DIS3-like 3 0-5 0 exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. Significance: These findings establish the role and mechanism of the 3 0-5 0 exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.
To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition effect against c-Myc to contribute to medication design and development. A series of computer-aided virtual screening techniques were performed to identify potential inhibitors of c-Myc. LibDock from the software Discovery Studio was used to do a structure-based screening after ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was utilized to show the binding affinity and potential mechanism between ligands and c-Myc. Stability of the ligand-receptor complex was analyzed by molecular dynamic simulation at the end of the research. Compounds with more interactive energy which are confirmed to be the potential inhibitors for c-Myc were identified from the ZINC15 databases. Additionally, those compounds are also anticipated with fewer ames mutagenicity, rodent carcinogenicity, nondevelopmental toxic potential, and tolerant with cytochrome p450 2D6(CYP2D6). Dynamic simulation analysis also revealed that the very compounds had more favorable potential energy compared with 10058-F4(ZINC12406714). Furthermore, we prove that those compounds are stable and can exist in natural conditions. This study demonstrates that the compounds are potential therapeutic inhibitors for c-Myc. These compounds are safe and stable for drug candidates and may play a critical role in c-Myc inhibitor development.
<p>Supplementary Figures: SF1, DIS3L2 promotes cell growth in Hep3B and HepG2 cells. SF2, DIS3L2 interacts hnRNP U in Hep3B and HepG2 hepatocellular carcinoma cells. SF3, DIS3L2 and hnRNP U promote exon 3b inclusion during pre-Rac1 splicing. SF14, The effect of knockdown of pre-Rac1. SF5, DIS3L2 promotes HCC growth via Rac1b. Supplementary Tables: Table S1, clinicopathological characteristics of clinical samples. Table S2, the expression of DIS3L2 in relation to clinicopathological characteristics of liver cancer patients by the chi-square test. Table S3, the correlation between DIS3L2 and clinicopathological characteristics of clinical samples by Spearman analysis. Table S4, Univariate analysis and multivariate analyses of parameters associated with overall survival of HCC patients. Table S5-S7, Nucleotide sequences of primers used for semi-RT-PCR, RIP assays, quantitative real-time RT-PCR. Table S8, Sequences of the oligonucleotides for shRNA.</p>
<p>Supplementary Figures: SF1, DIS3L2 promotes cell growth in Hep3B and HepG2 cells. SF2, DIS3L2 interacts hnRNP U in Hep3B and HepG2 hepatocellular carcinoma cells. SF3, DIS3L2 and hnRNP U promote exon 3b inclusion during pre-Rac1 splicing. SF14, The effect of knockdown of pre-Rac1. SF5, DIS3L2 promotes HCC growth via Rac1b. Supplementary Tables: Table S1, clinicopathological characteristics of clinical samples. Table S2, the expression of DIS3L2 in relation to clinicopathological characteristics of liver cancer patients by the chi-square test. Table S3, the correlation between DIS3L2 and clinicopathological characteristics of clinical samples by Spearman analysis. Table S4, Univariate analysis and multivariate analyses of parameters associated with overall survival of HCC patients. Table S5-S7, Nucleotide sequences of primers used for semi-RT-PCR, RIP assays, quantitative real-time RT-PCR. Table S8, Sequences of the oligonucleotides for shRNA.</p>
Background Cytokines in tissue microenvironments regulate the balance between pro-and anti-inflammatory signaling. Dysregulated cytokine expression causes deleterious immunosuppression or inflammation, underpinning the pathophysiology of numerous diseases. As examples, anti-inflammatory cytokines in solid tumors suppress immune activation and safeguard the tumor, whereas pro-inflammatory cytokines in rheumatoid arthritis drive chronic inflammation. Rebalancing inflammation/immunosuppression by targeting aberrant cytokine signaling offers a generalizable approach to treating many diseases, but systemic cytokine blockade carries risks such as increased risk of infection. Cellular immunotherapies may offer a localized platform that could activate in response to cytokines then proportionately remodel the microenvironment's inflammatory state as needed. Macrophages are tissueinfiltrating homeostatic regulators responsible for initiating and resolving inflammation. Engineered macrophages have demonstrated a promising ability to target tumor cells utilizing chimeric antigen receptors. Here, we leveraged the ability of macrophages to regulate inflammation by generating macrophages that express synthetic cytokine switch receptors. We termed this platform "Engineered Microenvironment Converters" (EM-C) and evaluated its modular ability to convert immunosuppressive M2 signals into pro-inflammatory M1 responses for solid tumor microenvironment conversion, or vice versa for inflammatory disease. Methods EM-C were generated by expressing switch receptors (SR) in primary human macrophages. To convert IL10, a prevalent immunosuppressive cytokine in the TME, into a proinflammatory signal, an IL10 SR was designed and delivered to macrophages using VPX-Lentiviral particles. The in vitro response of IL10 EM-Cs to IL10 was monitored using phenotypic characterization of surface molecules, measurement of cytokine production, and biochemical analysis of downstream signaling. To assess the ability of EM-Cs to alter the inflammatory status of their environment, in vitro co-culture assays were established with M2-polarized bystander cells, and the phenotype of bystanders and EM-Cs was assessed individually. Similarly, EM-Cs targeting TGFb or IFNg were characterized. Results IL10 EM-Cs converted IL10 into a pro-inflammatory signal. Unlike wildtype macrophages, IL10 EM-Cs treated with IL10 upregulated M1 markers and cytokines in a dose-dependent manner. Furthermore, IL10 EM-Cs repolarized bystander M2 macrophages towards a pro-inflammatory phenotype following co-culture. Additionally, TGFb EM-Cs were generated and converted TGFb to a pro-inflammatory signal. IFNg EM-Cs were generated and converted IFNg, a canonical M1 cytokine, into an M2 signal. Conclusions We present for the first time a novel immunotherapy platform that harnesses macrophages as "living converters" to locally regulate inflammation for oncology and inflammatory applications. By demonstrating EM-Cs in the M2-to-M1 and M1-to-M2 direction, this platform offers modularity in co...
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