dramatically attenuated after forced expression of IRF-1. In conclusion, IRF-1 and IRF-2 are able to regulate tumorigenicity of ESCC cells as antioncoprotein and oncoprotein, respectively. Relative amounts of IRF-1 to IRF-2 are functionally very important for the development and progression of ESCCs, and reduction of the ratio of IRF-1/IRF-2 may lead to the enhancement of tumorigenicity of ESCC cells. Therefore, levels of IRF-1 and IRF-2 are useful indicators in diagnosis and prognosis for ESCCs, and these molecules are potential drug targets for ESCC therapy.
The MHC class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-gamma in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-gamma in multiple myeloma cells, first the ability of these cells to respond to IFN-gamma was examined. RT-PCR analyses show that IFN-gammaR1, the IFN-gamma-binding chain of the IFN-gamma receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-gamma treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-gamma. RT-PCR and functional promoter analyses show that IFN-gamma upregulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to upregulate CIITA pIV and MHC II expression in response to IFN-gamma treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-gamma.
Choo A, Palladinetti P, Passioura T, et al.The role of IRF1 and IRF2 transcription factors in leukaemogenesis.
Curr Gene Ther. 2006; 6(5):543-50 [PubMed
] Related Publications
Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. Although of the order of 75-85% of patients will achieve complete remission after induction chemotherapy, long-term survival is still relatively low. Despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathogenomic event to act as a drug target. Interferon regulatory factor 1 (IRF1) is a member of a family of related proteins that act as transcriptional activators or repressors. IRF1 and its functional antagonist IRF2 originally discovered as transcription factors regulating the interferon-beta (IFN-beta) gene, are involved in the regulation of normal haematopoiesis and leukaemogenesis. IRF1 appears to act as a tumour suppressor gene and IRF2 as an oncogene. IRF1 acts to repress IRF2 function through the repression of cyclin-dependent kinase (CDK) inhibitor p21WAF1 critical for cell growth control. It appears that the tumour suppression function of IRF1 is abolished by IRF2. This review focuses on the interaction between IRF1 and IRF2 in myeloid development and leukaemogenesis, particularly in relation to the Ras signalling pathway. IRF2 may be a viable and specific therapeutic target in human leukaemia.
De Ambrosis A, Casciano I, Croce M, et al.An interferon-sensitive response element is involved in constitutive caspase-8 gene expression in neuroblastoma cells.
Int J Cancer. 2007; 120(1):39-47 [PubMed
] Related Publications
We previously identified a 1.2 Kb DNA element (P-1161/+16), 5' to caspase-8 exon-1, that acts as promoter in caspase-8-positive, but not in caspase-8-negative neuroblastoma (NB) cells. The P-1161/+16 DNA element regulates both constitutive and interferon IFN-gamma-inducible caspase-8 expression. Two GAS (IFN-activated sequence, STAT-1 binding site) and two ISRE (interferon sensitive response element, IRF binding site) were present in P-1161/+16. Deletion studies indicated that elements essential for promoter activity in NB cells were present in a 167 bp region 5' flanking exon-1 (P-151/+16), which contains an ISRE at position -32. The transcription initiation site was mapped by 5' rapid amplification of cDNA end (RACE) at position -20 from caspase-8 cDNA reference sequence. Disruption of the ISRE-32 indicated that it is required for both constitutive and IFN-gamma-inducible caspase-8 expression. IRF-1 and IRF-2 transcription factors bind to the (-151/+16) DNA fragment in vitro. Chromatin immunoprecipitation (ChIP) assays showed that IRF-1 and IRF-2 bind to the DNA region at the 5' of caspase-8 gene in NB cells, which show constitutive expression but not in caspase-8 negative cells. In these last cells, up-regulation of caspase-8 by IFN-gamma was associated to induction of IRF-1 and IRF-2 binding to caspase-8 promoter and increased histone acetylation. Moreover, RNA interference experiments also supported the involvement of IRF-1 and IRF-2 in constitutive caspase-8 expression in NB cells.
Diallo JS, Péant B, Lessard L, et al.An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell lines.
Prostate. 2006; 66(12):1245-56 [PubMed
] Related Publications
BACKGROUND: Inositol hexakisphosphate (IP6) is a phytochemical exhibiting anticancer activity. Because few prostate cancer (PCa) cell lines have been used to study IP6, we assessed its efficacy in a panel of PCa cell lines.
METHODS AND RESULTS: Using WST-1 assays we observed that, although androgens did not modulate its efficacy, IP6 was more active in androgen receptor (AR) negative cells than in AR-positive cells. Stable expression of the AR in PC3 cells (PC3(AR)) decreased the response to IP6, which was reversed by an AR-targeting siRNA. Furthermore, AR expression in PC3 cells resulted in significantly reduced caspase-3 activation (P < 0.001) and DNA fragmentation (P < 0.05) in response to IP6. Similarly, although treatment with IP6 caused the upregulation of NF-kappaB-responsive (IkappaB-alpha, IRF-2) and p53/E2F-responsive genes (Puma, Noxa) in PC3 cells, this increase was reduced in PC3AR cells (P < 0.01).
CONCLUSION: We conclude that resistance to IP6 can be linked to a ligand-independent AR function.
The nuclear transcription factor interferon regulatory factor-1 (IRF-1) is a putative tumor suppressor, but the expression and function of IRF-1 in esophageal adenocarcinoma (EA) remain unknown. We hypothesized that IRF-1 expression was reduced or lost in EA and that restoration of IRF-1 would result in the apoptosis of EA cells in vitro and the inhibition of tumor growth in vivo. Three EA cell lines were used to examine IRF-1 expression, IFN-gamma responsiveness, and the effects of IRF-1 overexpression using a recombinant adenoviral vector (Ad-IRF-1). All three EA cell lines produced IRF-1 protein following IFN-gamma stimulation, although IFN-gamma did not induce cell death. In contrast, Ad-IRF-1 infection resulted in high levels of IRF-1 protein and triggered apoptosis in all three EA cell lines. Potential mechanisms for the differential response to IFN-gamma versus Ad-IRF-1--such as modulation of c-Met or extracellular regulated kinase signaling, or altered expression of IRF-2, Fas, or survivin--were investigated, but none of these mechanisms can account for this observation. In vivo administration of IRF-1 in a murine model of EA modestly inhibited tumor growth, but did not lead to tumor regression. Strategies aimed at increasing or restoring IRF-1 expression may have therapeutic benefits in EA.
Connett JM, Badri L, Giordano TJ, et al.Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays.
J Interferon Cytokine Res. 2005; 25(10):587-94 [PubMed
] Related Publications
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine with potent antitumor effects, both in vitro and in vivo. The antitumor activity of IFN-gamma is mediated in part through IFN regulatory factor-1 (IRF-1) and may be blocked by IRF-2. To test our hypothesis that some tumors escape the antitumor effects of IFN-gamma by cellular changes reflected in IRF-1 and IRF-2 expression, we examined IRF-1 and IRF-2 expression in tissue microarrays (TMA) containing 187 specimens of clinically defined invasive breast carcinoma. TMAs (Cooperative Breast Cancer Tissue Resource [CBCTR], National Cancer Institute [NCI]) were stained and then scored by three evaluators blinded to the patients' clinical status. After final scoring, the CBCTR provided the available clinical data for each patient. Whether sorted by carcinoma type or for all data together, statistical analysis showed a significant positive correlation between IRF-1 and IRF-2 expression (p = 0.01) and a negative correlation between IRF-1 expression and tumor grade (p = 0.005). IRF-1 expression is consistent with its role as a tumor suppressor; high-grade breast carcinomas were less likely to maintain expression of IRF-1, a finding consistent with a role for IRF-1 as a tumor suppressor. Further, tumors maintained expression of IRF-2 if there was coincident expression of IRF-1. These data support a model in which alterations of the expression of intracellular effectors of IFN-gamma signaling may diminish the immune-mediated tumor control mechanisms of IFN-gamma.
Connett JM, Hunt SR, Hickerson SM, et al.Localization of IFN-gamma-activated Stat1 and IFN regulatory factors 1 and 2 in breast cancer cells.
J Interferon Cytokine Res. 2003; 23(11):621-30 [PubMed
] Related Publications
The aim of the present work was to evaluate the induction and localization of Stat1, interferon (IFN) regulatory factor-1 (IRF-1), and IRF-2 after IFN-gamma exposure of human breast cancer cell lines, SKBR3, MDA468, MCF7, and BT20. Results from growth assays, Western staining, electrophoretic mobility shift assay (EMSA), and immunohistochemical staining were collated to test our hypothesis that immunohistochemical analysis of Stat1, IRF-1, and IRF-2 would provide additional information about the functionality of the IFN-gamma signaling pathway in human tumor lines. EMSA results showed that in each of four cell lines, Stat1 expression was increased and demonstrated functional activity after IFN-gamma stimulation. Western and EMSA analysis showed upregulation of IRF-1 but not IRF-2 in each cell line. Confocal microscopy of cells stained for Stat1, IRF-1, and IRF-2 confirmed the results and also provided novel information about the intracellular localization of proteins and intercellular variations in responses. The proportion of cells with IRF-1 stimulation and translocation was positively correlated with the IFN-gamma growth suppression in vitro. In conclusion, using four independent assays, we have demonstrated that heterogeneity in IFN-gamma-mediated upregulation of signal transduction proteins can be detected in vitro and that these differences can explain distinct cellular growth effects.
Yim JH, Ro SH, Lowney JK, et al.The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-gamma growth inhibition of human breast carcinoma cell lines.
J Interferon Cytokine Res. 2003; 23(9):501-11 [PubMed
] Related Publications
Interferon (IFN) regulatory factor-1 (IRF-1) and IRF-2 play opposing roles in the regulation of many IFN-gamma-inducible genes. To investigate the signal transduction pathway in response to IFN-gamma in light of differences in growth effects, we selected four human breast carcinoma cell lines based on a spectrum of growth inhibition by IFN-gamma. MDA468 growth was markedly inhibited by IFN-gamma, and it showed substantial induction of IRF-1 mRNA but little IRF-2 induction. SKBR3 showed little growth inhibition and little induction of IRF-1 mRNA but significant induction of IRF-2 mRNA. HS578T and MDA436 growth inhibition and IRF-1/IRF-2 induction were intermediate. All four cell lines showed intact receptor at the cell surface and Stat1 translocation to the nucleus by immunostaining. By EMSA, there were marked differences in the induced ratio of IRF-1 and IRF-2 binding activity between the cell lines that correlated with growth inhibition. Finally, antisense oligonucleotides specific for IRF-1 attenuated IFN-gamma growth inhibition in MDA436 and MDA468, confirming the direct role of IRF-1 in IFN-gamma growth inhibition. Induction of IRF-1 causes growth inhibition in human breast cancer cell lines, and induction of IRF-2 can oppose this. The relative induction of IRF-1 to IRF-2 is a critical control point in IFN-gamma response.