IRF6 Is Directly Regulated by ZEB1 and ELF3, and Predicts a Favorable Prognosis in Gastric Cancer

Li, Dandan; Cheng, Ping; Wang, Jingjie; Qiu, Xuemei; Zhang, Xudong; Xu, Li; Liu, Ying; Qin, Shanshan

doi:10.3389/fonc.2019.00220

Cited by 42 publications

(48 citation statements)

References 41 publications

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“…15 IRF6 expression was shown to be significantly decreased in gastric cancer, and gastric cancer patients with lower expression of IRF6 are predicted to have a shorter overall survival time and disease-free time. 18 Recent studies have confirmed that IRF6 can be regulated by multiple transcription factors, such as tumor protein 63, zinc finger E-box binding homeobox 1 and E74-like ETS transcription factor 3. 18,32 Moreover, miRs, as post-transcriptional regulators, are negatively related to the expression of target genes by fully or partially binding with their 3'-UTRs to repress mRNA and/or protein expression.…”

Section: Discussionmentioning

confidence: 97%

“…16,17 However, IRF6 does not participate in mediating the gene expression of interferon. 18 Intriguingly, IRF6…”

mentioning

confidence: 99%

“…has been validated as a promising prognostic indicator of gastric cancer and is negatively correlated with its promoter methylation. 18 In addition, IRF6 is down-regulated in breast cancer tissues and regulates the PI3K/AKT pathway to impede breast cancer progression. 15 IRF6 is also associated with premalignant and malignant cervicallesions.…”

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confidence: 99%

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miR‐587 promotes cervical cancer by repressing interferon regulatory factor 6

Ren

Dong

et al. 2020

The Journal of Gene Medicine

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Background: Interferon regulatory factor 6 (IRF6) exhibits tumor-suppressive functions in several cancer types. In the present study, the antitumor properties and related pathway mechanism of IRF6 were investigated in cervical cancer. Methods: Forty-one pairs of cervical cancer specimens and para-carcinoma tissues were collected to evaluate IRF6 expression using immunohistochemical staining and miR-587. The effects of miR-587 and IRF6 on cervical cancer cell growth were explored by MTT assays and in a HeLa tumor xenograft mouse model. The migration and invasion of cervical cancer cells were monitored using transwell assays. Results: IRF6 expression in cervical cancer specimens and cell lines was significantly reduced compared to that in the corresponding control group. In addition, IRF6 expression was negatively correlated with miR-587 in cervical cancer tissues. Bioinformatics algorithms and luciferase assays revealed that IRF6 is a potential target of miR-587, and miR-587 mimic transfection led to a significant repression of IRF6 protein levels in cervical cancer cells. We also discovered that the antineoplastic properties of IRF6 could be reversed by overexpressing miR-587 in cervical cancer cells. The up-regulation of miR-587 was correlated with poor overall survival in cervical cancer. In an in vivo experiment, miR-587 silencing induced HeLa tumor growth inhibition, which was associated with the up-regulation of IRF6 protein in the tumor. Conclusions: miR-587 post-transcriptionally represses IRF6 protein expression to abrogate the antineoplastic activity of IRF6. The miR-587/IRF6 signaling pathway plays a crucial role in the progression of cervical cancer and serves as a potential therapeutic target for the treatment of cervical cancer. K E Y W O R D S cervical cancer, interferon regulatory factor 6, miR-587, prognosis 1 | INTRODUCTION Cervical cancer is one of the most common gynecologic malignant neoplasms and ranks fourth for both incidence and mortality in females. 1 According to an epidemiological investigation, cervical cancer accounted for approximately 6.6% of the total incidents and 7.5% of the total cancer deaths among females in 2018. 1 In general, persistent human papillomavirus infection can lead to intraepithelial lesions of the cervix uteri, which is an inevitable cancerous process of cervical cancer. 2,3 The mechanisms of cervical carcinogenesis are complicated. Different signaling pathways, such as nuclear factorkappa B, mammalian target of rapamycin, phosphoinositide 3-kinase Yuefang Ren and Jie Dong contributed equally to this work.

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Section: Discussionmentioning

confidence: 97%

“…16,17 However, IRF6 does not participate in mediating the gene expression of interferon. 18 Intriguingly, IRF6…”

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confidence: 99%

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miR‐587 promotes cervical cancer by repressing interferon regulatory factor 6

Ren

Dong

et al. 2020

The Journal of Gene Medicine

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“…Moreover, the tissue repair phenotype is added to the list of other malfunctions observed in the heterozygous mouse (ie, brain volume, endotoxic shock response) validating this model as a powerful tool to understand IRF6‐related human conditions. As recent reports continue to implicate IRF6 in cancer, and the well‐established link between chronic wounds and cutaneous carcinogenesis, this model could be a great tool to further investigate this aspect of IRF6 biology.…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor 6 is required for proper wound healing in vivo

Rhea

Canady

et al. 2019

Developmental Dynamics

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Background Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft caused predominantly by mutations in Interferon Regulatory Factor 6 (IRF6). We previously reported that individuals with VWS have increased risk of wound healing complications following cleft repair compared with individuals with nonsyndromic orofacial clefts (nonsyndromic cleft lip and palate—NSCLP). In vitro, absence of IRF6 leads to impaired keratinocyte migration and embryonic wound healing. However, there is currently no data on tissue repair in adult animals and cells with reduced levels of IRF6 like in VWS. Results Excisional wounds of Irf6+/− and wild‐type animals were analyzed 4 and 7 days post‐wounding. Although all wounds were reepithelialized after 7 days, the epidermal and wound volume of repaired wounds was larger in Irf6+/−. These data were supported by increased keratinocyte proliferation in the neoformed epidermis and a less mature granulation tissue with increased cytokine levels. This effect was not cell autonomous, as Irf6+/− neonatal keratinocytes in vitro did not exhibit defects in scratch wound closure or proliferation. Keratinocytes from individuals with VWS also migrated similarly to keratinocytes from NSCLP individuals. Conclusions These data support a role for IRF6 in wound healing by regulating keratinocyte proliferation, granulation tissue maturation, and cytokine levels.

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“…The primers for wildtype and mutant CCND1 3'UTR were as follows, F: 5'-gggagctcCTGTCCCACTC CTACGATAC-3', R1 (wildtype): 5'-tctctagaTGTAACATCAAAGGCAGAAGG-3', R2 (Mutant): 5'-tctctagaTGTTTTTTCAAAGGCAGAAGGTTTGTGT-3'. The luciferase reporter assay was conducted as we previously described before [14]. Brie y, the BGC823 cells were seeded into 12-well-tissue plates 24h before transfection, and then co-transfected with 5 nM siRNA and 1mg plasmid using the Lipofectamine 2000 Reagent (Invitrogen), according to the manufacturer's instructions.…”

Section: Luciferase Reporter Assaymentioning

confidence: 99%

Global miRNA Expression Analysis Identifies miR-194, miR-100, miR-125b and miR-199a as Promising Biomarkers for Gastric Cancer and miR-194 Inhibits Gastric Cancer Cell Growth by Targeting CCND1

Li¹,

Wang²,

Zhang³

et al. 2020

Preprint

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BackgroundDifferent gastric cancer (GC) subtypes usually possess distinct clinical outcomes. The function of miR-194 in gastric cancer remains unclear and controversial. This study aimed to identify potential microRNAs that differentially expressed in subtypes and to elucidate the molecular mechanisms of miR-194 in GC.MethodsComprehensive miRNA expression analysis was performed using the available miRNA-seq data from TCGA stomach cancer cohort. The preferences of miR-194 in regulating target genes were determined by RNA sequencing studies. The function of miR-194 in GC was explored in GC cell lines by performing qRT-PCR assays, western blot assays, cell proliferation assays, luciferase report assays and flow cytometry assay.ResultsIn this study, we identified a series of miRNAs that can serve as prognostic biomarkers for GC. Among them, miR-100, miR-125b, miR-199a and miR-194 were the 4 most promising prognostic biomarkers in GC due to their significant associations with various clinical characteristics of patients. MiR-100, miR-125b and miR-199a predicted poor prognosis in GC, while miR-194 predicted favorable prognosis in GC. Besides, we provided the first comprehensive transcriptome analysis about miR-194 in GC. The results showed that miR-194 tended to regulated target genes by binding on their 3' untranslated regions in a 7-mer-A1 or 7-mer-m8 or 8-mer manner. The KEGG pathway analysis showed that cell cycle was one of the most affected pathways by miR-194 in GC. Moreover, CCND1 was proved to be a novel target gene of miR-194 in GC. Additionally, the downregulation of CCND1 by miR-194 in GC further led to cell growth inhibition and cell cycle arrest. ConclusionsMiR-100, miR-125b, miR-199a and miR-194 could serve as prognostic and diagnostic biomarkers for GC. MiR-194 might suppress GC cell growth mainly through targeting CCND1 and induction of cell cycle arrest.

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IRF6 Is Directly Regulated by ZEB1 and ELF3, and Predicts a Favorable Prognosis in Gastric Cancer

Cited by 42 publications

References 41 publications

miR‐587 promotes cervical cancer by repressing interferon regulatory factor 6

miR‐587 promotes cervical cancer by repressing interferon regulatory factor 6

Interferon regulatory factor 6 is required for proper wound healing in vivo

Global miRNA Expression Analysis Identifies miR-194, miR-100, miR-125b and miR-199a as Promising Biomarkers for Gastric Cancer and miR-194 Inhibits Gastric Cancer Cell Growth by Targeting CCND1

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