Dysregulation of the MiR-324-5p-CUEDC2 Axis Leads to Macrophage Dysfunction and Is Associated with Colon Cancer

Abstract

CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.

CUEDC2 Protects Against Experimental Colitis and Suppresses Excessive Proliferation of Intestinal Mucosa

“…So, in our study we chose the littermate WT and CUEDC2 KO mice, avoiding the influence of other genetic factors. Although there was a report that CUEDC2 plays a role in protecting against colitis and maintaining intestinal length [3], our study demonstrated that colitis in CUEDC2 KO mice was much more severe than WT mice, showing the formation of larger and deeper ulcers, not limited to more ulcers as well as the worse diarrhea and bloody stool. The destruction of the function of the mucosal barrier in CUEDC2 KO mice was worsened, which in turn aggravated the inflammatory responses of colon.…”

“…Sustained inflammatory reactions may also promote genomic instability. Therefore, since CUEDC2 inhibits inflammatory reactions in the colon, suppresses the activation of NF-jB and STAT3 pathways as well as the following expression of downstream anti-apoptotic genes, these mechanisms can explain the finding that CUEDC2 can inhibit the formation of colitis-associated cancer (CAC) [3]. These results suggest that CUEDC2 has the potential to become the clinical marker for the evaluation of colitis and CAC, however, which also need to be confirmed in clinical samples.…”

“…All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of the National Center of Biomedical Analysis. CUEDC2 KO mice and WT littermates control were generated by germline transmission [3]. In the CUEDC2 gene of KO mice, LoxP-flanked sequences of EcoR V vector was deleted and exons 2-9 was removed.…”

Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells – Liquid biopsies for monitoring complications of pregnancy

“…Of those upregulated, most are tumor supppressors and are involved in the disruption of cell migration and proliferation. These miRNAs have previously been implicated in cancers, namely miRNA 324-5p in hepatocellular carcinoma, breast cancer, and colon cancer [48–50], miRNA 935 in gastric signet ring cell carcinoma [51], and miRNA 15b-3p in prostate cancer [52]. More specifically, miRNA 16-5p has been found to block the proliferation and blood vessel formation of mesenchymal cells in women with PE [53].…”

Cancer-derived exosomic microRNAs shape the immune system within the tumor microenvironment: State of the art

“…The level of CUEDC2 in TAMs is downregulated by miR-324-5p, which in turn is upregulated by IL-4. Notably, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p [36]. Sonda et al showed that miR-142-3p downregulation enhanced macrophage M2-differentiation with immunosuppressive functions in tumor.…”