ABSTRACT
Introduction: Pseudorabies virus (PRV) is the pathogenic virus of porcine pseudorabies (PR), belonging to the Herpesviridae family. PRV has a wide range of hosts and in recent years has also been reported to infect humans. N6-methyladenosine (m6A) modification is the major pathway of RNA post-transcriptional modification. Whether m6A modification participates in the regulation of PRV replication is unknown. Methods: Here, we investigated that the m6A modification was abundant in the PRV transcripts and PRV infection affected the epitranscriptome of host cells. Knockdown of cellular m6A methyltransferases METTL3 and METTL14 and the specific binding proteins YTHDF2 and YTHDF3 inhibited PRV replication, while silencing of demethylase ALKBH5 promoted PRV output. The overexpression of METTL14 induced more efficient virus proliferation in PRV-infected PK15 cells. Inhibition of m6A modification by 3-deazaadenosine (3-DAA), a m6A modification inhibitor, could significantly reduce viral replication. Results and Discussion: Taken together, m6A modification played a positive role in the regulation of PRV replication and gene expression. Our research revealed m6A modification sites in PRV transcripts and determined that m6A modification dynamically mediated the interaction between PRV and host.
ABSTRACT
N6 -methyladenosine (m6 A) modification is the most common and reversible posttranscriptional modification of RNA in eukaryotes, which is mainly regulated by methyltransferase, demethylase, and specific binding protein. The replication of the virus and host immune response to the virus are affected by m6 A modification. In different kinds of viruses, m6 A modification has two completely opposite regulatory functions. This paper reviews the regulatory effects of m6 A modification on different viruses and provides a reference for studying the regulatory effects of RNA epitranscriptomic modification.
Subject(s)
Adenosine/analogs & derivatives , Viruses/genetics , Adenosine/metabolism , Humans , Methylation , Methyltransferases/genetics , Methyltransferases/metabolism , RNA, Viral/geneticsABSTRACT
Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Manganese Compounds/pharmacology , Nanoparticles/chemistry , Neovascularization, Pathologic/drug therapy , Oxides/pharmacology , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents/chemistry , Carcinoma, Hepatocellular/pathology , Drug Carriers/chemistry , Drug Carriers/pharmacology , Humans , Liver Neoplasms/pathology , Male , Manganese Compounds/chemistry , Mice , Mice, Inbred C3H , Neovascularization, Pathologic/pathology , Oxides/chemistry , Particle Size , Surface Properties , Tumor Cells, Cultured , Tumor Escape/drug effects , Tumor Hypoxia/drug effectsABSTRACT
Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.
