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Abstract PLK1 is a key serine/threonine kinase as well as a master mitotic regulator, but it has never been reported that PLK1 regulates DNA methylation. In the present study, we for the first time found that PLK1 inhibition disrupted global DNA methylation and elevated the expression level of tumor suppressor genes. Mechanistically, we found that PLK1 interacts UHRF1 protein to induce its phosphorylation at serine 265. Phosphorylation is required for the maintenance of UHRF1 protein stability by recruiting a deubiquitinase USP7. Conversely, PLK1 inhibition decreases UHRF1 protein interaction with USP7 and activates the ubiquitin-proteasome pathway, thereby accelerating UHRF1 protein degradation. UHRF1 degradation decreases the recruitment of DNMT1 to chromatin, and decreases the level of genome-wide DNA methylation, thereby elevating the expression of tumor suppressor genes and decreasing cell viability. We here presented the first report on the novel role of PLK1 in DNA methylation maintenance through UHRF1-DNMT1 pathway, and revealed a novel anticancer mechanism of PLK1 inhibitors.

Abstract Background Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10–17% CRPC patients. The detailed mechanisms remain unclear.. Methods The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting. Results The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists. Conclusions TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Abstract Background The function of the insula has been increasingly mentioned in neurocircuitry models of obsessive-compulsive disorder (OCD) for its role in affective processing and regulating anxiety and its wide interactions with the classic cortico-striato-thalamo-cortical circuit. However, the insular resting-state functional connectivity patterns in OCD remain unclear. Therefore, we aimed to investigate characteristic intrinsic connectivity alterations of the insula in OCD and their associations with clinical features. Methods We obtained resting-state functional magnetic resonance imaging data from 85 drug-free OCD patients and 85 age- and sex-matched healthy controls (HCs). We performed a general linear model to compare the whole-brain intrinsic functional connectivity maps of the bilateral insula between the OCD and HC groups. In addition, we further explored the relationship between the intrinsic functional connectivity alterations of the insula and clinical features using Pearson or Spearman correlation analysis. Results Compared with HCs, patients with OCD exhibited increased intrinsic connectivity between the bilateral insula and bilateral precuneus gyrus extending to the inferior parietal lobule and supplementary motor area. Decreased intrinsic connectivity was only found between the right insula and bilateral lingual gyrus in OCD patients relative to HC subjects, which was negatively correlated with the severity of depression symptoms in the OCD group. Conclusion In the current study, we identified impaired insular intrinsic connectivity in OCD patients and the dysconnectivity of the right insula and bilateral lingual gyrus associated with the depressive severity of OCD patients. These findings provide neuroimaging evidence for the involvement of the insula in OCD and suggest its potential role in the depressive symptoms of OCD.

Resting-state fMRI analysis of patients with obsessive-compulsive disorder (OCD) compared to controls suggests a specific role of amygdala subregions in neurocircuitry models of OCD.

BackgroundInsomnia is a commonly seen symptom in adolescents with major depressive disorder (MDD). The suprachiasmatic nucleus (SCN), which is the circadian rhythm regulation center, plays a crucial role in the regulation of sleep-wake circulation. Nevertheless, how SCN function contributes to the exact neural mechanisms underlying the associations between insomnia and depressive symptoms has not been explored in adolescents. In the current study, we aimed to explore the relationship between SCN functional connectivity (FC) and insomnia symptoms in adolescents with MDD using a seed-based FC method.MethodsIn the current study, we recruited sixty-eight first-episode drug-naïve adolescents with MDD and classified them into high insomnia (MDD-HI) and low insomnia (MDD-LI) groups according to the sleep disturbance subscale of the Hamilton Depression Rating Scale (HAMD-S). Forty-three age/gender-matched healthy controls (HCs) were also recruited. SCN FC maps were generally for all subjects and compared among three groups using one-way ANOVA with age, gender and adjusted HAMD score as covariates. We used partial correlations to explore associations between altered FC and clinical symptoms, including sleep quality scores.ResultsAdolescents with MDD showed worse sleep quality, which positively correlated with the severity of depression. Compared to MDD-LI and HCs, MDD-HI adolescents demonstrated significantly decreased FC between the right SCN and bilateral precuneus, and there was no significant difference between the MDD-LI and HC groups. The HAMD-S scores were negatively correlated with bilateral SCN-precuneus connectivity, and the retardation factor score of HAMD was negatively correlated with right SCN-precuneus connectivity.ConclusionThe altered FC between the SCN and precuneus may underline the neural mechanism of sleep-related symptoms in depressive adolescents and provide potential targets for personalized treatment strategies.

BackgroundMethamphetamine (METH) use induces neurotoxic effects in brain structures and affective symptoms that persist during abstinence. However, the brain morphometry of individuals with METH use disorder (MUD) remains unclear, as well as their associations with affective symptoms during abstinence.MethodsForty-eight abstinent males with MUD and 66 age-, sex-, and education-matched healthy controls (HCs) underwent high-resolution T1-weighted magnetic resonance imaging. Cortical thickness, surface area, volume, local gyrification index (LGI), and subcortical volume were obtained with FreeSurfer software. Brain morphometry differences between groups and their associations with affective symptoms and drug abuse history within the males with MUD were examined, with intracranial volume, age, and years of education as covariates.ResultsCompared with the HCs, the individuals with MUD showed a significantly higher LGI in the right cuneus gyrus, left lingual gyrus, bilateral supramarginal gyrus, right inferior parietal gyrus (IPG), and right dorsal anterior cingulate cortex (clusterwise p < 0.05, Monte Carlo-corrected), as well as a smaller volume of the left nucleus accumbens (NAcc) (p < 0.05, FDR-corrected). However, there were no significant group differences in cortical thickness, area or volume. In addition, the LGI in the right IPG was positively associatedwith the severity of depression and anxiety symptoms in MUDs (p < 0.05, FDR-corrected).ConclusionBrain morphometric abnormalities in abstinent males with MUD were characterized by hypergyrification across multiple mid-posterior brain regions anda smaller volume of the left NAcc.Gyrification of the right IPG may be a potential neural substrate underlying the affective symptoms experienced by MUDs during abstinence.

Abstract Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative treatment for obsessive-compulsive disorder (OCD). However, the most effective rTMS parameters, such as the targets and stimulation frequencies, remain controversial. Therefore, we aimed to compare and rank the efficacy and tolerability of different rTMS strategies for OCD treatment. We searched five electronic databases from the date of their inception to March 25, 2020. Pairwise meta-analyses and network meta-analyses were performed to synthesize data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Twenty-two eligible randomized controlled trials (RCTs) were included. For efficacy, low-frequency (LF) rTMS over the dorsolateral prefrontal cortex (DLPFC; mean difference (MD) 6.34, 95% credible interval (CrI) 2.12–10.42) and supplementary motor area (MD 4.18, 95% CrI 0.83–7.62), and high-frequency rTMS over the DLPFC (MD 3.75, 95% CrI 1.04–6.81) were more effective than sham rTMS. Regarding tolerability, all rTMS treatment strategies were similar to the sham rTMS. The estimated ranking probabilities of treatments showed that LF-rTMS over the DLPFC might be the most effective intervention among all rTMS strategies. However, the quality of evidence regarding efficacy was evaluated as very low. Current evidence suggested a marginal advantage for LF-rTMS over the DLPFC on OCD treatment. High-quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for the OCD treatment.

Soybean (Glycine max) is a staple crop and a major source of vegetable protein and vegetable oil. The growth of soybean is dramatically inhibited by salt stress, especially by the excessive toxic Na+. Salt Overly Sensitive 1 (SOS1) is the only extensively characterized Na+ efflux transporter in multiple plant species so far. However, the role of GmSOS1 in soybean salt stress responses remains unclear. Herein, we created three gmsos1 mutants using the CRISPR-Cas9 system in soybean. We found a significant accumulation of Na+ in the roots of the gmsos1 mutants, resulting in the imbalance of Na+ and K+, which links to impaired Na+ efflux and increased K+ efflux in the roots of the gmsos1 mutants under salt stress. Compared to the wild type, our RNA-seq analysis revealed that the roots of the gmsos1-1 showed preferential up and downregulation of ion transporters under salt stress, supporting impaired stress detection or an inability to develop a comprehensive response to salinity in the gmsos1 mutants. Our findings indicate that the plasma membrane Na+/H+ exchanger GmSOS1 plays a critical role in soybean salt tolerance by maintaining Na+ homeostasis and provides evidence for molecular breeding to improve salt tolerance in soybean and other crops.

BackgroundFamily environment and life events have long been suggested to be associated with adolescent depression. The hippocampus plays a crucial role in the neural mechanism of major depressive disorder (MDD) through memory during stressful events. However, few studies have explored the exact neural mechanisms underlying these associations. Thus, the current study aimed to explore alterations in hippocampal functional connectivity (FC) in adolescent MDD based on resting-state functional magnetic resonance imaging and further investigate the relationship between hippocampal FC, environmental factors, and clinical symptom severity.MethodsHippocampal FC was calculated using the seed-based approach with the bilateral hippocampus as the seed for 111 adolescents with and without MDD; comparisons were made between participants with MDD and controls. We applied the Chinese version of the Family Environment Scale (FES-CV) and Adolescents Self-Rating Life Events Checklist (ASLEC) to evaluate family environment and life stress. Their relationship with hippocampal FC alterations was also investigated.ResultsWe found that compared to controls, adolescents with MDD showed decreased connectivity between the left hippocampus and bilateral orbital frontal cortex (OFC) and right inferior temporal gyrus. In addition, the hippocampal-OFC connectivity was negatively correlated with conflict scores of the FES-CV in the MDD group and mediated the association between family conflict and depressive and anxiety symptoms.ConclusionOur findings are novel in the field and demonstrate how family conflict contributes to MDD symptomatology through hippocampal-OFC connectivity; these findings may provide potential targets for personalized treatment strategies.

Abstract Background The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. Methods Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. Results Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. Conclusion This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.

Background: Bipolar disorder (BD) is a mental disorder characterized by mood fluctuations between an acute episodic state of either mania or depression and a clinically remitted state. Dysfunction of large-scale intrinsic brain networks has been demonstrated in this disorder, but it remains unknown whether those network alterations are related to different states. Methods: In the present study, we performed a meta-analysis of whole-brain seed-based resting-state functional connectivity (rsFC) studies in BD patients to compare the intrinsic function of brain networks between episodic and remitted states. Thirty-nine seed-based voxel-wise rsFC datasets from thirty publications (1047 BD patients vs 1081 controls) were included in the meta-analysis. Seeds were categorized into networks by their locations within a priori functional networks. Seed-based d mapping analysis of between-state effects identified brain systems in which different states were associated with increased connectivity or decreased connectivity within and between each seed network. Findings: We found that BD patients presented decreased connectivity within the affective network (AN) in acute episodes but not in the remitted state of the illness. Similar decreased connectivity within the default-mode network (DMN) was also found in the acute state, but it was replaced by increased connectivity in the remitted state. In addition, different patterns of between-network dysconnectivity were observed between the acute and remitted states. Interpretation: This study is the first to identify different patterns of intrinsic function in large-scale brain networks between the acute and remitted states of BD through meta-analysis. The findings suggest that a shift in network function between the acute and remitted states may be related to distinct emotional and cognitive dysfunctions in BD, which may have important implications for identifying clinically relevant biomarkers to guide alternative treatment strategies for BD patients during active episodes or remission. Funding: This study was supported by grants from the National Natural Science Foundation of China (81171488, 81671669 and 81820108018) and by a Sichuan Provincial Youth Grant (2017JQ0001). Keywords: Bipolar disorder (BD), Resting-state functional connectivity (rsFC), Meta-analysis, Functional network, Mood states

The dorsolateral prefrontal cortex (DLPFC), a key structure in the executive system, has consistently emerged as a crucial element in the pathophysiology of obsessive–compulsive disorder (OCD). However, the neural primacy of the DLPFC remains elusive in this disorder. We investigated the causal interaction (measured by effective connectivity) between the DLPFC and the remaining brain areas using bivariate Granger causality analysis of resting-state fMRI collected from 88 medication-free OCD patients and 88 matched healthy controls. Additionally, we conducted seed-based functional connectivity (FC) analyses to identify network-level neural functional alterations using the bilateral DLPFC as seeds. OCD patients demonstrated reduced FC between the right DLPFC and right orbitofrontal cortex (OFC), and activity in the right OFC had an inhibitory effect on the right DLPFC. Additionally, we observed alterations in both feedforward and reciprocal influences between the inferior temporal gyrus (ITG) and the DLPFC in patients. Furthermore, activity in the cerebellum had an excitatory influence on the right DLPFC in OCD patients. These findings may help to elucidate the psychopathology of OCD by detailing the directional connectivity between the DLPFC and the rest of the brain, ultimately helping to identify regions that could serve as treatment targets in OCD.

Background: Although dysfunction of amygdala-related circuits is centrally implicated in major depressive disorder (MDD), little is known about how this dysfunction differs between adult and adolescent MDD patients. Methods: Voxel-wise meta-analyses of abnormal amygdala resting-state functional connectivity (rsFC) were conducted in adult and adolescent groups separately, followed by a quantitative meta-analytic comparison of the two groups. Findings: Nineteen studies that included 665 MDD patients (392 adults and 273 adolescents) and 546 controls (341 adults and 205 adolescents) were identified in the current study. Adult-specific abnormal amygdala rsFC in MDD patients compared to that in controls was located mainly within the affective network, including increased connectivity with the right hippocampus/parahippocampus and bilateral ventromedial orbitofrontal cortex and decreased connectivity with the bilateral insula and the left caudate. Adolescent MDD patients specifically demonstrated decreased amygdala rsFC within the cognitive control network encompassing the left dorsolateral prefrontal cortex and imbalanced amygdala rsFC within the default mode network, which was manifested as hyperconnectivity in the right precuneus and hypoconnectivity in the right inferior temporal gyrus. Additionally, direct comparison between the two groups showed that adult patients had strengthened amygdala rsFC with the right hippocampus/parahippocampus as well as the right inferior temporal gyrus and weakened amygdala rsFC with the bilateral insula compared to that in adolescent patients. Interpretation: Distinct impairments of amygdala-centered rsFC in adult and adolescent patients were related to different network dysfunctions in MDD. Adult-specific amygdala rsFC dysfunction within the affective network presumably reflects emotional dysregulation in MDD, whereas adolescent-specific amygdala rsFC abnormalities in networks involved in cognitive control might reflect the neural basis of affective cognition deficiency that is characteristic of adolescent MDD. Fund: This study was supported by a grant from the National Natural Science Foundation of China (81671669) and by a Sichuan Provincial Youth Grant (2017JQ0001). Keywords: Major depressive disorder, Amygdala, Functional connectivity, Adults, Adolescents, Meta-analysis

Abstract Background The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. Methods Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. Results PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. Conclusions Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.

Recent developments in psychoradiological researches have highlighted the disrupted organization of large-scale functional brain networks in obsessive-compulsive disorder (OCD). However, whether abnormal activation of localized brain areas would affect network dysfunction remains to be fully characterized. We applied both univariate analysis and multivariate pattern analysis (MVPA) approaches to investigate the abnormalities of regional homogeneity (ReHo), an index to measure the localized connectivity, in 88 medication-free patients with OCD and 88 healthy control subjects (HCS). Resting-state functional magnetic resonance imaging (RS-fMRI) data of all the participants were acquired in a 3.0-T scanner. First, we adopted a traditional univariate analysis to explore ReHo alterations between the patient group and the control group. Subsequently, we utilized a support vector machine (SVM) to examine whether ReHo could be further used to differentiate patients with OCD from HCS at the individual level. Relative to HCS, OCD patients showed lower ReHo in the bilateral cerebellum and higher ReHo in the bilateral superior frontal gyri (SFG), right inferior parietal gyrus (IPG), and precuneus [P < 0.05, family-wise error (FWE) correction]. ReHo value in the left SFG positively correlated with Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score (r = 0 0.241, P = 0.024) and obsessive subscale (r = 0.224, P = 0.036). The SVM classification regarding ReHo yielded an accuracy of 78.98% (sensitivity = 78.41%, specificity = 79.55%) with P < 0.001 after permutation testing. The most discriminative regions contributing to the SVM classification were mainly located in the frontal, temporal, and parietal regions as well as in the cerebellum while the right orbital frontal cortex was identified with the highest discriminative power. Our findings not only suggested that the localized activation disequilibrium between the prefrontal cortex (PFC) and the cerebellum appeared to be associated with the pathophysiology of OCD but also indicated the translational role of the localized connectivity as a potential discriminative pattern to detect OCD at the individual level.

Background: The specific role of the corticospinal tract with respect to inattention and impulsive symptoms in children with attentiondeficit/ hyperactivity disorder (ADHD) has been explored in the past. However, to our knowledge, no study has identified the exact regions of the corticospinal tract that are affected in ADHD. We aimed to determine comprehensive alterations in the white matter microstructure of the corticospinal tract and underlying neuropsychological substrates in ADHD. Methods: We recruited 38 drug-naïve children with ADHD and 34 typically developing controls. We employed a tract-based quantitative approach to measure diffusion parameters along the trajectory of the corticospinal tract, and we further correlated alterations with attention and response inhibition measures. Results: Compared with controls, children with ADHD demonstrated significantly lower fractional anisotropy and higher radial diffusivity at the level of cerebral peduncle, and higher fractional anisotropy at the level of the posterior limb of the internal capsule in the right corticospinal tract only. As well, increased fractional anisotropy in the posterior limb of the internal capsule was negatively correlated with continuous performance test attention quotients and positively correlated with reaction time on the Stroop Colour--Word Test; increased radial diffusivity in the right peduncle region was positively correlated with omissions in the Stroop test. Limitations: The sample size was relatively small. Moreover, we did not consider the different subtypes of ADHD and lacked sufficient power to analyze subgroup differences. Higher-order diffusion modelling is needed in future white matter studies. Conclusion: We demonstrated specific changes in the right corticospinal tract in children with ADHD. Correlations with measures of attention and response inhibition underscored the functional importance of corticospinal tract disturbance in ADHD. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miRBART3- 3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo. Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RASG12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, andEBNA3Cis not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RASG12V or chemotherapeutic drugs can induce senescence, and here we show that both RASG12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is the first human virus found to encode many microRNAs. It is etiologically linked to nasopharyngeal carcinoma and EBV-associated gastric carcinoma. During the latent infection period, there are only a few EBV proteins expressed, whereas EBV microRNAs, such as the BamHI-A region rightward transcript (BART) microRNAs, are highly expressed. However, how these BART miRNAs precisely regulate the tumor growth in nasopharyngeal carcinoma and gastric carcinoma remains obscure. Here, we report that upregulation of EBV-miR-BART5-3p promotes the growth of nasopharyngeal carcinoma and gastric carcinoma cells. BART5-3p directly targets the tumor suppressor gene TP53 on its 3'--untranslated region (3--UTR) and consequently downregulates CDKN1A, BAX, and FAS expression, leading to acceleration of the cell cycle progress and inhibition of cell apoptosis. BART5-3p contributes to the resistance to chemotherapeutic drugs and ionizing irradiation-induced p53 increase. Moreover, BART5-3p also facilitates degradation of p53 proteins. BART5-3p is the first EBVmicroRNA to be identified as inhibiting p53 expression and function, which suggests a novel mechanism underlying the strategies employed by EBV to maintain latent infection and promote the development of EBV-associated carcinomas. [ABSTRACT FROM AUTHOR]