Bao Sun

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma

Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

Up-Regulation of Long Non-Coding RNA AB073614 Predicts a Poor Prognosis in Patients with Glioma

Dysregulated long noncoding RNAs (lncRNAs) have been found in human diseases, especially in cancer. Emerging evidence indicates that dysregulated lncRNAs are implicated in tumorigenesis and cancer progression. LncRNA AB073614 characterized as a new candidate lncRNA promotes the development of ovarian cancer. However, the role of lncRNA AB073614 in human gliomas remains unknown. The expression of AB073614 was detected in 65 glioma tissues and 13 normal brain tissues by qRT-PCR, showing that lncRNA AB073614 expression was significantly up-regulated in cancerous tissues compared with normal brain tissues (p < 0.001), and it was positively correlated with tumor grade (I–II grades vs. III–IV grades, p = 0.013) in glioma patients. Kaplan-Meier analysis demonstrated that increased AB073614 expression contributed to poor overall survival (HR (hazard ratio) = 1.952, 95%CI: 1.202–3.940, p = 0.0129). Further, univariate Cox regression analysis indicated that lncRNA AB073614 overexpression was an unfavorable prognostic factor in gliomas (HR = 1.997, 95%CI: 1.135–3.514, p = 0.016), regardless of the tumor grade (I–II grades vs. III–IV grades, HR = 1.902, 95%CI: 1.066–3.391, p = 0.029). Finally, after adjustment with age, sex, tumor grade and tumor location, multivariate Cox regression analysis suggested that both highly expressed lncRNA AB073614 (HR = 2.606, 95%CI: 1.408–4.824, p = 0.002) and high tumor grade (III–IV grades, HR = 2.720, 95%CI: 1.401–5.282, p = 0.003) could be considered independent poor prognostic indicators for glioma patients. In conclusion, our study suggested that increased lncRNA AB073614 expression may be identified as a poor prognostic biomarker in gliomas.

DNA methylation perspectives in the pathogenesis of autoimmune diseases

DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases.

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial–mesenchymal transition in vitro and predicts poor prognosis in glioma

Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial–mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin β1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

DNA methylation alterations in the pathogenesis of lupus.

Although lupus is, by definition, associated with genetic and immunological factors, its molecular mechanisms remain unclear. The up‐to‐date research findings point out that various genetic and epigenetic factors, especially gene‐specific and site‐specific methylation, are believed to contribute to the initiation and development of systemic lupus erythematosus (SLE). This review presents and summarizes the association between abnormal DNA methylation of immune‐related cells and lupus‐like diseases, as well as the possible mechanisms of immune disorder caused by DNA methylation, aiming at a better understanding of the roles of aberrant DNA methylation in the initiation and development of certain forms of lupus and providing a new insight into promising therapeutic regimens in lupus‐like diseases.

Clinical Significance of Long Non-Coding RNA CASC8 rs10505477 Polymorphism in Lung Cancer Susceptibility, Platinum-Based Chemotherapy Response, and Toxicity

Long non-coding RNA (lncRNA) CASC8 rs10505477 polymorphism has been identified to be related to risk of many kinds of cancers, such as colorectal cancer, gastric cancer, and invasive ovarian cancer, and it may be involved in the prognosis of gastric cancer patients who have received platinum-based chemotherapy after surgical treatment. So far, there is no study investigating the clinical significance of lncRNA CASC8 rs10505477 in lung cancer susceptibility and treatment. In this study, we genotyped 498 lung cancer patients and 213 healthy control subjects to explore the correlation between the rs10505477 polymorphism and lung cancer risk in a Chinese population. Among the 498 patients, 467 were selected for the chemotherapy response and toxicity study. We found that the single nucleotide polymorphisms (SNP) rs10505477 was greatly related to lung cancer risk in male and adenocarcinoma subgroups in recessive model (adjusted OR = 0.51, 95%CI = 0.29–0.90, p = 0.02; adjusted OR = 0.52, 95%CI = 0.30–0.89, p = 0.02, respectively). It was also closely correlated with platinum-based chemotherapy response in dominant model (adjusted OR = 1.58, 95%CI = 1.05–2.39, p = 0.03). Additionally, we observed that CASC8 rs10505477 polymorphism was significantly relevant to severe hematologic toxicity in non-small-cell lung cancer (NSCLC) subgroup in dominant model (adjusted OR = 0.59, 95%CI = 0.35–0.98, p = 0.04) and in additive model (adjusted OR = 0.62, 95%CI = 0.43–0.90, p = 0.01). Furthermore, it was found that rs10505477 polymorphism was greatly associated with gastrointestinal toxicity in SCLC and cisplatin subgroups in dominant model (adjusted OR = 7.82, 95%CI = 1.36–45.07, p = 0.02; adjusted OR = 1.94, 95%CI = 1.07–3.53, p = 0.03, respectively). Thus, lncRNA CASC8 rs10505477 could serve as a possible risk marker for diagnosing lung cancer, and could be used to forecast the response and toxicity of platinum-based treatment in lung cancer patients.

The dysregulation of tRNAs and tRNA derivatives in cancer

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese

Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune diseases. However, the potential role of aberrant DNA methylation in allopurinol-SCARs is largely unknown. Objective: To address the knowledge gap between allopurinol-SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from allopurinol-SCARs and allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with allopurinol-SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched allopurinol-tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (cytosine-guanine dinucleotide) sites in an independent cohort of 40 allopurinol-SCARs and 48 allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between allopurinol-SCARs and allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 × 10−13), and SCARs and controls (P = 5.93 × 10−15). Conclusions: Our data identified differentially methylated genes between allopurinol-SCARs and allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with allopurinol-SCARs (OR = 30.22, 95%CI = 4.73–192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of allopurinol-SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease-associated changes of epigenome precede disease onset, or result from the disease progression, needs further investigation. Comparing the methylation status before patients develop allopurinol-SCARs and after may help examine methylation levels from disease onset to disease progression.

Cause-specific risk of major adverse cardiovascular outcomes and hypoglycemic in patients with type 2 diabetes: a multicenter prospective cohort study

PurposeGlycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) was identified to account for the risk of cardiovascular diseases in type 2 diabetic patients, but no study evaluated the risk based on both HbA1c and FPG levels. We described the risk of major adverse cardiovascular events (MACE) and hypoglycemic in type 2 diabetic patients according to both HbA1c and FPG levels.MethodsWith the usage of databases of Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 1815 patients from 61 centers in China was identified and grouped according to the criterion value of HbA1c and FPG: Good glycemic control (HbA1c < 6.5%, FPG < 6.1 mmol/L); Insufficient glycemic control (HbA1c < 6.5%, FPG ≥ 6.1 mmol/L or HbA1c ≥ 6.5%, FPG < 6.1 mmol/L); Poor glycemic control (HbA1c ≥ 6.5%, FPG ≥ 6.1 mmol/L). Time-varying multivariable Cox proportional hazards models were employed.ResultsAverage age was 64.8 ± 5.8 years, with a median of 4.8 years of follow-up. Overall, the incidence rates of MACE were 20.6 per 1000-person-years in Good glycemic control compared with 45.9 per 1000-person-years in Insufficient glycemic control (adjusted hazard ratio (aHR): 1.99; 95% CI 1.11–3.56; p = 0.02) and 54.7 per 1000-person-years in Poor glycemic control (aHR: 2.46; 95% CI 1.38–4.40; p = 0.002), respectively. The risk of hypoglycemic was highest in Insufficient glycemic control; 67.3 per 1000-person-years compared with 46.3 per 1000-person-years in Good glycemic control (aHR: 1.62; 95% CI 1.03–2.56; p = 0.04). Apart from this, we also observed that both MACE (aHR:1.41; 95% CI 1.13–1.77; p = 0.003) and hypoglycemic episodes (aHR: 1.82; 95% CI 1.48–2.24; p < 0.001) were sufficiently more frequent in the insulin-exposed group than the non-exposed group. In a post-hoc analysis, the risk of MACE (aHR:1.43; 95% CI 1.09–1.86; p = 0.01) and hypoglycemic (aHR: 1.99; 95% CI 1.46–2.69; p < 0.001) were more pronounced in Insufficient glycemic control with insulin exposure.ConclusionsWe observed a significant association of cause-specific risk of MACE and hypoglycemic with Insufficient glycemic control, particularly with insulin exposure.

The minor alleles HCP 5 rs3099844 A and PSORS 1C1 rs3131003 G are associated with allopurinol‐induced severe cutaneous adverse reactions in Han Chinese: a multicentre retrospective case–control clinical study

DEAR EDITOR, Allopurinol-induced severe cutaneous adverse reactions (SCARs), which include drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens– Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are life-threatening conditions and occur almost exclusively in HLA-B*5801 positive individuals in Han Chinese. Recent studies have shed light on epigenetic modifications across autoimmune diseases and have described associations between drug hypersensitivities and single-nucleotide polymorphisms (SNPs). We therefore undertook a study to investigate whether other genetic factors, such as epigenetic variation and SNPs, are associated with allopurinol-induced SCARs in Han Chinese. The study was a multicentre retrospective case–control study. It was registered in the Chinese Clinical Trial Registry (ChiCTR-RCC-12002927) and was approved by the Independent Ethics Committee of the Institute of Clinical Pharmacology, Central South University (CTXY-110011-2). We enrolled 97 participants with allopurinol-induced SCARs (the SCARs group) and 97 who were allopurinol tolerant (the control group) of Han descent. The diagnosis was made by dermatologists according to the RegiSCAR or Roujeau criteria. Details of inclusion and exclusion criteria have been described previously. Genome-scale DNA methylation profiling on an Illumina Infinium HumanMethylation450 platform (Illumina, San Diego, CA, U.S.A.) involving 484 660 CpG dinucleotides in 15 patients with allopurinol-induced SCARs and 20 ageand sex-matched controls was performed. Weighted gene co-expression network analysis (WGCNA) and differentiated methylated positions (DMPs) analysis were used to pick up candidate genes for SNP analysis. TP53AIP1 was among one of the top 10 hub genes in the yellow module after the WGCNA analysis. The genes DUSP22, PDCD1LG2, NOTCH4 and ATP6V1C1 were selected from the top 20 DMPs. TSHZ2 was selected after reviewing its DMP expression data and WGCNA analysis. Other SNPs were selected after reviewing the drug-hypersensitivity reports. Finally, six SNPs selected from methylation profiling and 13 reported drug-hypersensitivity-related SNPs were examined in the SCARs (n = 97, 41% DRESS syndrome, 41% SJS, 6% SJS/ TEN overlap, 11% TEN) and control (n = 97) groups. Genomic DNAs extracted from participants’ peripheral blood were sent for SNP genotyping. SNPs were typed using iPLEX Chemistry (Agena Bioscience, San Diego, CA, U.S.A.) on a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS, Sequenom, San Diego, CA, U.S.A.). A v-test was used for comparison of categorical variables. Linkage disequilibrium (LD) and haplotype analysis were conducted using Haploview (Broad Institute, Cambridge, MA, U.S.A.). Logistic regression analysis with covariates was applied to correct for multiple factors. The corrected P (Pc) values were adjusted by multiplying by 19 using a post-hoc Bonferroni correction. After analysis, five out of 19 SNPs were found to be associated with SCARs with significance (P < 0.05, details available from the authors on request). After logistic regression analysis with age and sex as covariates, four SNPs HCP5 rs3099844 (C>A), PSORS1C1 rs3131003 (A>G), TSHZ2 rs2010156 (C>T) and NOTCH4 rs367398 (G>A) were still found significantly associated with SCARs. Among five differentiated polymorphisms (Table 1), the risk of developing SCARs was 32.41folder higher in HCP5 rs3099844 A carriers than in CC carriers (Pc < 0.0019). The risk of developing SCARs was 17.75-fold higher in PSORS1C1 rs3131003 G carriers than AA carriers (Pc < 0.0019). In the recessive model of PSORS1C1 rs3131003, the GG homozygous carriers were at 3.33-fold higher risk of developing SCARs than individuals with GA + AA (Pc = 0.019). The TSHZ2 rs2010156 T carriers had a lower risk of developing SCARs [odds ratio (OR) 0.27] than CC homozygotes (this finding was no longer significant after correction). Individuals with NOTCH4 rs367398 A variants were at lower risk of developing SCARs in both dominant and recessive models. Results for both dominant and recessive model for PSORS1C1 rs3815087 were not significant. The study confirmed that the minor alleles HCP5 rs3099844 A and PSORS1C1 rs3131003 G are strongly associated with allopurinol-induced SCARs. Our data do not support an association between the other tested SNPs and allopurinol-induced SCARs in Han Chinese. In haplotype analysis, the frequency of the GGA (rs3131003/rs3815087/rs3099844) haplotype at chromosome 6 was significantly higher in the SCARs group than the control group (44% vs. 8%, OR 9.26, Pc = 1.1305 9 10). This shows that the patients carrying the GGA haplotype are 9.26-fold more susceptible to developing allopurinol-induced SCARs. This finding is in agreement with a former result that the chromosome 6 haplotype CACGAC formed by six SNPs