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-. 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-. The results Rabbit Polyclonal to OR4D6 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- 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. Introduction Colorectal cancer is the second most prevalent form of cancer worldwide. Currently, in most of the developing countries, there are no organized screening and diagnostic programs , . Previous studies have shown that colorectal cancer is a multifactorial disease, in which the expression of many specific genes, known as oncogenes or tumor suppressors, is abnormally altered . In this regard, the PIK3CA gene, which is involved in the PI3K/AKT signaling pathway, is up-regulated in colorectal cancer. The tumor suppressor gene phosphatase and tensin homolog (PTEN) is down-regulated due to a genetic mutation or deletion . However, molecular mechanisms of colorectal carcinogenesis remain to be elucidated. Toward such efforts, it is crucial to identify specific molecular markers for the detection and identification of mechanisms contributing to colorectal carcinogenesis. One such representative biomarker is K-ras, an oncogene with guanosine triphosphate (GTP) binding properties . Due to its ability to interact with key signaling molecules including the signal transducer and activator of transcription (STAT), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK), the K-ras gene delivers an essential function in cell division, cell growth and differentiation. Thus, mutations in the K-ras gene (especially, single nucleotide substitutions) are implicated in most types of tumors, including lung adenocarcinoma, lung cancer, ductal carcinoma of the pancreas, and colorectal carcinoma . Over the past few years, evidence has demonstrated that interleukins carry out important functions in tumor development, cell differentiation, inflammation and metastasis , . In this respect, IL-17, which is largely produced by activated memory T lymphocytes, stimulates both innate immunity and host defense, and plays an active role in inflammatory diseases, autoimmune diseases, and cancer. More specifically, IL-17 induces the expression of nuclear factor-kappa B (NF-B), chemokines CXCL8, CXCL6 and CXCL1, growth factors G-CSF, GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-6, and adhesion molecules (ICAM-1), leading to augmented neutrophil accumulation, granulopoeisis, and inflammatory responses , . On the other hand, IL-22 acts as a mediator of cellular inflammatory Polygalacic acid responses by activating intracellular kinases (JAK1, Tyk2, and MAP kinases) and transcription factors such as STAT3 . Furthermore, IL-22 exhibits anti-apoptotic and Polygalacic acid tumorigenic functions, with recent data showing that over-expression of that molecule protects lung cancer cell lines from apoptosis via a) activation of Polygalacic acid STAT3 and its downstream anti-apoptotic proteins Bcl-2 and Bcl-xL, and b) inactivation of extracellular signal-regulated kinases . Likewise, IL-23 plays a key role in chronic intestinal inflammation and its up-regulation in malignant tissues parallels augmented levels of the metastatic biomarker matrix metalloproteinase MMP-9, tumor necrosis factor TNF-alpha, and increased levels of angiogenesis , , . In an effort to discover molecular links between tumorigenic and immuno-inflammation pathways in cancer physiology, research was launched in our labs to probe into the interactions and potential interwoven roles that the aforementioned molecular targets might play in colorectal multistage cancer progression. To this end, we report herein for the first time that a) the specific interleukins are up-regulated in colorectal carcinoma compared to healthy colorectal tissues, b) interleukins are over expressed in all K-ras patients and can promote cell growth and inhibit cell.