Background: N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined. Methods: Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitro and in vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429. Results: KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3′ UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. Conclusion: Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.
Silver nanoparticles (AgNPs) are the nanomaterials most widely used as antimicrobial agents in a range of consumer products, due to the environmental release of either the AgNPs themselves or silver ions. Although AgNPs appear to be more potent than silver ions, the mechanism behind the activity is not fully elucidated yet. The most common mechanism of toxicity of AgNPs proposed to date is the release of silver ions and/or the particle-specific functions. In this study, Pseudomonas aeruginosa (a model for Gram-negative bacteria) was treated with AgNPs, and its proteomic response was comprehensively characterized to elucidate the antimicrobial mechanism of AgNPs in the microorganism. In total, 59 silver-regulated proteins (27 up-regulated and 32 down-regulated proteins) and 5 silver-binding proteins were identified. Bioinformatic analysis revealed that interference with the cell-membrane function and generation of intracellular reactive oxygen species (ROS) were the main pathways for the antibacterial effect. The pattern of membrane proteins regulated by AgNPs was similar to that found for silver ions. In addition, the same silver-binding proteins were obtained with both AgNPs and silver ions, which indicated that AgNPs probably affect the cell membrane and react with proteins by releasing silver ions. The elevation of intracellular ROS relative to that with silver ions confirmed oxidative damage caused by AgNPs, which may be ascribed to the nano-characteristics and higher uptake efficiency of the particles. These results demonstrate that the antimicrobial activity of AgNPs is due to the synergistic action of release of dissolved silver ions and particle-specific effects. The proteomic analysis of silver-binding and silver-regulated proteins in the present study provides insight into the mechanism of antimicrobial activity of such nanomaterials.
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