Abstract
Three-dimensional cell cultures, such as multicellular spheroids (MCS), reflect the in vivo architecture of solid tumours and multicellular drug resistance. We previously identified interferon regulatory factor 9 (IRF9) to be responsible for the up-regulation of a subset of interferon (IFN)-stimulated genes (ISGs) in MCS of colon carcinoma cells. This set of ISGs closely resembled a previously identified IFN-related DNA-damage resistance signature (IRDS) that was correlated to resistance to chemo- and radiotherapy. In this study we found that transcription factor STAT3 is activated upstream of IRF9 and binds to the IRF9 promoter in MCS of HCT116 colorectal carcinoma cells. Transferring conditioned media (CM) from high cell density conditions to non-confluent cells resulted in STAT3 activation and increased expression of IRF9 and a panel of IRDS genes, also observed in MCS, suggesting the involvement of a soluble factor. Furthermore, we identified gp130/JAK signalling to be responsible for STAT3 activation, IRF9, and IRDS gene expression in MCS and by CM. Our data suggests a novel mechanism where STAT3 is activated in high cell density conditions resulting in increased expression of IRF9 and, in turn, IRDS genes, underlining a mechanism by which drug resistance is regulated.
Highlights
Interferon (IFN) signalling plays a critical role in the immune response and regulates pathways involved in antiviral defence, proliferation and apoptosis
We previously showed that STAT1, STAT2 and IFN regulatory factor 9 (IRF9), along with a majority of the IFN-related DNA-damage resistance signature (IRDS) genes, were induced in HCT116 colorectal carcinoma cells grown as MCS14
We set out to investigate whether STAT3 is activated in HCT116 multicellular spheroids (MCS) and if it can be responsible for the induction of IRF9 and IRDS genes
Summary
Interferon (IFN) signalling plays a critical role in the immune response and regulates pathways involved in antiviral defence, proliferation and apoptosis. High expression of a subset of IFN-stimulated genes (ISGs), referred to as the IFN-related DNA-damage resistance signature (IRDS), is correlated to therapy resistance, poor overall prognosis, and has been identified in samples from patients with glioma, head and neck, prostate, lung, and breast cancer[4,5]. These contradictive effects suggest a multifaceted involvement of ISGs in cancer and that the activity of the IFN signalling pathway and its effect on tumour progression may vary between types of cancer and possibly with the stage and/or grade. In line with Luker et al, we found that overexpression of IRF9 alone triggered the expression of the panel of IRDS genes in the absence of IFNs and conferred resistance to chemotherapeutic drugs[10,14]
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