Differential Expression of IL-17, 22 and 23 in the Progression of Colorectal Cancer in Patients with K-ras Mutation: Ras Signal Inhibition and Crosstalk with GM-CSF and IFN-γ

Abstract

Recent studies have suggested that aberrant K-ras signaling is responsible for triggering immunological responses and inflammation-driven tumorigenesis. Interleukins IL-17, IL-22, and IL-23 have been reported in various types of malignancies, but the exact mechanistic role of these molecules remains to be elucidated. Given the role of K-ras and the involvement of interleukins in colorectal tumorigenesis, research efforts are reported for the first time, showing that differentially expressed interleukin IL-17, IL-22, and IL-23 levels are associated with K-ras in a stage-specific fashion along colorectal cancer progression. Specifically, a) the effect of K-ras signaling was investigated in the overall expression of interleukins in patients with colorectal cancer and healthy controls, and b) an association was established between mutant K-ras and cytokines GM-CSF and IFN-γ. The results indicate that specific interleukins are differentially expressed in K-ras positive patients and the use of K-ras inhibitor Manumycin A decreases both interleukin levels and apoptosis in Caco-2 cells by inhibiting cell viability. Finally, inflammation-driven GM-CSF and IFN-γ levels are modulated through interleukin expression in tumor patients, with interleukin expression in the intestinal lumen and cancerous tissue mediated by aberrant K-ras signaling. Collectively, the findings a) indicate that interleukin expression is influenced by ras signaling and specific interleukins play an oncogenic promoter role in colorectal cancer, highlighting the molecular link between inflammation and tumorigenesis, and b) accentuate the interwoven molecular correlations as leads to new therapeutic approaches in the future.

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

“…So far, the mechanism by which PAK regulates the production of GM-CSF has not been fully elucidated. However, Kras activation is found to be positively associated with GM-CSF expression in cancer patients when compared to normal controls[ 142 ], and this observation is consistent with an early study indicating that oncogenic Kras-dependent secretion of GM-CSF can promote the development of pancreatic neoplasia via immunosuppression mediated by Gr-1 + CD11b + myeloid cells[ 143 ]. As Kras is the most important oncogenic mutation in pancreatic cancer and a potent up-stream regulator of PAK, these studies provided possible evidence implicating the involvement of PAK in a pathway linking aberrantly activated Kras to GM-CSF-induced immuno-evasion.…”

Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients

“…Because of its role in immunity, these molecular features were evaluated in the context of IL-23 to ensure no confounding of our results. A recent work by Petanidis and colleagues showed that inhibition of KRAS using manumycin A could cause a significant decrease in IL-23 levels establishing a correlation between these two molecules [ 26 ]. We found no association between IL-23p19, and these molecular changes.…”

Mechanisms and Αpplications of Ιnterleukins in Cancer Immunotherapy

“…Consistent with a positive role of IL-17 in promoting tumor development, tumor tissues have a higher frequency of IL-17 + T cells compared with untransformed bowel tissues [ 78 ]. The role of IL-17 in promoting tumor growth provides additional support for the already well-established connection between inflammation and tumorigenesis [ 79 ]. However, this study did not identify whether Ad-si-IL-17 induced IL-17 ablation only in T effector cells or its effects were also extended to Treg cells, a population also capable of producing IL-17 and intimately linked to the development of inflammation and cancer in the bowel.…”