Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration. Circular RNAs (circRNAs) have emerged as pivotal players in OA progression, orchestrating various biological processes such as proliferation, apoptosis, inflammation, and extracellular matrix (ECM) reorganization. Among these circRNAs, circSLTM exhibits aberrant expression in OA, yet its precise regulatory mechanism remains elusive. This study aimed to elucidate the regulatory mechanisms of circSLTM in OA pathogenesis, with a focus on its role as a competing endogenous RNA (ceRNA). Human cartilage tissues were procured from both OA patients and non-OA individuals, while human chondrocyte cells were subjected to lipopolysaccharide (LPS) treatment to mimic OA-like conditions. Our findings revealed upregulation of circSLTM in OA patients and LPS-treated chondrocytes. Loss-of-function assays were conducted, demonstrating that silencing circSLTM via shRNAs mitigated LPS-induced effects on chondrocytes, as evidenced by enhanced proliferation, reduced apoptosis, and inflammatory factors, and altered expression of extracellular matrix proteins. Further exploration into the regulatory mechanism of circSLTM unveiled its interaction with microRNA-515-5p (miR-515-5p) to modulate vesicle-associated membrane protein (VAPB) expression in chondrocytes. VAPB, also upregulated in OA, was positively regulated by circSLTM. Rescue assays corroborated that VAPB overexpression reinstated the protective effects of circSLTM knockdown on LPS-treated chondrocytes. Moreover, concurrent knockdown of both circSLTM and VAPB demonstrated synergistic protection against LPS-induced chondrocyte injury. Additionally, we delineated that LPS triggered the activation of the NF-κB pathway in chondrocytes, which was counteracted by circSLTM silencing. To assess the effects of circSLTM on OA in vivo, anterior cruciate ligament transection (ACLT) mouse models were established, revealing that circSLTM deficiency ameliorated cartilage defects in vivo . In conclusion, circSLTM exacerbates osteoarthritis progression by orchestrating the miR-515-5p/VAPB axis and activating the NF-κB pathway, providing novel insights for targeted therapy in OA management.
Background Increasing studies have revealed that circular RNAs (CircRNAs) make great contributions to regulating tumor progression. Therefore, we intended to explore the expression characteristics, function, and related mechanisms of a novel type of circRNA, PIP5K1A, in glioma.Methods Firstly, reverse transcription-polymerase chain reaction (RT-PCR) was carried out to examine CircPIP5K1A expression in glioma tissues and adjacent normal tissues, and the correlation between CircPIP5K1A level and the clinical-pathological indicators of glioma was analyzed. Then, the CircPIP5K1A expression in various glioma cell lines was detected, and CircPIP5K1A overexpression and knockdown cell models were constructed. Subsequently, cell proliferation and viability were detected by the CCK8 method and BrdU staining. Cell apoptosis was detected by flow cytometry, and cell invasion was examined by Transwell assay. The expression of TCF12, PI3K/AKT pathway apoptotic related proteins (Caspase3, Bax, and Bcl2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin, and N-cadherin) was determined by western blot or RT-PCR.Results The results manifested that CircPIP5K1A was upregulated in glioma tissues (compared with that in normal adjacent tissues), and overexpressed CircPIP5K1A was related to glioma volume and histopathological grade. Functionally, overexpressing CircPIP5K1A notably elevated glioma cell proliferation, invasion, and EMT and inhibited apoptosis both in vivo and in vitro. Besides, CircPIP5K1A upregulated TCF12 and PI3K/AKT activation. Bioinformatics analysis testified that miR-515-5p was a common target of CircPIP5K1A and TCF12, while the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment further confirmed that CircPIP5K1A targeted miR-515-5p, which bound the 3′-untranslated region (UTR) of TCF12.Conclusion sOverall, the study illustrated that CircPIP5K1A is a potential prognostic marker in glioma and regulates glioma evolvement by modulating the miR-515-5p-mediated TCF12/PI3K/AKT axis.
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