Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells

Ohsugi, Tomoyuki; Yamaguchi, Kiyoshi; Zhu, Ce; Ikenoue, Tsuneo; Takane, Kiyoko; Shinozaki, Masaru; Tsurita, Giichiro; Yano, Hideaki; Furukawa, Yoichi

doi:10.1038/s41388-019-0856-9

Cited by 27 publications

(19 citation statements)

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“…8 Each IRF family member exhibits functional specificity and plays a vital role in the initiation and progression of carcinogenesis. 9 For example, IRF1, 3, 5, 7 and 9 have tumor-promoting functions, [9][10][11][12][13] whereas IRF2 and IRF6 are candidate tumor suppressor genes. 14,15 Classically, IRF6 is a key determinant of skin development and keratinocyte differentiation.…”

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confidence: 99%

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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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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“…It is now clear that IRF1 has anti-oncogenic activity by blocking cell cycle progression, inducing tumor suppressor genes, downregulating growth-promoting genes and upregulating the apoptosis process ( 6 , 45 ). The present study revealed that when IRF1 was upregulated, the proliferation rate of CRC cells was decreased, and the tumor size was smaller than that of the control.…”

Section: Discussionmentioning

confidence: 99%

IRF1 regulates the progression of colorectal cancer via interferon‑induced proteins

et al. 2021

Int J Mol Med

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Radiation is one of the main methods for the treatment of colorectal cancer (CRC) before or after surgery. However, radiotherapy tolerance of patients with CRC is often a major concern. Interferon regulatory factor 1 (IRF1) is a member of the IRF family and is involved in the development of multiple diseases, including tumors. The present study investigated the role of IRF1 in the development and radiation sensitivity of CRC. Immunohistochemistry was performed to examine the expression levels of IRF1 in tissue samples from patients with CRC, as well as in nude mice. MTT, 5-ethynyl-20-deoxyuridine, colony formation, cell cycle alteration and apoptosis assays were performed in CRC cell lines. Western blotting and immunofluorescence were used to detect the expression levels of a series of proteins. RNA sequencing was applied to identify genes whose expression was upregulated by IRF1 overexpression. Xenograft nude mouse models and hematoxylin and eosin staining were used to validate the present findings in vivo . It was revealed that the expression levels of IRF1 were significantly lower in CRC tissues than in adjacent tissues. IRF1 upregulation inhibited cell proliferation and colony formation, caused G 1 cell arrest, promoted cell apoptosis, and enhanced the sensitivity of CRC cells to X-ray irradiation. The role of IRF1 in promoting the radiosensitivity of CRC was further demonstrated in nude mice with CRC xenografts. In addition, RNA sequencing revealed that overexpression of IRF1 in CRC cells significantly increased the expression levels of interferon-induced protein family members interferon α inducible protein 6, interferon induced transmembrane protein 1 and interferon induced protein 35 (fold change >2.0). In summary, the present study demonstrated that the upregulation of IRF1 inhibited the progression and promoted the radiosensitivity of CRC, likely by regulating interferon-induced proteins.

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“…Loss of interferon regulatory factor 1 (IRF1) function causes severe susceptibility to infections in mice and humans (81). IRF1 suppresses tumor cell growth, stimulating immune responses against tumor cells (81)(82)(83)(84). Defects in IRF1 are associated with gastric and lung cancer, and myelogenous leukemia (82).…”

Section: Discussionmentioning

confidence: 99%

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

Maestri

Duszka

Kuznetsov

2021

Preprint

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Systematic analysis of calorie restriction (CR) mechanisms and pathways in cancer biology has not been carried out, leaving therapeutic benefits unclear. Using a systems biology approach and metadata analysis, we studied gene expression changes in the response of normal mouse duodenum mucosa (DM) to short-term (2-weeks) 25% CR as a biological model. We found a high similarity of gene expression profiles in human and mouse DM tissues. Surprisingly, 26% of the 467 CR responding differential expressed genes (DEGs) in mice consist of cancer-associated genes, most never studied in CR contexts. The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways (MRP) that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest a misbalance in telomere maintenance and activation of metabolic pathways playing dual (anti-cancer and pro-oncogenic) roles. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor immune evasion controls. Thus, CR induces MRP suppressing multiple immune mechanics and activating oncogenic pathways, potentially driving pre-malignant and cancer states. These findings may change the paradigm regarding the anti-cancer role of CR and initiate specific treatment target development.

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Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells

Cited by 27 publications

References 60 publications

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

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

IRF1 regulates the progression of colorectal cancer via interferon‑induced proteins

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

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