Abstract
Simple SummaryLung cancer is the leading cause of cancer-related deaths worldwide, accounting for more than 1.6 million deaths per year. The tumor microenvironment (TME) has been shown to play a crucial role in tumor progression and metastasis, and transcription factors link TME signaling to oncogenesis. Type I interferons (IFNs) are strong immune modulators that possess antiproliferative and proapoptotic properties. In this study, we investigated the role of the transcription factor interferon regulatory factor 9 (IRF9) in the IFN pathway in lung cancer. We performed in vitro and in vivo experiments to reveal the oncogenic properties of IRF9, which was highly upregulated in lung adenocarcinoma. For the first time, we showed that IRF9 binds to the promoter of the known oncogene versican, regulates its expression, and thereby promotes oncogenic activity. Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide and accounts for approximately 388,000 deaths annually in Europe [1]
We stained a tissue microarray obtained from patients with lung cancer and found that Interferon regulatory factor 9 (IRF9) was expressed in both tumor and stromal cells in different types of lung cancers, including LUAD (Figure 1a), adenosquamous cell carcinoma, squamous cell carcinoma, small-cell carcinoma, and bronchioloalveolar carcinoma (Figure S1)
On analyzing data from The Cancer Genome Atlas (TCGA), we found expression levels of IRF9 (Figure 1c), STAT1, and STAT2 in patients with lung cancer (Figure 1d), and IRF9 expression levels were positively correlated with those of STAT1 and STAT2 (Figure 1e)
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide and accounts for approximately 388,000 deaths annually in Europe [1]. Due to the inconspicuous symptoms associated with late-stage diagnosis, the survival rate of patients with lung cancer is considerably reduced. In the late stages of lung cancer, a combination of available therapeutic options such as surgery, radiation, and chemotherapy can be used as therapy [2]. The tumor microenvironment (TME), which is composed of various cell types and immune cells, is known to play a crucial role in tumor progression and metastasis [3]. Chemokines, and additional factors secreted by stromal cells, interferons (IFNs), a major family of cytokines, are known to be involved in immune cell activation and modulation [4]. In the TME, IFNs primarily act as tumor-suppressing, antiangiogenic, and proapoptotic cytokines that both directly target tumor cells and enhance the response of other stromal cells [5,6,7,8]. Severe side effects and the introduction of novel alternative therapies have gradually shifted the role of IFNs to second line or maintenance therapy [9,10]
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