Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican

Abstract

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.

Transcriptome characteristics of epithelial cells from advanced non‐small cell lung cancer were revealed by single‐cell RNA sequencing

“…23 In LUAD, IRF9 was also identified as an oncogenic transcription factor that promoted proliferation and migration. 24 Overexpressed GATA6 could adjust the transcription process of SOX12 with suppressive effects. 25 In addition, we complementally predicted two most significant transcriptional factors MXD3 and GATA4 in LUAD.…”

The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis

“…IRF9 facilitates the anti-proliferative effects of IFN-α in prostate cancer cells [ 56 ], reduces tumor growth in renal carcinoma cells [ 57 ], and represses cell growth in acute myeloid leukemia [ 58 ]. In contrast, IRF9 can also have oncogenic properties [ 59 , 60 ]. Oncogenes can be associated with cell death pathways [ 61 ], and in vitro, IRF9 has been previously shown to modulate cell death [ 62 , 63 ].…”

Understanding the functional inflammatory factors involved in therapeutic response to immune checkpoint inhibitors for pan-cancer

“…In contrast, IL-1α/β promotes IL-6 and IL-8 and inhibits ECM, by regulating the expression of Versioncan ( Chang et al, 2017 ; Osei et al, 2020 ). Interferon regulatory factor 9 regulates VCAN transcription independently of JAK-STAT signaling ( Brunn et al, 2021 ). Immune cells are also involved in engineering ECM components ( Bhattacharjee et al, 2019 ).…”