PLX276257

GSE149262: RNA-sequencing analysis of transcriptional changes in DLD-1 KRAS MUT and WT isogenic cells following IL-22 or IL-6 stimulation

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

The cytokine IL-22 promotes tumor progression in murine models of colorectal cancer (CRC). However, the clinical significance of IL-22 in human CRC remained unclear. Using a rigorous discovery/verification analysis of tumor gene expression from over 1,000 patients, we discovered that among CRC patients with high expression of either or both subunits of the heterodimeric IL-22 receptor, KRAS mutation confers poor prognosis. Analysis of human CRC cell lines and primary tumor organoids, including a DLD-1 isogenic cell line pair that differed only in KRAS mutation status, showed that IL-22 and mutant KRAS cooperatively enhance cancer cell proliferation. The purpose of this study was to identify unique mechanisms of interaction between IL-22 signaling and mutant KRAS. Taking advantage of the DLD-1 isogenic pair with match IL-22 receptor expression, differing only in the presence or absence of mutant KRAS global transcriptomic changes were explored in an unbiased manner following IL-22 stimulation. RNA-sequencing was performed on DLD-1 isogenic cells stimulated with 10ng/mL IL-22 for 2h to identify early transcriptional changes and after 24h to explore late changes. Given that IL-6 receptor expression does not interact with mutant KRAS in a prognostically significant manner, nor did it enhance proliferation in KRAS mutant versus WT cells, DLD-1 isogenic cells were also stimulated with 10ng/mL IL-6 for 2 and 24h to identify pathways uniquely regulated by IL-22 and not IL-6. SOURCE: Fiona Powrie (fiona.powrie@kennedy.ox.ac.uk) - Kennedy Institute of Rheumatology University of Oxford