miR-1299/NOTCH3/TUG1 feedback loop contributes to the malignant proliferation of ovarian cancer

Recent studies have revealed the oncogenic role of notch reporter 3 (NOTCH3) in ovarian cancer (OC). However, the possible regulators and mechanisms underlying notch receptor 3 (NOTCH3)-mediated behaviors in OC remain to be completely investigated. In the present study, we aimed to identify regulators of NOTCH3 and their interactions underlying the pathogenesis of OC. Bioinformatics analysis and luciferase reporter assay were used to identify potential regulatory miRNAs and lncRNAs of NOTCH3 in OC. Several in vivo and in vitro assays were performed to evaluate their effects on the proliferative ability mediated by NOTCH3. We identified microRNA-1299 (miR-1299) as a novel negative regulator of NOTCH3. miR-1299 was downregulated in OC and was found to be considerably correlated with tumor differentiation. Upregulation of miR-1299 inhibited cell proliferation, colony formation, and 5-ethynyl-2 ' -deoxyuridine (EdU) incorporation, as well as induced cell cycle arrest in the G0G1 phase in OC cells. Overexpression of miR-1299 in xenograft mouse models suppressed tumor growth in vivo. The lncRNA taurine upregulated gene 1 (TUG1), acting as a sponge of miR-1299, was found to upregulate NOTCH3 expression and promote cell proliferation in OC through the competing endogenous RNA mechanism. In addition, TUG1 was found to be a potential downstream target of NOTCH3, forming a miR-1299/NOTCH3/TUG1 feedback loop in the development of OC. Collectively, our findings improve the understanding of NOTCH3-mediated regulation in OC pathogenesis and facilitate the development of miRNA- and lncRNA-directed diagnostics and therapeutics against this disease.