Long noncoding RNA Pvt1 promotes the proliferation and migration of Schwann cells by sponging microRNA-214 and targeting c-Jun following peripheral nerve injury

Research has shown that long-chain noncoding RNAs(lncRNAs) are involved in the regulation of a variety of biological processes, including peripheral nerve regeneration, in part by acting as competing endogenous RNAs. c-Jun plays a key role in the repair of peripheral nerve injury. However, the precise underlying mechanism of c-Jun remains unclear. In this study, we performed microarray and bioinformatics analysis of mouse crush-injured sciatic nerves and found that the lncRNA Pvt1 was overexpressed in Schwann cells after peripheral nerve injury. Mechanistic studies revealed that Pvt1 increased c-Jun expression through sponging miRNA-214. We overexpressed Pvt1 in Schwann cells cultured in vitro and found that the proliferation and migration of Schwann cells were enhanced, and overexpression of miRNA-214 counteracted the effects of Pvt1 overexpression on Schwann cell proliferation and migration. We conducted in vivo analyses and injected Schwann cells overexpressing Pvt1 into injured sciatic nerves of mice. Schwann cells overexpressing Pvt1 enhanced the regeneration of injured sciatic nerves following peripheral nerve injury and the locomotor function of mice was improved. Our findings reveal the role of lncRNAs in the repair of peripheral nerve injury and highlight lncRNA Pvt1 as a novel potential treatment target for peripheral nerve injury.

Methodological survey of using Bayesian Network for predicting pharmacology-based bioactivities of Chinese medicines:a scoping review

Background:It seems to be numerous unclear black-box mechanisms of Chinese Medicines(CMs)with multiple bioactivities in the real-world clinical practice.Meanwhile,prior prediction is necessary before the implementation of pharmacodynamics-pharmacokinetics-based researches.With emergent ML techniques for TCM domain,Bayesian Network(BN)has shown its potentials for CM-bioactivity prediction and syndromes identification in Traditional Chinese Medicine(TCM),benefited from many advantages,such as flexibility in addressing,data-driven and probability-based inference under complex uncertainty.Although BN has been extensively used in TCM,the scarcity of researches on refining methodological features of BN-modelling for optimization poses a significant challenge.Our goal is to present methodological overview of BN-modelling for CM-bioactivities prediction towards pharmacology,which tends to acquire a sequence of intimations for boosting in-depth and optimized CM-BN collaboration based on detected gaps.Methods:We performed systematic search of 13 databases from their inception to November 10th 2022 regardless of language written,which excluded unindexed journals and clinical trial registries,using the 3 keywords(CM,Pharmacology,BN).And full-text original researches with the given subject were under consideration.Afterwards,selection of eligible studies,data refinement and inspection were totally conducted by 6 review authors.Results:A total of 7 studies involving 17 BN models were included for synthesis and refinement,based on existing literatures and databases with 2 modelling functions:regression and tagging.There were 3 prediction patterns:property-bioactivity,efficacy-bioactivity and constituent-bioactivity inference,covering 8 feature-utilized efficacies,5 feature-utilized properties and 10 feature-utilized constituents.Thereafter,without an independent validation dataset,established BNs were mostly utilized to predict the root-node probabilities of unknown data.Indeed,incomplete report on modelling samples,directed acyclic graphs,conditional probability tables and algorithms hindered us from gathering information.Conclusion:A spot of studies were found in this work.And current evidence suggested that some breakthroughs should be achieved in CM-BN integration in the future.At last,to our knowledge,we preliminarily proposed certain recommendations and elicited implications for future work.

Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression

Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis

BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.

Overexpression of RBM34 Promotes Tumor Progression and Correlates with Poor Prognosis of Hepatocellular Carcinoma

Background and Aims:Emerging evidence suggests that RNA-binding motif(RBM)proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors.The objective of this study was to investigate the role of RBM34,an RBM protein,in hepatocellular carcinoma(HCC).Methods:We first examined the expression of RBM34 across cancers.The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated.Functional enrichment analysis of RBM34-related differentially expressed genes(DEGs)was performed to explore its biological function.RNA sequencing(RNA-seq)was applied to identify downstream genes and pathways affected upon RBM34 knockout.The correlation of RBM34 with immune characteristics was also analyzed.The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.Results:RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis.RBM34 was positively associated with tumor immune cell infiltration,biomarkers of immune cells,and immune checkpoint expression.A positive correlation was also observed between RBM34,T cell exhaustion,and regulatory T cell marker genes.Knockout of RBM34 significantly inhibited cell proliferation,migration,and xenograft tumor growth,and sensitized HCC cells to sorafenib treatment.RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.Conclusions:Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

A p53/CPEB2 negative feedback loop regulates renal cancer cell proliferation and migration

The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability.Thus,cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint.In this study,we identified the gene encoding RNAbinding protein cytoplasmic polyadenylation element-binding protein 2(CPEB2)as a p53 target.In turn,CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level.Specifically,we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p5330-untranslated region,and the RNA recognition motif and zinc finger(ZF)domains of CPEB2 are required for this binding.Furthermore,we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration.The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53.Overall,we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53,suggesting that CPEB2 is a potential therapeutic target in human renal cancer.