br The RBP family is composed of approximately
The RBP family is composed of approximately 800 proteins with conserved domains. RBPs bind to double- or single-stranded RNA and regulate RNA fate from synthesis to decay . The insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) stabilizes and facilitates the translation of numerous target mRNAs . IGF2BP3 belongs to a conserved family of RBPs. Previous studies have demonstrated that the binding of IGF2BP3 to target mRNAs stabilizes the mRNA, thereby preventing its decay . Interestingly, one putative mechanism suggests that IGF2BP3 and miRNAs converge on the 3′-UTRs of target transcripts to upregulate or downregulate genes that are associated
Research in context
Evidence before this study
IGF2BP3 is up-expressed in a variety of malignant tumors and rep-resents a promising cancer biomarker. Previously studies have shown that IGF2BP3 as RBP regulators of gene expression acts in various important aspects of cell function. TRIM25, an estrogen-responsive RING finger protein (Efp), several studies have shown it is significantly correlated with poor prognosis in pa-tients with breast cancer. Although their functions are being unraveled, but their mechanism of biogenesis remains poorly understood.
Added value of this study
The results presented a novel mechanism of cross-talk between IGF2BP3 and miR-3614 in the regulation of TRIM25 expression, and clearly demonstrate that IGF2BP3-miR-3614-3p-TRIM25 axis promoted proliferation of breast cancer.
Implications of all the available evidence
Our study shown that silencing of IGF2BP3 reduces TRIM25 ex-pression, suppresses cell proliferation, and exhibits a synergistic effect with miR-3614 overexpression. It was suggested IGF2BP3-miR-3614-3p-TRIM25 axis could provide valuable tar-gets in breast cancer treatment.
with malignancy . However, whether and how IGF2BP3 is involved in the miRNA-mediated gene silencing to regulate translation in cancer SC 79 remains to be determined. MiRNAs are synthesized as longer transcripts primary (Pri)miRNAs that are processed by the nuclear RNase III Drosha into 70-nt, hairpin precursor miRNAs (Pre)miRNAs. These are further processed in the cytoplasm by RNase III, giving rise to mature miRNAs that assemble with members of the Argonaute (Ago) protein family to form the RNA-induced silencing complex (RISC) [9–11]. The biogenesis of miRNAs occurs at two locations. The intergenic miRNAs are derived from noncoding regions between genes and are transcribed by uniden-tified promoters . Most miRNAs are recognized as intergenic miRNA. A minority of miRNAs are derived from noncoding introns or the 5′-UTRs and the 3′-UTRs of host genes. These miRNAs are termed intronic or intragenic miRNAs , and have been reported to play var-ious roles in host gene regulation . Although several studies on intronic miRNAs have been conducted, whether intronic miRNAs can exhibit inhibitory effects on host genes remains to be determined.
In this study, we report that the intragenic mature miR-3614 can silence the expression of its host gene, tripartite motif-containing 25 (TRIM25), which is also regulated by IGF2BP3. Several studies have shown that IGF2BP3 is involved in the stabilization of mRNAs encoding IGF2, HMGA2, CD44, and PDPN [14–16]. However, little is known about the role of IGF2BP3 in modulating the cytoplasmic fate of TRIM25 mRNA. TRIM25, an estrogen-responsive RING finger protein (Efp), is mainly expressed in estrogen target tissues, such as mammary glands and the uterus . Accumulating evidence demonstrates that in MCF-7 BC cells, TRIM25 mediates degradation of 14-3-3σ, a negative cell cycle regulator. Loss of TRIM25 in mouse embryonic fibroblasts causes an accumulation of 14-3-3σ, which is responsible for reduced cell proliferation . More recently overexpression of TRIM25 has also been associated with lung and gastric cancers [19,20]. In agreement with these findings, TRIM25 is significantly correlated with poor prog-nosis in patients with different cancers, especially breast cancer .
Walsh et al. uncovered a transcriptional hierarchy underlying breast cancer metastasis using patient-matched primary and metastatic sam-ples, they propose TRIM25 is a master regulator of this hierarchy and promoting metastasis and poor survival, targeting TRIM25 may repre-sent promising future targets for cancer intervention. .
We analyzed the sequence of the TRIM25 gene and found that pri-miR-3614 is located in the TRIM25 3′-UTR and shares the same pro-moter. Using the miRNA target prediction software, TargetScan, we found the miR-3614-3p and the miR-3614-5p binding sites at the 3′-UTR of TRIM25, which could likely be occupied to impair host gene transcription or translation. As TRIM25 is aberrantly overexpressed in various types of cancer, including breast cancer (BC), we speculated that there may be an unknown mechanism that can protect TRIM25 mRNA from degradation by miR-3614. Next, we used the starBase website to predict the RBP binding sites on TRIM25 mRNA and found that IGF2BP3 can bind to the TRIM25 3′-UTR at a site proximal to and partially overlapping the miR-3614-3p binding site. Thus, we hypothe-sized that IGF2BP3 can bind to the TRIM25 3′-UTR and block the matu-ration of miR-3614, thereby preventing miR-3614-mediated translational repression in BC cells.