Infection processes induce various soluble factors that are carcinogens in humans; therefore, research into the soluble factors of chronic disease released from cells that have been infected with parasites is warranted. Parasitic infections in host cells release high levels of IFNγ. Studies have hypothesised that parasitosis-associated carcinogenesis might be analogous to colorectal cancers developed from inflammatory bowel diseases, whereby various cytokines and chemokines are secreted during chronic inflammation. IL-18 and IL-21 are other factors that might be involved in the development of colorectal cancer in schistosomiasis patients and patients with other infections. IL-21 has profound effects on tumour growth and immunosurveillance of colitis-associated tumourigenesis, thereby emphasising its involvement in the pathogenesis of colorectal cancer. The prominent role of IL-21 in antitumour effects greatly depends on the enhanced cytolytic activity of NK cells and the pathogenic role of IL-21, which is often associated with enhanced risks of cancer and chronic inflammatory processes. As IL-15 is also related to chronic disease, it is believed to also play a role in the antitumour effect of colorectal carcinogenesis. IL-15 generates and maintains long-term CD8+ T cell immunity against T. gondii to control the infection of intracellular pathogens. The lack of IL-15 in mice contributes to the downregulation of the IFNγ-producing CD4+ T cell response against acute T. gondii infection. IL-15 induces hyperplasia and supports the progressive growth of colon cancer via multiple functions. The limited role of IL-15 in the development of NK and CD8+ T cells suggests that there may be other cytokines compensating for the loss of the IL-15 gene.
The interleukin-21 (IL-21) protein was found to be expressed at an elevated level in clinical samples of colorectal cancer patients without or with a parasitic infection that were collected from Sudan in our previous study. The IL-21 gene in HT29 and HCT116 cells was then correlated to cell proliferation and cell migration, as well as the cellular mechanisms associated with gene expressions in our present study. Our results demonstrated that silencing the IL-21 gene in HCT116 cells increased the cytotoxic level and fibroblast growth factor-4 (FGF4) mRNA expression in the cancer cells. Moreover, specific gene silencing reduced the migration of cancer cells compared to non-silenced cancer cells. These events were not observed in IL-21-silenced HT29 cells. Neutralizing FGF4 in conditioned medium of IL-21-silenced HCT116 cells further increased the cytotoxic level and restored the migratory activity of HCT116 cells in the culture compared to silencing the IL-21 gene alone in the cancer cells. Our results indicate the importance of both silencing the IL-21 gene and co-expression of the FGF4 protein in HCT116 cells, which pave the way for the discovery of important factors to be used as biomarkers for the design of drugs or cost-effective supplements to effectively treat the patients having infectious disease and HCT116 cells of colorectal cancer simultaneously in the future.