br Previous studies have demonstrated that TRIM and IGF BP
Previous studies have demonstrated that TRIM25 and IGF2BP3 play an essential role in cancer cell proliferation . For example, TRIM25 is a potent regulator of metastatic disease and associated with poor survival outcomes for breast cancer [22,39]. TRIM25 also acts as an on-cogene in colorectal cancer and it activates TGF-β signaling pathway to promote tumor proliferation and metastasis . Besides, IGF2BP3 protein is variably expressed in mantle cell lymphoma and that strong expression in a high percentage of tumor cells is tightly associated with an increased proliferation capacity of the tumor cells. In breast carcinomas, a significantly upregulated expression of IGF2BP3 was found in adenoid cystic carcinomas  and a novel biomarker for triple-negative invasive mammary carcinoma associated with a more aggressive phenotype [42,43]. In this study, the results demonstrate that the expression patterns and functions of TRIM25/IGF2BP3 and miR-3614-3p in BC are quite different. TRIM25 and IGF2BP3 promotes
cell proliferation and functions as a tumor oncogene in cancer cells. However, miR-3614-3p inhibits BC cell growth, thus acting as a tumor suppressor. In vivo, both the silencing of IGF2BP3 and the overexpression of miR-3614 can effectively inhibit the growth of BC tumors in xenograft models. Interestingly, co-treatment with siIGF2BP3, TAM, and miR-3614-3p effectively reduced TRIM25 expres-sion and inhibited the proliferation of BC cells, indicating a synergistic effect.
Based on our observations, we propose a model for the regulation of TRIM25 mRNA translation in which IGF2BP3 and miR-3614-3p can competitively bind to the 3´-UTR of TRIM25 mRNA. IGF2BP3 protects TRIM25 mRNA from degradation and suppresses miR-3614 maturation in BC (Fig. 8A and B). Moreover, the tumor-promoting role of TRIM25 in breast cancer was exerted through its regulation of PF 06424439 by interac-tion with IGF2BP3 and miR-3614-3p. Altogether, the IGF2BP3– TRIM25–miR-3614 axis functions represent a new pathway that regu-lates tumor cell proliferation, thereby providing a rationale for targeting IGF2BP3 and TRIM25 in breast cancer treatment.
This work was supported by grants from the Scientific Research and Sharing Platform Construction Project of Shaanxi Province (Grant no. 2018PT-09), Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research (2018LHM-KFKT005), China Postdoctoral Science Foundation (2017M623194) and The Na-tional Natural Science Foundation of China (81874192).
Conflicts of interest
The authors declare no conflicts of interest.
C.H., Y.K.C. and A.L. conceived and supervised the project. Z.Z.W., Y.K.C., D.D.T., C.H. and Z.H.Z designed and performed most of the experiments. X.F·W and Q.L conducted bioinformatic and biostatistical
analyses. L.C, T.J. and X.Y.L. acquired the patient data and assisted in the in vivo tumor model experiments. Z.Z.W, Y.K.C wrote the paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
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