RNA silencing can be induced by highly transcribed transgenes through a pathway dependent on RNA-DEPENDENT RNA POLYMERASE6 (RDR6) and may function as a genome protection mechanism against excessively ...expressed genes. Whether all transcripts or just aberrant transcripts activate this protection mechanism is unclear. Consistent RNA silencing induced by a transgene with three direct repeats of the β-glucuronidase (GUS) open reading frame (ORF) is associated with high levels of truncated, unpolyadenylated transcripts, probably from abortive transcription elongation. Truncated, unpolyadenylated transcripts from triple GUS ORF repeats were degraded in the wild type but accumulated in an rdr6 mutant, suggesting targeting for degradation by RDR6-mediated RNA silencing. A GUS transgene without a 3' transcription terminator produced unpolyadenylated readthrough mRNA and consistent RDR6-dependent RNA silencing. Both GUS triple repeats and terminator-less GUS transgenes silenced an expressed GUS transgene in trans in the wild type but not in the rdr6 mutant. Placing two 3' terminators in the GUS transgene 3' reduced mRNA 3' readthrough, decreased GUS-specific small interfering RNA accumulation, and enhanced GUS gene expression. Moreover, RDR6 was localized in the nucleus. We propose that improperly terminated, unpolyadenylated mRNA from transgene transcription is subject to RDR6-mediated RNA silencing, probably by acting as templates for the RNA polymerase, in Arabidopsis thaliana.
H-RasV12 oncogene has been shown to promote autophagic cell death. Here, we provide evidence of a contextual role for H-RasV12 in cell death that is varied by its effects on miR-130a. In ...E1A-immortalized murine embryo fibroblasts, acute expression of H-RasV12 promoted apoptosis, but not autophagic cell death. miRNA screens in this system showed that miR-130a was strongly downregulated by H-RasV12 in this model system. Enforced expression of miR-130a increased cell proliferation in part via repression of PTEN. Consistent with this effect, miR-130a overexpression in human breast cancer cells promoted Akt phosphorylation, cell survival, and tumor growth. In clinical specimens of multiple human cancers, expression of miR-130 family members correlated inversely with PTEN expression. Overall, our results defined miR-130a as an oncogenic miRNA that targets PTEN to drive malignant cell survival and tumor growth.
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In a single-observer passive localization system, the velocity and position of the target are estimated simultaneously. However, this can lead to correlated errors and distortion of the estimated ...value, making independent estimation of the speed and position necessary. In this study, we introduce a novel optimization strategy, suboptimal estimation, for independently estimating the velocity vector in single-observer passive localization. The suboptimal estimation strategy converts the estimation of the velocity vector into a search for the global optimal solution by dynamically weighting multiple optimization criteria from the starting point in the solution space. Simulation verification is conducted using uniform motion and constant acceleration models. The results demonstrate that the proposed method converges faster with higher accuracy and strong robustness.
Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust ...and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.
Lee et al. show that RNA nanoparticle (RNP) configured based on three-way-junction (3WJ) of pRNA of bacteriophage phi29 successfully delivered anti-miR-21 LNA into glioblastoma cells and intracranial mouse brain glioblastoma and reduced tumor growth with significantly improved survival rate by rescuing tumor suppressor genes, demonstrating the therapeutic potential of 3WJ-based RNP as miRNA delivery platform for glioblastoma targeted therapy.
Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains ...frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identifymicroRNA-224(miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. IncreasedmiR-224expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated thatmiR-224functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation ofmiR-224expression in NSCLC. Up-regulatedmiR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targetingmiR-224could be effective in the treatment of certain lung cancer patients.
Dwarf bamboos are clonal plants with potential applications in the remediation of heavy metal-polluted soils, although their pollution adaptation strategies are unknown. This study examined the ...biomass allocation strategies and lead (Pb) enrichment characteristics of various dwarf bamboo tissues by the end of the growing season and explored their potential for phytoremediation of Pb stress in the soils. Six dwarf bamboo genotypes were treated with three levels (0, 300, and 1500 mg kg–1) of soil Pb stress. The majority of the bamboos adopted two biomass allocation strategies to adapt to Pb stress, namely, “reducing biomass allocation into new bamboo growth” and “increasing/stabilizing biomass allocation into rhizomes”. Pb accumulation was highest in the roots, rhizomes, and old stems and showed the following trend: rhizomes/old stems> new roots/old roots> old leaves> new leaves> new stems among various tissues. Moreover, the six bamboos used three different Pb-enrichment strategies, as follows: (i) “rhizome domination and old stem synergy” (Sasaella glabra (Nakai) f. albo-striata Muroi, Sasa auricoma (Mitford) E.G. Camus, Sasa fortunei (Van Houtte) Fiori, and Shibataea lanceifolia C.H. Hu); (ii) “old stem domination and rhizome synergy” (Indocalamus decorus Q.H. Dai); and (iii) “old stem domination and new root synergy” (Sasa argenteostriata (Regel) E.G. Camus). In Pb-contaminated soils, genotypes with TFs greater than 1 were Sasa fortunei (Van Houtte) Fiori, Sasa argenteostriata (Regel) E.G. Camus, and Indocalamus decorus Q.H. Dai; in addition, only S. argenteostriata had BCF values greater than 1. Furthermore, this study provides the first evidence that S. argenteostriata can extract 0.22 and 0.58 mgplant−1 of Pb ions in soil polluted with 300 and 1500 mg kg−1 Pb, respectively. S. argenteostriata showed the greatest potential for phytoremediation among the bamboo genotypes in both Pb-contaminated urban and mining sites.
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•Dwarf bamboos use two biomass allocation strategies in Pb-polluted soils.•Six dwarf bamboos formed three different Pb-enrichment modes.•“Old-stem-dominant-new-root-synergy” was the optimal mode for avoiding Pb damage.•Sasa argenteostriata (Regel) E.G. Camus is a promising Pb-hyperaccumulating species.
MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses ...pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.
•ERK phosphorylation followed by Pin1-mediated isomerization impairs XPO5 activity•Downregulation of miR-122 leads to taxol resistance through septin-9 and MARK4•XPO5 phosphorylation correlates with poor prognosis in HCC patients•Pin1 and MARK4 are potential targets for clinical intervention in liver cancer
Sun et al. find that ERK phosphorylates XPO5, which induces a Pin1-mediated conformational change that inhibits the ability of XPO5 to load and export pre-miRNA from the nucleus. Phosphorylation of XPO5 is associated with global miRNA downregulation and correlates with poor survival in hepatocellular carcinoma.
Phytoremediation is an effective way to remediate metal-contaminated soils. During phytoremediation, plants immobilize heavy metals through the roots to reduce the mobility, toxicity and dispersal of ...the metals, and the changes in the activity of the roots are often accompanied by changes in the rhizosphere ecosystems, in which rhizobacteria are essential components and interact with roots to maintain the stability of the rhizosphere ecosystem and improve soil health. In this study, the phytoremediation potential of Sasa argenteostriata (Regel) E.G. Camu and the response of rhizobacteria were revealed with different levels of lead-zinc tailing contamination (Pb, Zn, and Cd concentrations of 1197.53, 3243.40, and 185.44 mg/kg for M1 and 2301.71, 6087.95, and 364.00 mg/kg for M2, respectively). The BCF of Sasa argenteostriata increased with increasing soil pollution, and the BCFPb, BCFZn, and BCFCd were 0.19, 0.27, and 0.08, respectively, under the M2 treatment; in contrast, the TF decreased with increasing soil pollution, and the TFPb, TFZn, and TFCd were 0.39, 0.85, and 0.07, respectively, under the M1 treatment. The mobility of Pb in the rhizosphere was higher than that of Zn and Cd, and the percentage of residual (Res) Zn and Cd in the rhizosphere increased, while the acid-soluble (Aci) Pb was significantly higher, leading to obvious uptake of Pb by the roots. Correlation analysis showed that Sasa argenteostriata affected the rhizobacterial community by changing the rhizosphere soil pH, the contents of organic matter and NRFM, and bacteria such as Proteobacteria and MND1, which are highly resistant to heavy metals (HMs), became the dominant species in the community. Further PICRUSt2 analysis showed that reducing metal transport across the membranes and increasing the efficiency of cellular reproduction were the main metabolic mechanisms of bacterial tolerance to HMs. Overall, the roots of Sasa argenteostriata were able to immobilize more heavy metals in PbZn tailing-contaminated soil, reducing the toxicity of HMs in the soil, and then influencing the rhizobacteria to change the community structure and metabolism mechanism to adapt to the HM-contaminated environment, and the soil fertility was increased, which together promoted the health and stability of the soil. This study is the first to illustrate the phytoremediation potential and response of the rhizobacterial community of Sasa argenteostriata under multimetal contamination of PbZn tailings. The results of the study provide some guidance for the practice of lead-zinc tailing-phytoremediation and soil health.
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•BCF of S. argenteostriata increased with increasing pollution level, BCFZn>BCFPb>BCFCd, especially in roots.•TF of S. argenteostriata decreased with increasing pollution level, TFZn>TFPb>TFCd.•Soil organic matter increased significantly with increasing pollution level.•Bacteria like Burkholderiales are biomarkers with metal resistance in rhizosphere.
MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients ...show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b–target transcripts that are potentially involved in the aforementioned metabolic pathways and defined a miR-125b–dependent CLL metabolism-related transcript signature. Thus, miR-125b acts as a master regulator for the adaptation of cell metabolism to a transformed state. MiR-125b and miR-125b–dependent metabolites therefore warrant further investigation as possible novel therapeutic approaches for patients with CLL.
Ethylenediaminetetraacetic acid (EDTA) is one of the most effective chelating agents for enhancing lead (Pb) accumulation in various plant organs. However, it has a higher risk of causing secondary ...pollution than other chelating agents. To reduce such environmental risks and increase remediation efficiency, EDTA can be combined with degradable chelating agents for use in phytoremediation, but there are few reports on the combination of EDTA and nitrilotriacetic acid (NTA). This study evaluated the effects of combined EDTA and NTA application at different concentrations (900, 1200, or 1500 mg/kg) and with different methods (1 application or 3 applications) on dwarf bamboo (Sasa argenteostriata (Regel) E.G. Camus) growth and phytoremediation efficiency and on the soil environment in pot experiments with Pb-contaminated soil. Applying EDTA and NTA together resulted in lower soil water-soluble Pb concentrations than applying EDTA alone and therefore resulted in lower environmental risk. The increased availability of soil Pb produced a stress response in the dwarf bamboo plants, which increased their biomass significantly. Moreover, under the chelating treatments, the soil Pb availability increased, which promoted Pb translocation in plants. The Pb content in the aerial parts of the dwarf bamboo increased significantly in all treatments (translocation factors increased by 300~1500% compared with that in CK). The Pb content increase in the aerial parts caused high proline accumulation in dwarf bamboo leaves, to alleviate Pb toxicity. Maximum Pb accumulation was observed in the EN1500 treatment, which was significantly higher than that in the other treatments except the EN900 treatment. This study elucidates the choice of remediation techniques and the physiological characteristics of the plants used in such studies. In conclusion, the EN900 treatment resulted in the lowest environmental risk, greatest biomass production, and highest phytoremediation efficiency of all treatments, indicating that it has great potential for application in phytoremediation with dwarf bamboo in Pb-contaminated soil.
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•EDTA and NTA combination has lower environmental risk than EDTA.•Chelating agents can increase the plant biomass of S. argenteostriata.•The addition of chelating agent can effectively enhance the phytoremediation efficiency of S. argenteostriata.•EDTA and NTA combination shows great potential in enhancing Pb remediation efficiency by S. argenteostriata.
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