Background: Intrinsic tumor resistance to therapy remains a major problem in the management of cancer patients. Multiple mechanisms are believed to contribute to this phenomenon. Recently, a subset of interferon-stimulated genes (referred to as interferon-related DNA damage signature or IRDS) has been associated with poor therapy response and short overall survival for several cancer types. In this study we aimed to investigate the mechanism of IRDS regulation in different cancer types.

Materials and methods: Using both 2D and 3D cancer cell line models, RNAi and over expression approaches, we investigated the expression of IFN-stimulated genes using qRT-PCR and Western blotting approaches.

Results: a microarray analysis of a 2D and a 3D cultures( multicellular spheroids, MCS) of a human carcinoma cell line HCT116 revealed that IRDS genes are highly enriched in MCSs what reflects their relative resistance to chemotherapeutics. Analysis of a panel of cancer cell lines (MCF7, SKOV3, DLD1, HCT116) demonstrated that IRF9 has a leading role in the regulation of interferon-stimulated genes (e.g. STAT1, STAT2, IFITM1, IFI27, OAS1) and promoting therapy resistance. We have also demonstrated that this phenomenon occurs in the absence of interferons and does not depend on STAT1, the main regulator of IFN-stimulated genes, but rather depends on STAT2. Furthermore, we showed that a subset of IRDS is regulated by crowding and might depend on cell-to-cell contacts and/or adhesion molecules.

Conclusion: Our findings demonstrate that IRF9 can act as a main regulator of interferon-stimulated genes rendering tumors resistant to therapy. Therefore, it can potentially be developed as a marker of clinical response in oncology.