Abstract
Alternative splicing (AS) of mRNA is known to be involved in regulation of immune cell differentiation and activation. Elongation factor Tu GTP binding domain containing 2 (Eftud2) is an AS factor to potentially modulate innate immune response in macrophages. In this study, we investigate its involvement in the pathogenesis of colitis-associated cancer (CAC). Using an established mouse model of CAC, we show that Eftud2 is constantly overexpressed in the colonic tissues as well as infiltrating macrophages. Myeloid-specific knockout of Eftud2 remarkably suppresses chronic intestinal inflammation and tumorigenesis, which is associated with decreased production of inflammatory cytokines and tumorigenic factors. Repression of colonic inflammation and colorectal tumor development in Eftud2-deficient mice is due to the impaired activation of NF-κB signaling in LPS-challenged macrophages. Furthermore, the alteration of Eftud2-mediated AS involving the components of TLR4-NF-κB cascades underlies the impairment of NF-κB activation. Overall, these findings provide new insights into the tight link between inflammation and cancer and modulation of AS in innate immune signals may be a potentially therapeutic avenue for CAC treatment.
Highlights
Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in developed countries.[1]
Eftud[2] expression is elevated significantly in mice suffering from colitis-associated cancer (CAC) and colitis First, we collected the colon samples of mice suffering from CAC
Since it has been previously shown that Eftud[2] has potentials to regulate innate immune responses,[17] we sought to determine the alteration of its expression in a model of colonic inflammation
Summary
Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in developed countries.[1]. The engagement of TLR4 with its ligand LPS leads to macrophage activation involving multiple innate immune receptors and kinases, among which the downstream transcription factor NF-κB is a central mediator of proinflammatory cytokine production.[9]
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