IRF1 is a transcription factor well known for its role in IFN signaling. Although IRF1 was initially identified for its involvement in inflammatory processes, there is now evidence that it provides a function in carcinogenesis as well. IRF1 has been shown to affect several important antitumor mechanisms, such as induction of apoptosis, cell cycle arrest, remodeling of tumor immune microenvironment, suppression of telomerase activity, suppression of angiogenesis and others. Nevertheless, the opposite effects of IRF1 on tumor growth have also been demonstrated. In particular, the “immune checkpoint” molecule PD-L1, which is responsible for tumor immune evasion, has IRF1 as a major transcriptional regulator. These and several other properties of IRF1, including its proposed association with response and resistance to immunotherapy and several chemotherapeutic drugs, make it a promising object for further research. Numerous mechanisms of IRF1 regulation in cancer have been identified, including genetic, epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms, although their significance for tumor progression remains to be explored. This review will focus on the established tumor-suppressive and tumor-promoting functions of IRF1, as well as the molecular mechanisms of IRF1 regulation identified in various cancers.

Tumor-suppressive effects of PTEN are well-known, but modern evidence suggest that they are not limited to its ability to inhibit pro-oncogenic PI3K/AKT signaling pathway. Features of PTEN structure facilitate its interaction with substrates of different nature and display its activity in various ways both in the cytoplasm and in cell nuclei, which makes it possible to take a broader look at its ability to suppress tumor growth. The possible mechanisms of the loss of PTEN effects are also diverse – PTEN can be regulated at many levels, leading to change in the protein activity or its amount in the cell, while their significance for the development of malignant tumors has yet to be studied. Here we summarize the current data on the PTEN structure, its functions and changes in its regulatory mechanisms during malignant transformation of the cells, focusing on one of the most sensitive to the loss of PTEN types of malignant tumors – endometrial cancer.

MicroRNAs play a significant role in the development of cancers, including lung cancer. A recent study revealed that smoking, a key risk factor for lung cancer, increased the levels of hsa-mir-301a in the tumor tissues of patients with lung squamous cell carcinoma (LUSC). The aim of the current study is to investigate the mechanism by which tobacco smoke increases hsa-mir-301a levels in LUSC tumor tissues using bioinformatics analysis. Bioinformatics tools and online databases, including The Cancer Genome Atlas (TCGA), LinkedOmics, and Encyclopedia of RNA Interactomes (ENCORI), were applied in this study. Our results showed a correlation between the upregulation of hsa-mir-301a in LUSC tissues and smoking exposure. However, no correlation was discovered between patients’ smoking status and the expression level of the hsa-mir-301a host gene, SKA2, prompting us to investigate possible changes in microRNA processing under tobacco smoke exposure. In silico results using online platforms suggest that post-transcriptional processes, which involve the RNA-binding proteins DGCR8 and FUS, contribute to the elevation of mature hsa-mir-301a levels in smoking patients with LUSC. Our findings suggest that RNA-binding proteins play a key role in controlling the processing of hsa-mir-301a, indicating a complex regulation of hsa-mir-301a in the LUSC tissues of smokers.

Smoking is an established risk factor for a variety of malignant tumors, the most well-known of which is lung cancer. Various molecular interactions are known to link tobacco smoke exposure to lung cancer, but new data are still emerging on the effects of smoking on lung cancer development, progression, and tumor response to therapy. In this study, we reveal in further detail the previously established association between smoking and hsa-mir-301a activity in lung squamous cell carcinoma, LUSC. Using different bioinformatic tools, we identified IRF1 as a key smoking-regulated target of hsa-mir-301a in LUSC. We further confirmed this relationship experimentally using clinical LUSC tissue samples and intact lung tissue samples. Thus, increased hsa-mir-301a levels, decreased IRF1 mRNA levels, and their negative correlation were shown in LUSC tumor samples. Additional bioinformatic investigation for potential pathways impacted by such a mechanism demonstrated IRF1’s multifaceted role in controlling the antitumor immune response in LUSC. IRF1 was then shown to affect tumor immune infiltration, the expression of immune checkpoint molecules, and the efficacy of immune checkpoint blockade therapy. As a result, here we suggest a smoking-regulated mir301a/IRF1 molecular axis that could modulate the antitumor immune response and immunotherapy efficacy in LUSC, opening up novel opportunities for future research.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, the limited predictive value of PD-L1 expression as a biomarker underscores the urgent need for more reliable predictors of ICI response. Interferon regulatory factor 1 (IRF1) is a transcription factor that lies downstream of interferon-γ signaling and directly regulates CD274 (PD-L1) transcription. Here, we performed a comprehensive bioinformatic analysis to identify microRNAs (miRNAs) that may be associated with IRF1 expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Using data from The Cancer Genome Atlas (TCGA), we identified 20 miRNAs whose expression levels consistently and negatively correlated with IRF1 mRNA levels in both LUAD and LUSC. Among these, only hsa-miR-301b possesses conserved binding sites in the 3′UTR of IRF1 mRNA, suggesting direct post-transcriptional repression. For the remaining 19 miRNAs, we hypothesized an indirect mechanism of action. Further analysis revealed that hsa-miR-183 and hsa-miR-141 may target the transcription factor genes NFKB1 and STAT4, respectively, both of which positively correlate with IRF1 expression and are themselves associated with improved survival in ICI-treated patients. This study delineates a multi-layer miRNA regulatory network associated with IRF1 expression in NSCLC and identifies hsa-miR-301b, hsa-miR-183 and hsa-miR-141 as candidate upstream regulators of IRF1. Direct survival analysis for these miRNAs in ICI-treated cohorts was not feasible due to the lack of publicly available miRNA-seq data with treatment annotations; therefore, their clinical predictive value remains hypothetical, and experimental validation is required to assess their potential as predictors of ICI response.

Tobacco smoking continues to represent the leading risk factor for multiple malignancies, most notably lung cancer (LC), which exhibits a complex molecular pathogenesis. While classical models prioritize direct DNA damage and mutagenesis, growing evidence points to the role of mechanisms not directly dependent on structural DNA lesions. In particular, dysregulation of oncogenic and tumor-suppressive microRNAs (miRNAs) has emerged as a promising area of research. Although numerous miRNAs potentially involved in LC pathogenesis have been reported to be altered by tobacco exposure, the available evidence is fragmented. This heterogeneity, compounded by the chemical complexity of tobacco smoke, prevents the formation of a comprehensive landscape of its pathogenetic mechanisms. This review aims to systematize existing data on tobacco smoke–induced changes in miRNA expression profiles in LC, with reference to individual tobacco smoke constituents, and to identify key biological processes likely modulated by these changes.