ELOVL2: a novel tumor suppressor attenuating tamoxifen resistance in breast cancer

Epigenetic events have successfully explained the cause of various cancer types, but little is known about tamoxifen resistance (TamR) that induces cancer recurrence. In this study, via genome-wide methylation analysis in MCF-7/TamR cells we show that elongation of very-long chain fatty acid protein 2 (ELOVL2) was hypermethylated and downregulated in the samples from TamR breast cancer patients (n = 28) compared with those from Tam-sensitive (TamS) patients (n = 33) (P < 0.001). Strikingly, in addition to having tumor suppressor activity, ELOVL2 was shown to recover Tam sensitivity up to 70% in the MCF-7/TamR cells and in a xenograft mouse model. A group of genes in the AKT and ERa signaling pathways, e.g., THEM4, which play crucial roles in drug resistance, were found to be regulated by ELOVL2. This study implies that the deregulation of a gene in fatty acid metabolism can lead to drug resistance, giving insight into the development of a new therapeutic strategy for drug-resistant breast cancer.     

PTPL1在血液系统恶性肿瘤中的表达及意义

PTPL1是一种大小为270 kD的蛋白质,在细胞存活、增殖、分化和运动中扮演重要角色。目前有证据表明,PTPL1与肿瘤具有相关性,既对肿瘤有抑制作用,也有促进作用,究竟哪种作用处于主导地位取决于相应的底物和所在的细胞环境。PTPL1在淋巴瘤中普遍处于低表达,而在髓系白血病中处于高表达。PTPL1已被认为是淋巴瘤的抑癌基因,PTPL1启动子的甲基化导致基因表达减少或缺失,导致其在淋巴瘤中的抑癌作用消失。本研究就PTPL1的结构域及其相互作用蛋白、PTPL1与血液系统肿瘤的关系进行综述。     

The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4⁺ T cells. The biological activities of CD4⁺ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4⁺ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4⁺ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4⁺ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.     

Epigenetics of epithelial‐to‐mesenchymal transition in pancreatic carcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases with late diagnosis, rapid progression, high invasiveness, and early metastasis. Epithelial‐to‐mesenchymal transition (EMT) is a crucial step in metastasis that enables polarized immotile epithelial cells to gain fibroblast‐like mesenchymal abilities such as enhanced motility. The dynamic process of EMT in PDAC with its powerful influence on disease progression and especially metastasis is of vigorous interest in biomedical research to elucidate its signaling pathways and regulation mechanisms. It is evident that epigenetics such as histone and DNA modification or noncoding RNAs such as microRNAs and long noncoding RNAs are of high importance in initiation and progress of EMT in PDAC. This review analyzes the latest research dealing with EMT and its epigenetic regulation in PDAC and summarizes its potentials in diagnostic, prognostic, and therapeutic management.     

Promoter hypermethylation in plasma‐derived cell‐free DNA as a prognostic marker for pancreatic adenocarcinoma staging

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell‐free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work‐up and treatment. Patients were staged according to the TNM classification. Methylation‐specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety‐five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51–8.66), 7.00 (95% CI; 5.93–8.07) and 6.77 (95% CI; 5.08–8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88–11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I‐III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I‐II from stage III‐IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell‐free DNA promoter hypermethylation has the potential to be blood‐based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.     

Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n > 6,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer

The ongoing Triage and Risk Assessment of Cervical Precancer by Epigenetic Biomarker (TRACE) prospective, multicenter study aimed to provide a clinical evaluation of the CONFIDENCE? assay, which comprises a human papillomavirus (HPV) DNA and a human epigenetic biomarker test. Between 2013 and 2015 over 6,000 women aged 18 or older were recruited in Hungary. Liquid‐based cytology (LBC), high‐risk HPV (hrHPV) DNA detection and single target host gene methylation test of the promoter sequence of the POU4F3 gene by quantitative methylation‐specific polymerase chain reaction (PCR) were performed from the same liquid‐based cytology sample. The current analysis is focused on the baseline cross‐sectional clinical results of 5,384 LBC samples collected from subjects aged 25 years or older. The performance of the CONFIDENCE HPV? test was found to be comparable to the cobas® HPV test with good agreement. When applying the CONFIDENCE Marker? test alone in hrHPV positives, it showed significantly higher sensitivity with matching specificity compared to LBC‐based triage. For CIN3+ histological endpoint in the age group of 25–65 and 30–65, the methylation test of POU4F3 achieved relative sensitivities of 1.74 (95% CI: 1.25–2.33) and 1.64 (95% CI: 1.08–2.27), respectively, after verification bias adjustment. On the basis of our findings, POU4F3 methylation as a triage test of hrHPV positives appears to be a noteworthy method. We can reasonably assume that its quantitative nature offers the potential for a more objective and discriminative risk assessment tool in the prevention and diagnostics of high‐grade cervical intraepithelial neoplasia (CIN) lesions and cervical cancer.     

颞叶癫痫microRNA基因甲基化模式分析及机制探究

目的重注释甲基化数据并构建microRNA(miRNA)基因甲基化谱,探究差异甲基化miRNA在颞叶癫痫(TLE)发生发展及耐药机制中的作用。方法收集TLE患者以及健康对照外周血,提取DNA进行全基因组DNA甲基化检测。将甲基化数据重注释至miRNA基因,统计分析筛选病例组与对照组以及临床亚组之间的差异甲基化miRNA,运用生物信息学方法对差异甲基化miRNA功能分析。结果 TLE和对照组间有82个miRNA基因甲基化存在差异(FDR5%),其中甲基化升高的70个。临床亚组间也存在差异甲基化miRNA基因(P0.01)。差异甲基化miRNA基因参与MAPK信号通路、神经营养信号通路等多条生物学通路。结论 TLE患者外周血miRNA基因组甲基化存在异常,以甲基化程度升高为主。差异甲基化miRNA基因参与多条生物学通路,可能在TLE发病及耐药机制中起到重要作用。     

卵巢癌基因1在人类恶性肿瘤中的研究进展

卵巢癌基因1(ovarian cancer gene 1,OVCA1)位于人染色体17p13.3,在哺乳动物细胞中高度保守,与酵母菌的DPH2具有同源性.在哺乳动物细胞中,OVCA1参与维持翻译的保真性、调控细胞周期及胚胎发育等多种生物学过程.OVCA1在卵巢癌、乳腺癌和宮颈癌等多种肿瘤中存在高频率的杂合性缺失和突变,作为候选肿瘤抑制基因在肿瘤发生发展中发挥重要作用.本文就OVCA1基因的生物学功能及与不同类型肿瘤关系的研究进展做一综述.     

自噬的表观遗传修饰在肿瘤发生发展中的作用

细胞自噬是一种进化上的保守过程,可降解胞质成分从而促进细胞存活和组织平衡,它的激活与生物学功能受到多种自噬相关基因和信号通路的调节。其中表观遗传修饰广泛参与细胞自噬过程,调节细胞凋亡和自噬,成为癌症的另一种标志,在肿瘤的发生、发展中发挥了重要作用。为了更深入了解自噬的表观遗传修饰与肿瘤发生、发展的关系,本文将近期相关的研究进展做一综述。