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During the long coevolution of human cytomegalovirus (HCMV) and humans, the host has formed a defense system of multiple layers to eradicate the invader, and the virus has developed various strategies to evade host surveillance programs. The intrinsic immunity primarily orchestrated by promyelocytic leukemia (PML) nuclear bodies (PML‐NBs) represents the first line of defense against HCMV infection. Here, we demonstrate that microrchidia family CW‐type zinc finger 3 (MORC3), a PML‐NBs component, is a restriction factor targeting HCMV infection. We show that depletion of MORC3 through knockdown by RNA interference or knockout by CRISPR‐Cas9 augmented immediate‐early protein 1 (IE1) gene expression and subsequent viral replication, and overexpressing MORC3 inhibited HCMV replication by suppressing IE1 gene expression. To relief the restriction, HCMV induces transient reduction of MORC3 protein level via the ubiquitin‐proteasome pathway during the immediate‐early to early stage. However, MORC3 transcription is upregulated, and the protein level recovers in the late stages. Further analyses with temporal‐controlled MORC3 expression and the major immediate‐early promoter (MIEP)‐based reporters show that MORC3 suppresses MIEP activity and consequent IE1 expression with the assistance of PML. Taken together, our data reveal that HCMV enforces temporary loss of MORC3 to evade its repression against the initiation of immediate‐early gene expression. [ABSTRACT FROM AUTHOR]

Background: Emerging cell- or tissue-based evidence has demonstrated that opsin 3 (OPN3) mediates a variety of pathological processes affecting tumorigenesis, clinical prognosis, and treatment resistance in some cancers. However, a comprehensive analysis of OPN3 across human cancers is unavailable. Therefore, a pancancer analysis of OPN3 expression was performed and its potential oncogenic roles were explored.Methods: The expression and characterization of OPN3 were evaluated among 33 tumour types using The Cancer Genome Atlas (TCGA) dataset. Additionally, the OPN3 RNA level and overall survival (OS) in relation to its expression level in 33 cancer types were estimated. Based on the analysis above, 347 samples from 5 types of tumours were collected and detected for the protein expression of OPN3 by immunohistochemical assay. Furthermore, the biological role of OPN3 in cancers was evaluated via gene set enrichment analysis (GSEA).Results: The OPN3 expression level was heterogeneous across cancers, yet a remarkable difference existed between OPN3 expression and patient overall survival among the 7 types of these 33 cancers. Consistently, a high immunohistochemical score of OPN3 was significantly associated with a poor prognosis among patients with 5 types of tumours. Additionally, OPN3 expression was involved in cancer-associated fibroblast infiltration in 5 types of tumours, and promoter hypomethylation of OPN3 was observed in 3 tumour types. Additionally, OPN3 protein phosphorylation sites of Tyr140 and Ser380 were identified via posttranscriptional modification analysis, suggesting the potential function of Tyr140 and Ser380 phosphorylation in tumorigenesis. Furthermore, the enrichment analysis was mainly concentrated in C7orf70, C7orf25 and the "ribosome" pathway by GSEA in 5 types of cancers, indicating that OPN3 might affect tumorigenesis and progression by regulating gene expression and ribosome biogenesis.Conclusions: High expression of OPN3 was significantly associated with a poor clinical prognosis in five types of cancers. Its molecular function was closely associated with the ribosomal pathway. [ABSTRACT FROM AUTHOR]

Background. Endoplasmic reticulum stress (ERS) in the retinal Müller cells is a key factor contributing to the retinal inflammation and vascular leakage in diabetic retinopathy (DR). This study was to investigate the underlying mechanisms through which the 3 main unfolded protein response (UPR) pathways regulate ERS and to examine the expression levels of vascular endothelial growth factor (VEGF) in Müller cells in vitro. Methods. Rat Müller cell lines were stimulated with high glucose to mimic a diabetic environment in vitro. PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) were downregulated or upregulated with shRNA or overexpression plasmids. The transfected Müller cells were cultivated in high glucose medium for 48 hours. Expression of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP1), ATF6, and VEGF was examined with immunofluorescence and western blot. Results. Our data indicated that ERS was found in both high glucose and osmotic control groups. Overexpression or downregulation of UPR pathways effectively increased or reduced the production of GRP78, ATF4, XBP1, ATF6, and VEGF, respectively. These 3 signaling pathways had similar regulatory effects on VEGF. Conclusion. The 3 UPR-mediated inflammatory pathways were dependent on each other. Inhibition any of these signaling pathways in UPR might be a potential therapeutic target for DR. [ABSTRACT FROM AUTHOR]

We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma. [ABSTRACT FROM AUTHOR]

Background/Aims: Acute myeloid leukemia (AML) is a heterogeneous clonal disease and patients with AML who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. This study aims to identify novel targets for explaining the dilemmas. Methods: We analyzed four microarray gene expression profiles to investigate changes in whole genome expression associated with FLT3-ITD mutation. Results: We identified 22 differentially expressed genes which are commonly expressed among all four profiles. Kaplan-Meier analysis of the dataset GSE12417 revealed that low expression of AHSP, EPB42, GYPC and HEMGN predicted poor prognosis (AHSP: P=0.0317, HR=1.894; EPB42: P=0.0382, HR=1.859; GYPC: P=0.0015, HR=2.051; HEMGN: P=0.0418, HR=1.838 in GSE12417 test cohort; AHSP: P=0.0279, HR=1.548; EPB42: P=0.0398, HR=1.505; GYPC: P=0.0408, HR=1.501; HEMGN: P=0.0143, HR=1.630 in GSE12417 validation cohort). When patients were FLT3-ITD positive, the expression of FLT3 was significantly increased (all P<0.05 in four profiles), and correleation analysis of four profiles revealed that the expression of the four candidate genes negatively correlated with FLT3 expression. Conclusions: Our findings suggest that AHSP, EPB42, GYPC and HEMGN may be suitable biomarkers for diagnostic or therapeutic strategies for FLT3-ITD-positive AML patients. [ABSTRACT FROM AUTHOR]

Purpose: Long non-coding RNA (LncRNA) urothelial carcinoma-associated 1 (UCA1) is reported to be dysregulated in hepatocellular carcinoma (HCC) progression. However, the functions of UCA1 in HCC still need further study. The aim is to detect the role of UCA1 involving in HCC cells proliferation and invasion, and epithelial-mesenchymal transition (EMT). Methods: The quantitative real-time PCR was used to detect the UCA1 and miR-203 expression levels in 60 cases' HCC tissues and adjacent normal tissues. Western blotting analysis was performed to detect the EMT markers E-cadherin, Vimentin and transcription factor Snail1, Snail2 expression. Luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays were used to evaluate whether miR-203 was a target of UCA1. Results: Our results showed that UCA1 was markedly upregulated in HCC tissues and higher UCA1 expression in HCC was positively associated with tumor size, vascular invasion and American Joint Committee on Cancer (AJCC) stage ( P < 0.05). Furthermore, gain-of-function and loss-of-function analysis showed that UCA1 knockdown inhibited HCC cells proliferation and invasion in vitro and xenograft tumour growth in vivo. Moreover, UCA1 overexpression promoted cell epithelial-mesenchymal transition (EMT) in HCC via effectively sponging to miR-203 and thereby activating the expression of transcription factor Snail2. Conclusions: Our results identified that UCA1/miR-203/Snail2 pathway might involve in HCC progression. Inhibition of UCA1 acted as a promising therapeutic target for HCC patients. [ABSTRACT FROM AUTHOR]

As a regulator of coagulation, abnormal Protein Z (PZ) expression may lead to the formation of blood clots in humans. While previous studies have shown that PZ protein is altered in several types of cancer, however, additional observations are needed to understand the complex biology involved. Herein, we investigated local alterations in PZ expression in lung adenocarcinomas by measuring gene and protein expression in both cancerous and normal lung tissues. Twenty-two (22) specimens of lung adenocarcinoma and 22 specimens of normal lung tissues from human patients were compared for the expression of PZ. In addition, A549 adenocarcinoma cells were compared to a normal epithelial cell line, 16-HBE, for in vitro PZ expression. In tissues and cells, PZ protein and gene expression were determined using western blot, immunohistochemistry and PCR. Lung adenocarcinoma tissues showed elevated expression of both PZ mRNA and protein compared with healthy tissue. Only protein expression was increased in cultured cell lines, which holds implications for the dominant source of PZ in tissues, as well as protein modifications necessary for PZ function. Protein Z appears to be associated with the presence of lung adenocarcinoma and may be a viable prognostic biomarker for lung cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study is to evaluate the effect of fluorescence in situ hybridization (FISH) detection for p16ink4a expression as an alternative triage for high risk HPV positive women in cervical cancer screening. Methods: Totally 191 cervical cell specimens from women with HPV positive were collected. The p16ink4a expression by FISH and liquid-based thin-layer cytology was performed and followed by colposcopy with or without biopsied histologic examination for all participants. The relationship between p16ink4a expression and histologic diagnosis, as well as cytology was analyzed. Results: The positive rate of p16ink4a was 5.35% in normal or inflammation cases, 56.67% in CIN 1, 83.78% in CIN 2–3, 100.00% in carcinoma, respectively, with a significance between

Background: As an essential member of the Polycomb group (PcG) proteins, chromobox homolog 7 (CBX7) is found deregulated in some human cancers, and is thought to be a contributing factor in carcinogenesis. However, the expression and role of CBX7 in hepatocellular carcinoma (HCC) is still not well characterized. Materials and Methods: The levels of the CBX7 protein were quantified in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry; comparisons were made using McNemar's chi-square test. The Kaplan–Meier estimate was used for survival analysis. Results: We found that the expression of CBX7 in HCC tissues was significantly lower than that of adjacent nontumor tissues. In addition, decreased CBX7 expression levels were correlated with liver cirrhosis in HCC patients. Furthermore, the survival times of HCC patients who were CBX7-expression-negative were shorter than HCC patients who were CBX7-expression-positive. Conclusion: Our results show that downregulation of CBX7 is related to HCC progression and a poor prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

T98G cells have been shown to support long-term human cytomegalovirus (HCMV) genome maintenance without infectious virus release. However, it remains unclear whether these viral genomes could be reactivated. To address this question, a recombinant HCMV (rHCMV) containing a GFP gene was used to infect T98G cells, and the infected cells absent of infectious virus production were designated T98G-LrV. Upon dibutyryl cAMP plus IBMX (cAMP/IBMX) treatment, a serial of phenomena were observed, including GFP signal increase, viral genome replication, lytic genes expression and infectious viruses release, indicating the reactivation of HCMV in T98G-LrV cells from a latent status. Mechanistically, HCMV reactivation in the T98G-LrV cells induced by cAMP/IBMX was associated with the PKA-CREB signaling pathway. These results demonstrate that HCMV was latent in T98G-LrV cells and could be reactivated. The T98G-LrV cells represent an effective model for investigating the mechanisms of HCMV reactivation from latency in the context of neural cells. [ABSTRACT FROM AUTHOR]