Project description:Dysregulation of microRNAs (miRNAs) plays a critical role in the development of intervertebral disc degeneration (IDD). In this study, we present evidence from in vitro and in vivo research to elucidate the mechanism underlying the role of miR-760 in IDD. miRNA microarray and quantitative reverse transcription-polymerase chain reaction were used to determine the miRNA profiles in patients with IDD. Functional analysis was performed to evaluate the role of miR-760 in the pathogenesis of IDD. Luciferase reporter and western blotting assays were used to confirm the miRNA targets. The expression of miR-760 was significantly decreased in degenerative nucleus pulposus (NP) cells and negatively correlated with disc degeneration grade. Functional assays demonstrated that miR-760 delivery significantly increased NP cell proliferation and promoted the expression of collagen II and aggrecan. Moreover, MyD88 was identified as a target gene of miR-760. miR-760 effectively suppressed MyD88 expression by interacting with the 3′-untranslated region, which was abolished by miR-760 binding site mutations. An in vivo experiment using an IDD mouse model showed that the upregulation of miR-760 could effectively suspend IDD. Therefore, miR-760 was found to play an important role in IDD and can be used as a promising therapeutic target for the treatment of patients with IDD.
Project description:TBR-760 (formerly BIM-23A760) is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R) and SST type 2 (SSTR2) receptors. Non-functioning pituitary adenomas (NFPAs) express both D2R and SSTR2 and, consequently, may respond to TBR-760. We utilized a mouse model with the pro-opiomelanocortin (POMC) gene knocked-out that spontaneously develops aggressive NFPAs. Both genomic microarray and DA and SST receptor mRNA expression analysis indicate that POMC KO mouse tumors and human NFPAs have similar expression profiles, establishing POMC KO mice as a valid model for study of NFPAs. Treatment with TBR-760 for 8 weeks resulted in nearly complete inhibition of established tumor growth, whereas tumors from vehicle-treated mice increased in size by 890 ± 0.7%. These results support the development of TBR-760 as a therapy for patients with NFPA.
Project description:The long non-coding RNA H19 has been widely attested as a promotor of breast cancer by favoring proliferation, migration, invasion, and tumor growth. In this study, we attempted to decipher molecular mechanisms underlying the oncogenic activities of H19. Transcriptomic analyses revealed that H19 overexpression correlates with increased BST2 expression at both transcriptional and protein levels in breast cancer cell lines. Functional assays demonstrated that BST2 overexpression mimics the oncogenic effects of H19 by enhancing tumor cell aggressiveness in vitro and tumor growth in vivo. Interestingly, we also observed a reciprocal regulation, where BST2 expression modulates H19 levels, suggesting a cross-regulatory mechanism. Further mechanistic studies identified miR-760 as a key post-transcriptional regulator orchestrating this interplay. Using luciferase reporter assays and miRNA modulation strategies, we found that miR-760 directly targets both H19 and BST2, thereby regulating their expression in a coordinated manner. Our findings uncover a novel H19/miR-760/BST2 regulatory axis that enhances breast cancer progression and suggest that this axis could be studied to identify potential targets for therapeutic intervention.
