Epigenetic Mechanisms and Events in Gastric Cancer-Emerging Novel Biomarkers

Gastric cancer is one of the most common malignancy worldwide. The various genetic and epigenetic events have been found to be associated with its carcinogenesis. The epigenetic is a heritable and transient/reversible change in the gene expression that is not accompanied by modification in the DNA sequence. This event is characterized by the alteration in the promoter CpG island of the gene or histone modification. These events are associated with silencing of critical tumor suppressor gene and activation of oncogenes leading to carcinogenesis. The DNA methylation is a chemical change in the DNA sequence that most commonly occurs at cytosine moiety of CpG dinucleotide and histone, primarily on N- terminal tail that ultimately effect the interaction of DNA with chromatin modifying protein.Hypermethylation of tumor suppressor genes and global hypomethylation of oncogenes are widely studied epigenetic modifications. There are large number of publish reports regarding epigenetic events involving gastric cancer. These changes are potentially useful in identifying markers for early diagnosis and management of this lethal malignancy. Also, role of specific miRNAs and long non coding RNAs in regulation of gene expression is gaining interest and is a matter of further investigation. In this review, we aimed to summarize major epigenetic events (DNA methylation) in gastric cancer along with alteration in miRNAs and long non coding RNAs which plays an important role in pathology of this poorly understood malignancy.     

miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer.     

微RNA在肺癌中的作用

微RNA分子(miRNA,miR)是一类长约18～25个核苷酸的非编码小分子RNA,起内源性RNA干扰作用.微RNA从转录后水平调控上百种靶基因表达,因而能控制广泛的生物学功能,如细胞增殖、分化、凋亡.通过与靶mRNA的3'端非翻译区(3'UTR)结合,抑制mRNA翻译或增加其稳定性而发挥作用.大部分微RNA定位于基因组肿瘤相关的脆性位点、杂合子缺失点、扩增区及常见断裂区,提示与肿瘤的发生关系密切.各种肿瘤中miR-NAs表达上调或下调,可能起致癌或抑癌基因作用.一直以为肿瘤的发生是由一系列致癌基因和抑癌基因突变逐步形成的.随着非编码RNA的发现,此传统观念被改变.研究表明非编码RNA中的成员microRNA对肿瘤形成起重要的调控作用.近来,越来越多的研究探讨不同的miRNA与各种肿瘤的发生发展乃至治疗预后的关系.肺癌位居世界癌症死因之首,其病因学主要是遗传和吸烟引起的后天损伤.对上百种基因的RNA和蛋白质系统分析有助于明确肺癌发生的分子网络.miRNA与肺癌的发生、发展关系密切,可能在肺癌的诊断、治疗及预后监测中发挥重要作用.目前文献报道的与肺癌关系比较密切的miRNA有miRNA-126、miRNA-221、miRNA-222、has-mir-221、miR-17-92簇、miRNA-128b、has-mir-137、has-mir-182、has-mir-372及miRNA-let7家族成员等.本文就这些miRNAs在肺癌的遗传易感性、诊断、侵袭转移、治疗及预后等方面进行综述.     

MicroRNA in colorectal cancer: from benchtop to bedside

Colon carcinogenesis represents a stepwise progression from benign polyps to invasive adenocarcinomas and distant metastasis. It is believed that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA (miRNA) research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of miRNAs exhibit differential expression in colon cancer tissues. These miRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within miRNA-binding sites are associated with the risk for colon cancer, whereas miRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of miRNA or polymorphisms in miRNA-related genes have also been shown to correlate with patient survival or treatment outcome. With further insights into miRNA dysregulation in colon cancer and the advancement of RNA delivery technology, it is anticipated that novel miRNA-based therapeutics will emerge.     

微RNA与肿瘤

微RNA(miRNA)是一类非编码单链小分子RNA,在转录后水平调节基因的表达。最新研究发现miRNA与人类肿瘤密切相关,甚至有人认为某些miRNA就是肿瘤基因或肿瘤相关基因。现综述miRNA与人类肿瘤发生、发展、诊断、治疗和预后的研究进展。     

微小ＲＮＡ与乳腺癌相关性的研究进展

微小ＲＮＡ（ｍｉＲＮＡ）通过与靶基因互补位点结合在转录后水平负性调控靶基因的表达。ｍｉＲＮＡ发挥类似于癌基因或抑癌基因的作用,参与肿瘤细胞的增殖、分化和细胞凋亡过程。乳腺癌是目前女性最常见的恶性肿瘤,ｍｉＲＮＡ在乳腺癌中的研究也是当前一大热点,ｍｉＲＮＡ在乳腺癌的诊断和治疗方面具有广阔的应用前景。本文就ｍｉＲＮＡ与乳腺癌相关的研究热点与难点作一综述。     

RNA异常与肿瘤调控研究进展

肿瘤的发生是一个多因素、多步骤的过程,其根本原因是细胞稳态的失衡.近年研究发现,在肿瘤的发生、发展中除了蛋白质功能紊乱、DNA突变之外,还存在着大量RNA的异常,包括异常的microRNA(miRNA)、长链非编码RNA(long non-coding RNA,IncRNA)、循环RNA等;此外,肿瘤细胞中还存在RNA转录、加工及调控功能的异常,如RNA选择性剪接、RNA编辑、竞争性内源RNA调控等.这些非编码RNA可以在转录后水平及表观遗传学水平调控癌基因和抑癌基因的功能,影响肿瘤的发生和发展,是肿瘤诊断、治疗及预后判断的潜在靶标.竞争性内源RNA使得lncRNA与mRNA通过miRNA相互调控,以“miRNA结合位点”为媒介,形成RNA调控网络.RNA选择性剪接使得癌基因或抑癌基因产生功能异常的转录本,进而影响其生物学功能.肿瘤中究竟哪些机制导致这些RNA表达及功能的异常,RNA表达及功能的异常又如何影响肿瘤的发生和发展,有哪些表达或功能异常的RNA可以作为肿瘤诊断及预后判断的标志物,又有哪些RNA可以作为肿瘤靶向治疗的靶标?等等问题亟待深入探讨,RNA异常与肿瘤调控已成为肿瘤研究的前沿热点领域.     

SERPINA3在子宫内膜癌中表达上调的临床意义及功能研究

背景与目的：SERPINA3是丝氨酸蛋白酶抑制剂超家族的一员,已有研究证实其在多种肿瘤细胞中异常表达。然而,它在子宫内膜癌中生物学功能及临床意义尚不清楚。本研究旨在探讨SERPINA3在子宫内膜癌细胞中的功能和子宫内膜癌预后评估中的价值。方法：①收集20对子宫内膜癌组织和正常子宫内膜组织,用实时定量PCR(quantitative real-time PCR)检测SERPINA3 mRNA在内膜组织中表达情况;②使用免疫组化方法,检测组织芯片(子宫内膜癌81例和正常对照37例)的SERPINA3表达情况,依据染色结果,用SPSS软件分析SERPINA3与子宫内膜癌临床病理特征之间的关系;③检测5株子宫内膜癌细胞系中SERPINA3的表达情况,选取表达量最高的HEC-1A细胞,利用小片段干扰RNA(small interfering RNA)干扰SERPINA3基因在HEC-1A细胞中的表达;④蛋白质印迹法(Western blot)和qPCR检测干扰后HEC-1A中SERPINA3基因在mRNA和蛋白水平表达情况,细胞迁移实验检测细胞运动能力的变化。结果：①SERPINA3 mRNA在内膜癌中表达明显高于对照内膜组织(n=20,P<0.05);②免疫组化结果显示SERPINA3在子宫内膜癌中的表达水平高于正常子宫内膜组织(P<0.001)。SERPINA3的表达水平与子宫内膜癌的临床分期、肿瘤细胞级别、脉管浸润、淋巴结转移之间比较差异有统计学意义(P<0.05);③干扰SERPINA3组细胞迁移能力显著减弱。结论：SERPINA3基因在子宫内膜癌中表达显著上调,可能与子宫内膜癌的侵袭和转移等相关。SERPINA3有望成为评估子宫内膜癌预后的生物学标志物,并可能作为子宫内膜癌生物靶向治疗的靶标之一。     

胰腺癌相关miRNA的研究进展

胰腺癌是一种死亡率高、侵袭性强的恶性肿瘤,临床诊断和治疗目前没有较大进展。晚期确诊、早期侵袭转移和化放疗抵抗是预后差的关键因素。研究发现微小RNA的异常表达与胰腺癌有关。微小RNA是一类小非编码RNA分子,常通过降解靶基因mRNA或抑制其翻译,调控靶基因表达,从而参与肿瘤的发生发展。最新研究发现微小RNA在胰腺癌组织、血循环和其他体液中存在差异性表达, 有助于胰腺癌诊断,而促癌或抑癌性微小RNA在肿瘤增殖、凋亡、进展中起重要作用,有望成为新的治疗靶点。因此,进一步深入研究胰腺癌诊断、治疗和预后相关的微小RNA,有利于从不同角度理解胰腺癌发病机制,为抗癌提供新思路。     

MicroRNAs in biological processes and carcinogenesis

MicroRNAs (miRNAs) encoding small non-coding RNAs have been recognized as a very large gene family present in most organisms. The precise biological effects of miRNAs are yet to be elucidated in detail, partly because each miRNA is believed to negatively regulate the expression of hundreds of target genes. Nevertheless, recent findings indicate that carcinogenic processes are associated with alterations in the expression of several miRNAs, suggesting that some function as oncogenes or tumor suppressor genes. The present review focuses on recent findings in this exciting new area of research, with special emphasis on the involvement of miRNAs in cancer development and progression. Further studies are clearly warranted to elucidate the molecular and biological roles of miRNAs, which may ultimately provide both a better understanding of disease development, as well as a foundation for novel strategies for cancer diagnosis and therapy.     

MicroRNA expression profile of MCF-7 human breast cancer cells and the effect of green tea polyphenon-60

This study reports for the first time the microRNA expression profile of human breast cancer MCF-7 cells and the effect of green tea. Although hundreds of miRNAs have been identified in humans, only a small proportion (25.6%) of miRNAs are expressed in MCF-7 cells. Low concentration treatment with Polyphenon-60 significantly alters the miRNA expression profile in MCF-7 cells. Twenty three miRNAs have been identified with differential expression after a 48 h treatment with 10 μg/ml Polyphenon-60 (green tea extract). These miRNAs include miR-21 and miR-27 that were found to be down-regulated following treatment with green tea. These two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. This data supports the hypothesis that Polyphenon-60-induced modification of the breast cancer miRNA expression profile contributes to the efficacy of green tea treatment. The resulting decrease in carcinogenesis is further supported by the altered miRNA regulation of potential oncogenes and tumor-suppressor genes.     

MicroRNA and endometrial cancer: Roles of small RNAs in human tumors and clinical applications (Review)

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 base pairs that regulate the expression of genes by targeting messenger RNA with complementarity with the miRNA base sequence. Regulation of gene expression by miRNAs is crucial in cellular development and differentiation, and recent studies suggest a relationship between human diseases and the breakdown of gene silencing mechanisms induced by miRNA abnormalities. In particular, abnormal miRNA expression has been detected in various types of cancer and the target genes have been identified. These results indicate that miRNAs act in a manner equivalent to oncogenes or tumor suppressors. miRNAs may also serve as diagnostic biomarkers and therapeutic targets. In this review, we introduce the latest findings on miRNAs in human endometrial cancer, a common malignancy, and discuss the potential of miRNAs as biomarkers and targets for molecular therapy.     

The Role of MicroRNA in Chemical Carcinogenesis

MicroRNAs (miRNAs) are important regulators of gene expression. Alteration of miRNA expression caused by exposure of different carcinogens has been well reported. This review aims to present the miRNAs dysregulated by exposure of different types of carcinogens in different biological systems and to discuss their potential roles in different stages of chemical carcinogenesis, following an introduction of miRNA biogenesis, regulatory mechanisms, and target identification. Available information shows that expression of a large number of miRNAs is readily changed by exposure of carcinogens in tissue- and chemical-specific manners. Carcinogenic agents generally induce many more changes in miRNA expression than non-carcinogenic chemicals. There are many more changes in cancer-target tissues than in the non-target tissues after acute or chronic exposure to carcinogens. Many of the miRNAs deregulated by carcinogens are involved in regulation of genes that are important for every stage of chemical carcinogenesis, including xenobiotic metabolism, carcinogen-induced hypomethylation, DNA repair, apoptosis, cell proliferation, tumor suppression, cell transformation, oncogenesis, tumor angiogenesis, tumor progress, mangliant transformation, and other functions. Many miRNAs function as putative oncogenes and tumor suppressor genes. The carcinogenic functions of carcinogens may be dependent on the balance between tumor-suppressor miRNAs and oncogenic miRNAs. Thus, the miRNA profiles and miRNAs specific to carcinogen exposure have the potential to be used as biomarkers for identifying genotoxicity and carcinogenicity of chemicals and indicating exposure of carcinogens.     

微小RNA-30a:肿瘤治疗的潜在靶点

微小RNA(miRNA)是长约20~25个核苷酸的内源性非编码RNA,主要通过抑制mRNA翻译和诱导mRNA降解而调节靶基因的表达,人类大约30%的基因受miRNAs调节。研究发现,大量miRNAs在肿瘤中表达失调,常常引起多种重要过程的紊乱,包括细胞增殖、侵袭与转移、凋亡以及耐药等。在肿瘤的发生过程中,不同的miRNA可能起着类似抑癌基因或者癌基因的作用,参与调节肿瘤细胞发生、发展等过程。miR-30a是miRNA的成员之一,通过调节靶基因的表达,参与调控肿瘤细胞增殖、转移和凋亡等过程。不同肿瘤血清中miR-30a的表达水平对肿瘤的早期诊断、治疗以及预后判断有着重要作用。此外,miR-30a的表达失调还与抗肿瘤药物耐药性的产生密切相关,推测其有望成为肿瘤治疗的一个潜在新靶标。本文就近年来miR-30a在肿瘤中作用的最新研究进展作一综述。     

miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer

Growing evidence suggests that microRNAs (miRNAs) are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the mechanism of carcinogenesis. However, the genetic or epigenetic regulations of these miRNAs have not yet been fully elucidated in bladder cancer (BC). Chromosomal alterations of cancer cells give us important information for the identification of tumor suppressor genes. Our miRNA array-comparative genomic hybridization (CGH) analysis showed several miRNAs to be candidate tumor suppressors of BC. Our array-CGH analysis revealed that chromosome 4 was lost in all BC cell lines. We selected 19 miRNAs located on chromosome 4 and evaluated their expression levels in cancer cell lines as well as clinical samples. Gain-of-function analysis revealed that miR-218 inhibited BC cell proliferation, migration and invasion. Furthermore, flow cytometry analysis showed that it induced BC cell apoptosis. Genome-wide gene expression analysis showed that it targeted multiple oncogenes in BC. Our study is the first to demonstrate that miR-218 located on chrosomosme 4p15.31 is a tumor suppressive miRNA in BC. The identification of tumor suppressive miRNAs and their target genes on the basis of array-CGH analysis could provide new insights into the mechanisms of BC carcinogenesis.     

p16基因与肺癌关系研究进展

肿瘤抑癌基因p16对于肺癌的早期诊断非常重要,启动子的异常甲基化、第二号外显子的纯合子缺失、基因点突变、蛋白及mRNA的缺失表达都与肺癌的发生关系密切,且与肺癌的基因治疗、药物靶向治疗有关.     

miRNA expression profiles associated with diagnosis and prognosis in lung cancer

miRNAs, which are small single-stranded RNA molecules composed of 18–23 nts, act as oncogenes or tumor suppressor genes playing important roles in the processes of tumor formation, infiltration and metastasis. Lung cancer currently has the highest morbidity and mortality among all malignant tumors; yet, lack of early specific diagnostic markers and effective treatments hinders its proper management. In lung cancer, about 40–45 abnormal expression patterns of miRNAs have been discovered and are involved in lung cancer development. miRNAs have functions together with oncogenes and tumor suppressor genes of lung cancer. miRNAs-based tests can be used for early clinical diagnosis and prediction of clinical outcomes of lung cancer. Studying the role of miRNAs in lung cancer development and its relationship with diagnostic and prognostic parameters might help to improve the sensitivity of diagnosis and the efficacy of lung cancer treatment.