Unlabelled: The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.
Significance: The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention.
Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) has been reported to be upregulated in thyroid cancer (THCA). However, the role and mechanism of TNFRSF12A in THCA remain largely unknown. TNFRSF12A expression in THCA samples was analyzed using bioinformatics analysis.
Intramuscular fat (IMF) content is a critical indicator of the beef nutritional value and flavor. In this study, we focused on bta-miR-484, a microRNA that is differentially expressed during the adipogenic differentiation of bovine intramuscular adipocytes and is negatively correlated with the IMF content across different cattle breeds. Our findings demonstrate that bta-miR-484 inhibits adipogenic differentiation without altering the fatty acid composition of bovine intramuscular adipocytes.
The MAP2K7 signaling pathway activates the c-Jun NH2-terminal protein kinase (JNK) in response to stress signals, such as inflammatory cytokines, osmotic stress, or genomic damage. While there has been interest in inhibiting JNK due to its involvement in inflammatory processes and cancer, there is increasing focus on developing MAP2K7 inhibitors to enhance specificity when MAP2K7 activation is associated with disease progression. Despite some progress, further research is needed to fully comprehend the role of MAP2K7 in cancer and assess the potential use of kinase inhibitors in cancer therapy.
Unlabelled: SARS coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and a C-terminal N7-methyltransferase (N7-MTase) domain that methylates viral mRNA caps. Nsp14 also modulates host functions. This includes the activation of NF-κB and downregulation of interferon alpha/beta receptor 1 (IFNAR1).
