Liu Yadong,Zhang Guiqi,Wu Jiani,Meng Yi,Hu Jianyu,Fu Hao,Yang Dongfang
Intervertebral disc degeneration (IDD) diseases are common and frequent diseases in orthopedics. The caspase recruitment domain (CARD) and membrane-associated guanylate kinase-like protein 3 (CARMA3) is crucial in the activation of the NF-κB pathway. However, the biological function of CARMA3 in IDD remains unknown. Here, CARMA3 expression was elevated in nucleus pulposus (NP) tissues of IDD rats and nutrient deprivation (ND)-induced NP cells. The main pathological manifestations observed in IDD rats were shrinkage of the NP, reduction of NP cells, fibrosis of NP tissues, and massive reduction of proteoglycans. These changes were accompanied by a decrease in the expression of collagen II and aggrecan, an increase in the expression of the extracellular matrix (ECM) catabolic proteases MMP-3, MMP-13, and metalloprotease with ADAMTS-5, and an increase in the activity of the pro-apoptotic protease caspase-3. The expression of p-IκBα Ser32/36 and p-p65 Ser536 was also upregulated. However, these effects were reversed with the knockdown of CARMA3. Mechanistically, CARMA3 bound to BCL10 and MALT1 to form a signalosome. Knockdown of CARMA3 reduced the CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation. CARMA3 activated the NF-κB signaling pathway in a manner that bound to BCL10 and MALT1 to form a signalosome, which affects NP cell damage and is involved in the development of IDD. This supports CARMA3-BCL10-MALT1-NF-κB as a promising targeting axis for the treatment of IDD.
Glioblastoma (GBM) is a highly malignant brain tumor with a poor prognosis. Long noncoding RNAs (lncRNAs) significantly influence GBM pathogenesis. Although lncRNA MIR4435-2HG is known to promote tumorigenesis in various cancers, its regulatory role in GBM remains undefined. We quantified MIR4435-2HG and miR-181d-5p expression using quantitative reverse transcription polymerase chain reaction. The functional impact of the MIR4435-2HG/miR-181d-5p/MALT1/NF-κB axis was assessed in A172 and U87 MG cells through cell counting kit-8 (CCK-8), wound healing, Transwell, flow cytometry, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), western blot, and immunofluorescence assays. Interactions between miR-181d-5p, MIR4435-2HG, and MALT1 were confirmed by dual-luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, and RNA pulldown experiments. Finally, a xenograft tumor model in C57BL/6 mice, combined with hematoxylin and eosin staining, immunohistochemistry, and TUNEL staining, was used to investigate the role of MIR4435-2HG in vivo. The results demonstrated that both MIR4435-2HG and MALT1 were upregulated in GBM tissues and cell lines, whereas the expression of miR-181d-5p was reduced. MIR4435-2HG promoted GBM cell proliferation and metastasis in both in vitro and in vivo experiments. Inhibition of MALT1 reversed the promotive effects of miR-181d-5p knock down on GBM cell proliferation and metastasis. Mechanistic studies revealed that MIR4435-2HG upregulates MALT1 expression and activates the NF-κB signaling pathway by sponging miR-181d-5p. In conclusion, MIR4435-2HG overexpression facilitates the malignant progression of GBM through the miR-181d-5p/MALT1/NF-κB pathway.
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