IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the RAS-RAC1 pathway.
Hong Min,Zhang Zuoyang,Chen Qing,Lu Yanxia,Zhang Jianming,Lin Chun,Zhang Fan,Zhang Wenjuan,Li Xiaomin,Zhang Wei,Li Xuenong
Cancer management and research
BACKGROUND:Interferon regulatory factor 1 (IRF1) plays a role in the immune response, cellular necrosis, DNA damage, and DNA repair, offering an attractive target for anticancer treatment. However, little is known about the role of IRF1 in the regulation of CRC progression. METHODS:Quantitative reverse transcription-PCR, Western blot, and immunohistochemistry were used to examine the expression level of IRF1; Cell Counting Kit-8, migration assay, and xenograft mouse models were used to examine the function of IRF1 in CRC cell lines; a ChIP assay was used to examine the binding between IRF1 and Ras association domain-containing protein 5 (RASSF5). RESULTS:IRF1 expression was lower in colorectal cancer (CRC) than in normal mucosa and the IRF1 expression level was inversely associated with CRC metastasis. In addition, IRF1 could inhibit CRC cell proliferation, migration, and metastasis in vivo and in vitro; IRF1 also induced cell cycle arrest but had no effect on cell apoptosis. IRF1 enhanced the expression of RASSF5 by increasing its promoter activity. Moreover, this study revealed a novel mechanism for inhibiting the RAS-RAC1 pathway by overexpression of RASSF5. CONCLUSION:Altogether, the results indicate that IRF1, which promotes RASSF5 expression, suppresses CRC metastasis and proliferation possibly through downregulation of the RAS-RAC1 pathway.
10.2147/CMAR.S186236
Interferon-inducible lncRNA IRF1-AS represses esophageal squamous cell carcinoma by promoting interferon response.
Huang Jianbing,Li Jiagen,Li Yuan,Lu Zhiliang,Che Yun,Mao Shuangshuang,Lei Yuanyuan,Zang Ruochuan,Zheng Sufei,Liu Chengming,Wang Xinfeng,Li Ning,Sun Nan,He Jie
Cancer letters
Interferons (IFNs) play crucial roles in the development and treatment of cancer. Long non-coding RNAs (lncRNAs) are emerging molecules involved in cancer progression. Here, we identified and characterized an IFN-inducible nuclear lncRNA IRF1-AS (Interferon Regulatory Factor 1 Antisense RNA) which was positively correlated with IRF1 expression. IFNs upregulate IRF1-AS via the JAK-STAT pathway. Knockdown and overexpression of IRF1-AS revealed that IRF1-AS inhibits oesophageal squamous cell carcinoma (ESCC) proliferation and promotes apoptosis in vitro and in vivo. Mechanistically, IRF1-AS activates IRF1 (Interferon Regulatory Factor 1) transcription through interacting with ILF3 (Interleukin Enhancer Binding Factor 3) and DHX9 (DExH-Box Helicase 9). In turn, IRF1 binds to the IRF1-AS promoter directly and activates IRF1-AS transcription. Global analysis of IRF1-AS-regulated genes indicated that IRF1-AS activates the IFN response in vitro and in vivo. IRF1 knockdown in IRF1-AS-overexpressing cells abolished the antiproliferative effect and activation of the IFN response. Furthermore, IRF1-AS was downregulated in ESCC tissues, and low expression correlated with poor prognosis. In conclusion, the interferon-inducible lncRNA IRF1-AS represses esophageal squamous cell carcinoma progression by promoting interferon response through a positive regulatory loop with IRF1.
10.1016/j.canlet.2019.05.038
Transcriptomics confirms IRF1 as a key regulator of pyroptosis in diabetic retinopathy.
Biochemical and biophysical research communications
BACKGROUND:Diabetic retinopathy (DR) is a retinal microvascular complication caused by hyperglycemia, which can lead to visual impairment or blindness. Pyroptosis is a type of inflammation-related programmed cell death, activated by caspase-1, resulting in the maturation of IL-1β and IL-18 and the rupture of the cell membrane. RNA sequencing (RNA-seq) is a high-throughput sequencing technique that reveals the presence and quantity of RNA in the genome at a specific time point, i.e., the transcriptome. RNA-seq can analyze gene expression levels, splicing variants, mutations, fusions, editing and other post-transcriptional modifications, as well as gene expression differences between different samples or conditions. It has been widely used in biological and medical research, clinical diagnosis and new drug development. This study aimed to establish an in vitro model of diabetic retinopathy by culturing human retinal endothelial cells (HREC) with high glucose (30 mmol/L), and to detect their transcriptome expression by RNA-seq, screen for key genes related to pyroptosis, and validate the sequencing results by subsequent experiments. METHODS:We used RNA-seq to detect the transcriptome expression differences between HREC cells cultured with high glucose and control group, and identified differentially expressed genes by GO/KEGG analysis. We constructed a PPI network and determined the key genes by Cytoscape software and CytoHubba plugin. We validated the expression of related factors by Western Blot, qPCR and ELISA. RESULTS:We performed GO and KEGG analysis on the RNA-seq data and found differentially expressed genes. We used Cytoscape and CytoHubba plugin to screen out IRF1 as the key gene, and then detected the expression of IRF1 in HREC under high glucose and control group by Western Blot and qPCR. We found that the expression of Caspase-1, GSDMD and IL-1β proteins in HREC under high glucose increased, while the expression of these proteins decreased after the inhibition of IRF1 by siRNA. ELISA showed that the secretion of IL-1β in HREC under high glucose increased, while the inhibition of IRF1 reduced the secretion of IL-1β. These results indicate that IRF1 plays an important role in DR, and provides a new target and strategy for the prevention and treatment of this disease.
10.1016/j.bbrc.2024.149760
IRF1 suppresses colon cancer proliferation by reducing SPI1-mediated transcriptional activation of GPX4 and promoting ferroptosis.
Experimental cell research
IRF1 is a tumor suppressor gene in colon cancer. This study aimed to explore the potential regulation of IRF1 on the ferroptosis of colon cancer and the mechanisms underlying its regulation of GPX4 transcription. IRF1 interacting transcription factors regulating GPX4 transcription were predicted and validated. The role of the IRF1/SPI1-GPX4 axis on the ferroptosis of colon cancer cells was explored. Results showed that IRF1 overexpression reduced GPX4 transcription, increased reactive oxygen species (ROS) and lipid ROS accumulation, and enhanced erastin-induced colon cancer cell growth in vitro and in vivo. SPI1 could directly bind to the GPX4 promoter (-414 to -409) and activate its transcription. IRF1 could bind to SPI1 and suppress its transcriptional activating effects on GPX4 expression. SPI1 overexpression reduced ROS and lipid ROS accumulation and increased colon cancer cell viability and colony formation upon erastin induction. These trends were reversed by IRF1 overexpression. In conclusion, this study revealed a novel oncogenic mechanism of SPI1 by reducing erastin-induced ferroptosis in colon cancer. IRF1 interacts with SPI1 and suppresses its transcriptional activating effect on GPX4 expression. Through this mechanism, IRF1 can enhance erastin-induced ferroptosis of colon cancer. The IRF1/SPI1-GPX4 axis might play a crucial role in modulating ferroptosis in colon cancer and might serve as a potential therapeutic target in the future.
10.1016/j.yexcr.2023.113733