Involvement of IFN Regulatory Factor (IRF)-1 and IRF-2 in the Formation and Progression of Human Esophageal Cancers

Wang, Yan; Liu, Dong Ping; Chen, Ping Ping; Koeffler, H. Phillip; Xiang, Tong; Xie, Dong

doi:10.1158/0008-5472.can-06-3530

Cited by 88 publications

(88 citation statements)

References 47 publications

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“…Our recent results also established that both IRF-1 and IRF-2 are involved in the development and progression of ESCCs (15), but thus far, little attention has been paid to the influences of IFN-g on ESCC cells. In the present work, therefore, we studied in detail the functions of IFN-g in ESCC cells and displayed novel results that IFN-g induced the up-regulation of IRF-2 and IRF-2 attenuated the IFN-g pathway by inhibiting IFNGR1 transcription, which implied an interesting, previously undescribed, negative feedback loop for IFN-g-induced pathway.…”

Section: Introductionsupporting

confidence: 54%

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

et al. 2008

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IFN-; is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-; receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-; by repressing transcription of IFN-;-induced genes. Thus far, few studies have explored the influences of IFN-; on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-; in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-; 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-; 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-;. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-;-induced pathway in esophageal cancer cells: IFN-; induced IRF-2 upregulation, 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-;. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-; and IFNGR1 in human esophageal cancers.

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Section: Introductionsupporting

confidence: 54%

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

et al. 2008

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“…Moreover, the molecular background of the growthpromoting and anti-apoptotic effects of IRF-2 has been largely substantiated by its direct stimulatory effect on the expression of histone H4, cyclin-D1 and Bcl-2 as well as by its down-regulating effect on activated caspase-9. 16,17 Here we report, however, that univariate survival analyses show not only high intratumoral IRF-1 expression but also high-level IRF-2 expression to be associated with improved disease-free and overall survival in a large cohort of 138 ovarian cancer patients. This meaningful, albeit unexpected, finding regarding IRF-2 stands in contrast to the data on solid tumors published so far.…”

Section: Discussionmentioning

confidence: 72%

“…Furthermore, statistical data indicated that IRF-2 expression was tightly correlated with disease progression in esophageal cancer. 16 Moreover, besides the association between high-level IRF-2 expression and improved survival in univariate analyses, other of our findings argue against an oncogenic role of IRF-2 in ovarian cancer: (i) in contrast to other solid tumors such as diffusely infiltrating astrocytomas, breast and as already mentioned esophageal cancers, 16,18,19 the expression of IRF-2 was not found to be upregulated in either ovarian cancer tissue or established ovarian cancer cell lines, (ii) significantly higher levels of IRF-2 mRNA were found in early-stage when compared with advanced-stage ovarian cancers, and (iii) IRF-2 expression was inversely related to residual disease after primary debulking surgery. Concerning the latter point, there is excellent evidence to show that ovarian cancers, whose complete surgical clearance is impossible at primary surgery, exhibit a more aggressive phenotype with a completely different molecular signature than do cancers allowing optimal cytoreduction.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral interferon regulatory factor (IRF)‐1 but not IRF‐2 is of relevance in predicting patient outcome in ovarian cancer

Zeimet

Reimer

Wolf

et al. 2009

Intl Journal of Cancer

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IRF‐1 and IRF‐2 expression was determined by real‐time PCR in 138 ovarian cancer samples and 30 healthy ovarian biopsies and was correlated with the expression of other relevant immunologic parameters and common clinicopathologic variables. Regulation of IRF‐1 and IRF‐2 was evaluated by cytokine treatment of various ovarian cancer cell lines, human peritoneal mesothelial cells and ovarian surface epithelium. IRF‐1 but not IRF‐2 was constitutively over‐expressed in 5 of 7 ovarian cancer cell lines. Both IRFs were inducible with IFN‐γ and to a lesser extent with IL‐1 or TNF‐α, but not with IL‐6. Epidermal growth factor (EGF) treatment down‐regulated both IRFs. In ovarian cancer samples only IRF‐1, but not IRF‐2 mRNA, was up‐regulated when compared with healthy ovarian tissue. IRF‐1 but not IRF‐2 expression was significantly associated with interferon (IFN)‐γ and forkhead box P3 (FoxP3). In univariate survival analysis, strong expression of IRF‐1 and IRF‐2 predicted improved disease‐free survival (DFS) and overall survival (OS). In Cox regression analyses, IRF‐1 retained independent prognostic significance for DFS and OS and IFN‐γ for OS. In contrast to other solid tumors, IRF‐2 expression cannot be regarded as a classic oncoprotein associated with poor prognosis in ovarian cancer. Of the immunologic parameters investigated, intratumoral IRF‐1 expression is the most powerful independent predictor of a favorable clinical outcome. © 2008 Wiley‐Liss, Inc.

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“…These IRF molecules play roles in antiviral defense, immunoresponse/modulation, and cell growth regulation under stimulation with IFN-␣, ␤, and ␥ (35-38). IRF-1 and -2 have been shown to act as an agonist-antagonist pair involved in the regulation of many IFN-␥-inducible genes (35)(36)(37)(38). Interestingly, IFN-␥ markedly suppressed BH mRNA expression (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…Therefore, IRF-1/2 transcriptional factor would also be required for the minimal promoter activity of the BH gene under basal conditions. The IRF family is a group of transcription factors, and so far, nine IRF members (IRF-1-9) have been identified in various cell types and tissues (35)(36)(37)(38). These IRF molecules play roles in antiviral defense, immunoresponse/modulation, and cell growth regulation under stimulation with IFN-␣, ␤, and ␥ (35-38).…”

Section: Discussionmentioning

confidence: 99%

Bleomycin Hydrolase Is Regulated Biphasically in a Differentiation- and Cytokine-dependent Manner

Kamata

Yamamoto

Kawakami

et al. 2011

Journal of Biological Chemistry

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Loss-of-function mutation in the profilaggrin gene is a major risk factor for atopic dermatitis (AD). Previously, we showed that a neutral cysteine protease, bleomycin hydrolase (BH), has a role in generating natural moisturizing factors, and calpain I is an upstream protease in the filaggrin degradation pathway. Here, we investigated the transcriptional regulatory mechanisms of BH and the relevance of BH to AD. First, we cloned the 5-flanking region of BH. Deletion analyses identified a critical region for BH promoter activity within ؊216 bp upstream. Electrophoretic mobility shift assay revealed that MZF-1, Sp-1, and interferon regulatory factor-1/2 could bind to this region in vitro. Moreover, site-directed mutagenesis of the MZF-1 and Sp-1 motifs markedly reduced BH promoter activity. These data indicate that BH expression is up-regulated via MZF-1 and Sp-1. Interestingly, a Th1 cytokine, IFN-␥, significantly reduced the expression of BH. Analyses with site-directed mutagenesis and small interference RNA supported the suppressing effect of IFN-␥ on BH expression. On the other hand, a Th2 cytokine, IL-4, did not show any direct effect on BH expression. However, it down-regulated MZF-1 and Sp-1 in cultured keratinocytes, indicating that IL-4 could work as a suppressor in BH regulation. Lastly, we examined expression of BH in skins of patients with AD. BH activity and expression were markedly decreased in AD lesional skin, suggesting a defect of the filaggrin degradation pathway in AD. Our results suggest that BH transcription would be modulated during both differentiation and inflammation.During terminal differentiation, keratinocytes synthesize characteristic proteins, including filaggrin, loricrin, trychohyalin, and involucrin, which are encoded by the so-called "epidermal differentiation complex," a cluster of genes on human chromosome 1q21 (1, 2). Filaggrin is a key protein in formation of the cornified cell envelope, which is critical for an effective epidermal barrier (3, 4). Recent genetic studies have shown that loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, are the cause of the semi-dominant skin scaling disorder ichthyosis vulgaris and are a major risk factor for the development of atopic dermatitis (AD), 2 eczemarelated asthma, and other allergic phenotypes (4 -6). These mutations are present in 10 -40% of the population, depending on race and country of habitation.Filaggrin is deiminated by peptidylarginine deiminase, resulting in its unfolding and further degradation into hygroscopic amino acids that constitute the natural moisturizing factors (NMF) that maintain epidermal hydration (7,8). NMF consist primarily of amino acids, including citrulline, and their derivatives, such as pyrrolidone carboxylic acid and urocanic acids, together with lactic acid, urea, citrate, and sugars (9 -11). Previously, we identified the neutral cysteine protease bleomycin hydrolase (BH) as an NMF-generating enzyme and also showed that calpain I is an upstream protease in the fil...

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Involvement of IFN Regulatory Factor (IRF)-1 and IRF-2 in the Formation and Progression of Human Esophageal Cancers

Cited by 88 publications

References 47 publications

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

Intratumoral interferon regulatory factor (IRF)‐1 but not IRF‐2 is of relevance in predicting patient outcome in ovarian cancer

Bleomycin Hydrolase Is Regulated Biphasically in a Differentiation- and Cytokine-dependent Manner

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