Background The cross-talk between RNA binding proteins (RBPs) and microRNAs (miRNAs) in the regulation of gene expression is a complex process. Here, we describe a new mode of regulation of TRIM25 expression mediated by an antagonistic interplay between IGF2BP3 and miR-3614-3p. Methods The expression level of TRIM25, IGF2BP3, pri-miR-3614 and miR-3614-3p in breast cancer (BC) tissues, non-tumor tissues and BC cell lines were detected by qRT-PCR, Western blot and Immunohistochemistry (IHC). Binding of miR-3614-3p and IGF2BP3 to TRIM25 RNA was verified using luciferase activation assays, RNA immunoprecipitation (RIP) and biotin pull-down assays. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and related mechanism of IGF2BP3-miR-3614-3p-TRIM25 axis in in breast cancer cells proliferation. Findings We found that an intragenic miRNA-3614-3p inhibits the expression of its host gene TRIM25 by binding to its 3′- untranslated region (UTR). Interestingly, IGF2BP3 can competitively occupy this binding site and inhibit miRNA-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation. The overexpression of miR-3614-3p dramatically inhibited breast cancer cell growth through the downregulation of TRIM25. Furthermore, the silencing of IGF2BP3 reduced TRIM25 expression, suppressed cell proliferation, and exhibited a synergistic effect with miR-3614-3p overexpression. Interpretation Collectively, these results demonstrate that control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation. Fund The scientific research and sharing platform construction project of Shaanxi Province, Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, China Postdoctoral Science Foundation and The National Natural Science Foundation of China.
MicroRNAs (miRNAs) have been explored in many critical cellular processes, including proliferation and apoptosis. The purpose of this study was to detect the biological function and regulation of miR-99b-5p and miR-203a-3p in gastric cancer (GC). Here, we demonstrated that miR-99b-5p/203a-3p were downregulated in both GC tissues and cell lines. MiR-99b-5p/203a-3p overexpression reduced GC cell proliferation and cell cycle progression in vitro. Notably, we combined bioinformatics tools with biological validation assays to demonstrate that insulin-like growth factor 1 receptor (IGF-1R) is a direct co-target and functional mediator of miR-99b-5p/203a-3p in GC cells. Mechanistically, the AKT pathway, which is downstream of IGF-1R, is essential for the functional roles of miR-99b-5p/203a-3p in GC cells. Taken together, our data revealed that IGF-1R is a direct co-target of miR-99b-5p/203a-3p, and miR-99b-5p/203a-3p may function as tumor suppressive miRNAs by negatively regulating IGF-1R expression in GC cells.
In human hepatocellular carcinoma (HCC), aberrant expression of miRNAs correlates with tumor cell proliferation, apoptosis, invasion, and migration by targeting downstream proteins. miR-15b levels are reported increased in HCC tissues; however, they negatively correlate to HCC recurrence. Our aim was to understand the reason for this phenomenon. We used the reverse transcription-polymerase chain reaction (RT-PCR) to measure miR-15b-5p expression in both HCC tissues and HCC cell lines. Our results were consistent with the report. Using bioinformatics and luciferase reporter assays, we identified Rab1A as a novel and direct target of miR-15b-5p. Inhibiting the function of Rab1A with shRab1A also inhibited the growth of HCC cells and induced endoplasmic reticulum stress (ERS) and apoptosis. Similarly, suppressing Rab1A by overexpression of miR-15b-5p also inhibited cell growth and induced ERS and apoptosis. Moreover, re-expression of Rab1A rescued the miR-15b-5p -induced ERS, apoptosis, and growth inhibition in HCC cells. In vivo assays were further performed to testify them. Taken together, our data suggest that miR-15b-5p induces ERS, apoptosis, and growth inhibition by targeting and suppressing Rab1A, acting as a tumor suppressor gene in HCC. This finding suggests a novel relation among Rabs, miRNAs, and apoptosis.
Objective: To investigate the characteristics and outcomes of low prognosis patients defined by POSEIDON criteria undergoing IVF treatment. Design: Retrospective cohort analysis. Setting: An IVF clinic in a public hospital. Patients: 18,455 fresh aspirated IVF cycles with subsequently frozen embryo transfer from Jan 2014 to Jan 2017 in a single IVF clinic were included in the analysis. The low prognosis patients were categorized into 4 groups based on POSEIDON criteria: group 1: age < 35, antral follicle count (AFC) ≥ 5, number of oocytes retrieved ≤ 9 in the previous cycle; group 2: age ≥ 35, AFC≥5, number of oocytes retrieved ≤ 9 in the previous cycle; group 3: age < 35, AFC < 5; group 4: age ≥ 35, AFC < 5. The non-low prognosis patients: group 5: AFC ≥ 5, previous number of oocytes retrieved > 9 oocytes; group 6: AFC ≥ 5, no previous ovarian stimulation. Intervention(s): None. Main Outcome Measure: The primary outcome was cumulative live birth rate (CLBR). Result(s): Taking group 1 as reference, the CLBR from young women in group 3 (35.5%, OR 0.9, 95% CI 0.7–1.2) was slightly lower than that in group 1 (44.6%, p = 0.615). The CLBR in group 2 (24.5%, OR 0.6, 95% CI 0.4–0.8, p = 0.004) and group 4 (12.7%, OR 0.4, 95% CI 0.3–0.6, p < 0.001) was significant lower than that in group 1. In non-poor prognosis patients, the CLBR from young women in group 5 (53.5% OR 1.3 95% CI 0.9, 1.7, p = 0.111) was a slight higher than the reference group 1 while the highest CLBR was originated from the first IVF patients with good ovarian reserve in group 6 (66.9%, OR 2.0, 95% CI 1.6, 2.4). Conclusion(s): The CLBRs and implantation rates in the young women (group 3) with diminished ovarian reserve was similar in those young women (group 1), and was significantly higher than in advanced age women with a fair ovarian reserve (group 2). Though patients in group 2 had better ovarian reserve, more oocytes and more embryos, the pregnancy outcome was inferior to that of group 3 patients with poorer ovarian reserve, fewer oocytes and fewer embryos.
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