脑胶质瘤患者组织和血清MGMT、hMLH1和hMSH2基因启动子甲基化状态检测

目的探讨脑胶质瘤患者组织和血清中MGMT、hMLH1和hMSH2基因启动子CpG岛甲基化发生率及相关性。方法甲基化特异性PCR（MSP）检测39例脑胶质瘤组织样本及32例预处理的脑胶质瘤血清样本中MGMT、hMLH1和hMSH2基因启动子区的甲基化状态。结果脑胶质瘤组织MGMT、hMLH1和hMSH2基因启动子区甲基化发生率分别为46．2％、10．3％和20．5％,肿瘤组织中至少有一种基因甲基化的发生率为64．1％（25／39）;在脑胶质瘤患者外周循环血液中检测到了相关基因甲基化系列,并且与组织中基因甲基化发生率明显相关。结论MGMT、hMLH1和hMSH2基因启动子甲基化是脑胶质瘤发生过程中常见的分子事件,血清中相关基因DNA甲基化检测有可能为脑胶质瘤诊断和个体化化疗提供一种稳定的无创性检测指标。     

DNA甲基化——肿瘤产生的一种表观遗传学机制

在人类基因组中,DNA甲基化是一种表观遗传修饰,它与肿瘤的发生关系密切。抑癌基因和DNA修复基因的高甲基化、重复序列DNA的低甲基化、某些印记基因的印记丢失与多种肿瘤的发生有关。目前研究发现,基因组中甲基化的水平不仅受DNA 甲基化转移酶（DNMT）的影响,还与组蛋白甲基化、叶酸摄入、RNA干扰等多种因素有关。DNA甲基化在基因转录过程中扮有重要角色,并与组蛋白修饰、染色质构型重塑共同参与转录调控。     

乳腺癌中beclin1基因下调机制的研究

目的探讨beclin1在乳腺癌中的可能下调机制。方法用Real-time RT-PCR检测34例乳腺癌中be-clin1 mRNA的表达;Q-PCR分析beclin1是否存在基因的缺失;亚硫酸氢钠测序法检测beclin1基因启动子区域的CpG岛甲基化。结果乳腺癌组织中beclin1的mRNA表达水平与癌旁组织比较显著下调（P=0.005）;Q-PCR发现62%的肿瘤标本中beclin1基因存在缺失;在6例乳腺癌mRNA表达下调的乳腺癌标本中发现启动子区域异常的DNA甲基化。结论beclin1基因的缺失和启动子区域的异常甲基化可能是其在肿瘤细胞中失活的两种机制。     

基因启动子异常甲基化及其作为肿瘤生物标志物的研究进展

基因启动子异常甲基化与肿瘤的发生关系密切,它可导致抑癌基因或其它肿瘤相关基因的表达失活。研究显示基因启动子异常甲基化是肿瘤形成过程中的一个早期、频发事件,广泛存在于几乎所有种类的人类肿瘤中,因此,基因启动子区异常甲基化是一个高灵敏度的肿瘤生物标志物,检测外周血血清或肿瘤累及器官体液中肿瘤相关基因的甲基化状态将为肿瘤的早期诊断、疗效观察及预后判断提供非常有价值的信息。     

hMLH1基因启动子CpG岛甲基化致MSI与肿瘤的关系

通过人类错配修复基因( hMLHl)启动子CpG岛甲基化与微卫星不稳定性(MSI)的分析,探讨癌症发病的机制.错配修复基因hMLH1启动子CpG岛甲基化是hMLH1基因失活的重要机制,而hMLH1的表达失活则可导致MSI的产生,促进癌症的发生.根据一系列研究得出结论,在肿瘤组织中hMLH1基因启动子CpG岛甲基化和微卫星不稳定(MSI)有显著相关性,并在癌症早期发生、发展过程中起重要作用.因此临床检测hMLH1基因启动子CpG岛甲基化及微卫星不稳定可能成为癌症鉴别诊断、评价预后、指导化疗的分子标志物之一.     

脑胶质瘤组织中p16基因启动子区CpG岛甲基化检测及其临床意义研究

目的：研究脑胶质瘤中p16基因启动子区甲基化情况及其临床意义。方法：用甲基化特异性PCR技术检测42例脑胶质瘤组织和癌旁正常脑组织中p16基因启动子甲基化,并分析该基因启动子甲基化与临床病理特征之间的关系。结果：脑胶质瘤组织中p16基因异常甲基化率（38.27%）显著高于癌旁正常脑组织中p16基因的异常甲基化率（8.8%,P=0.000）。发生甲基化的肿瘤组织或者正常脑组织中p16基因mRNA和蛋白表达显著降低。此外,p16基因异常甲基化和肿瘤病理分级有相关性（P=0.007）,而与患者性别、年龄及肿瘤类型等临床特征无关（P=0.669,0.869和0.944）。结论：p16基因启动子区CpG岛高甲基化与p16表达下调相关,推测p16启动子区CpG岛高甲基化是导致p16基因在脑胶质瘤中表达下调的重要因素,有望成为脑胶质瘤早期辅助诊断的分子标志物之一。     

TET家族DNA羟化酶与5-hmC在肿瘤中的作用机制的研究进展

DNA甲基化失调引起基因表达异常是表观遗传学的一个显著特点。目前已知,由DNA甲基转移酶（DNA methyltransferases,DMNTs）催化DNA甲基化,其酶基因突变或表达异常引起DNA甲基化水平的改变。近期研究发现了一种DNA去甲基化酶--TET（Ten-Eleventranslocation）家族DNA羟化酶,能通过多种途径催化5-甲基胞嘧啶（5．methylcytosine,5-mC）去甲基化,从而调控DNA基化的平衡。5-羟甲基胞嘧啶（5-hydroxymethylcytosine,5-hmC）作为DNA去甲基化多重步骤中重要的中间产物,其水平在肿瘤的发生和发展时期发生显著变化。该文从TET家族蛋白展开,介绍TET蛋白的结构、功能及作用机制以及多种人类肿瘤中丁E丁家族基因与5-hmC水平的相关性及其对肿瘤发生发展、诊断预后等临床意义的研究进展。     

DAB2IP与肿瘤的发生发展

基因DAB2IP（disabled homolog 2-interacting protein,DAB2 interacting protein）,也被称为AIP1（ASK1-interacting protein 1）,其编码的蛋白是Ras GTPase活化蛋白家族[Ras GTPase-activating protein（GAP）]的新成员之一.作为一个肿瘤抑制基因,DAB2IP常在前列腺癌、乳腺癌、肺癌、肝癌等肿瘤中表达下调,其机制与启动子甲基化及Ezh2相关.DAB2IP不仅参与肿瘤的增殖、存活和凋亡过程,还与肿瘤转移密切相关.     

骨肉瘤中RASSF1A基因的甲基化状态研究

目的：分析骨肉瘤组织中RASSF1A基因甲基化状况。方法：运用甲基化特异性PCR（MSP）分别检测44例骨肉瘤组织及相应的癌旁组织中RASSF1A基因启动子甲基化状态并分析其临床病理意义。结果：骨肉瘤组织中RASSF1A基因异常甲基化率（61.4%）显著高于癌旁正常骨组织中RASSF1A基因的异常甲基化率（20.5%）,二者之间差异具有统计学意义（P〈0.05）。RASSF1A基因异常甲基化导致组织中RASSF1A基因mRNA和蛋白表达水平均显著降低。另外,RASSF1A基因异常甲基化和肿瘤组织分化程度及全身有无转移情况有相关性（P值分别为0.022和0.016）,而与患者年龄、性别、肿瘤位置及大小等临床特征无关（P值分别为0.6944,0.977,0.786和0.831）。结论：RASSF1A基因启动子高甲基化可能是导致其在骨肉瘤中表达水平降低的分子机制之一,有望成为骨肉瘤早期辅助诊断的一个重要分子标志物。     

DNA 甲基化及其对肿瘤的作用

DNA甲基化是一种重要的表遗传修饰,在肿瘤细胞中表现为基因组整体水平的低甲基化和一些特定区域的高甲基化,发生低甲基化的序列主要是一些高度和中度重复序列,而发生高甲基化序列通常是跨越管家基因和肿瘤抑制基因启动子的CpG岛,它们在肿瘤的发生发展中起重要的作用,本文就这些序列的异常甲基化和其对肿瘤作用一些进展和观点作一介绍。     

减毒单核细胞增生李斯特氏菌作为疫苗载体在肿瘤治疗中的应用

肿瘤免疫疗法已成为继手术、化疗和放疗之后的第四种肿瘤治疗方法,是当今肿瘤治疗的新希望。将细菌疫苗应用于肿瘤治疗的研究已经历了多方面的探索。单核细胞增生李斯特氏菌因其能够趋向肿瘤病灶,在肿瘤微环境保护下激起肿瘤浸润细胞的免疫反应,削弱免疫抑制作用而受到研究者的广泛关注。并且,其在乳腺癌、肝癌、黑素瘤、胰腺癌等癌症中都已具有较为广泛的研究。本文就单核细胞增生李斯特氏菌的免疫应答方式、作为肿瘤载体的优势、减毒策略以及在多种肿瘤免疫治疗中的应用进行综述。     

The Agrobacterium tumefaciens T-DNA gene 6b is an onc gene

In this article it is shown that the T-DNA of Agrobacterium tumefaciens contains besides the well-known cyt and aux genes another gene with an oncogenic effect in plants. The gene in question is called 6^b and causes the formation of small tumors in plant species such as Nicotiana glauca and Kalanchoe tubiflora.     

MYCN-Related Suppression of Functional CD44 Expression Enhances Tumorigenic Properties of Human Neuroblastoma Cells

Highly malignant neuroblastoma tumors with MYCN amplification have been shown to downregulate the expression of the CD44 adhesion receptor. We have previously shown that MYCN amplified neuroblastoma cell lines either lack CD44 expression or express a nonfunctional, nonhyaluronic acid-binding CD44 receptor. By analysis of cells with manipulated expression of either CD44 or MYCN, we demonstrate that transfection of cells with a CD44 full-length cDNA construct produced a functional receptor in single copy MYCN cells and a nonfunctional CD44 receptor in MYCN amplified cells, similar to the CD44 receptor expressed by cells with enforced MYCN. Analysis of the in vivo growth properties of the transfectants revealed that the restoration of a functional CD44 receptor in nonamplified cells resulted in the suppression of in vivo cell growth, therefore linking the MYCN-related lack of hyaluronic acid-binding function of CD44 to the highly tumorigenic properties of a subset of neuroblastoma cells.     

Haploadaptivity of tumor suppressor lgl and ontogenesis in Drosophila melanogaster: Increased survival rate and life span under stress conditions

Mutations of tumor suppressor lgl induce neuroblastoma and malignant transformation of epithelial larval tissues in Drosophila. We have already shown that heterozygotes for lethal null variants lgl/+ are widespread in natural populations. In order to elucidate this paradox, we analyzed the parameters of biological adaptation of the carriers of one dose of the tumor suppressor. We studied the patterns of embryonic survival rate of lgl/+ flies under the conditions of competition for life resources and development at elevated and lowered temperatures (29 and 16°C), influence of stress thermal conditions on longevity, influence of short-term temperature stress during prezygotic period in the course of oogenesis of mothers on survival rate of F1 progenies, and resistance of heterozygotes for different lethal lgl alleles against RNA virus DCV. The loss of one dose of tumor suppressor lgl provided for increased survival rate and longevity of lgl/+ heterozygotes under stress conditions. This phenomenon was called haploadaptivity. Important features of adaptogenesis were established in lgl/+ heterozygotes: dependence on the maternal genotype and critical periods in development. The increased survival rate of F1 progenies was determined already during early oogenesis of their lgl/+ mothers at the proembryo stage. With respect to humans, this conclusion draws attention to the oogenesis-dependent transgeneration aspect of determination and expression of mutant factors of risk, including tumor suppressors. The data obtained are essential for understanding of the causes of spreading null variants for the genes related to multiple pathologies, including cancer, in human populations.     

Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L)

Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-x(L), but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-x(L) in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-x(L), in human lung cancer cells.     

microRNAs与TP53基因调控网络研究进展

TP53基因(编码p53蛋白)作为一个重要的抑瘤基因,通过调控一系列信号转导通路广泛参与了多种恶性肿瘤的发生发展,一直是肿瘤分子生物学研究领域的热点.最近的研究发现,microRNAs(miRNAs)参与了TP53的信号通路,它们之间存在着复杂的调控网络.一方面,p53通过调控一些miRNAs的转录及转录后成熟,促进细胞周期阻滞、诱导细胞凋亡和衰老,抑制肿瘤发生.另一方面,许多miRNAs,如miR-25、miR-30d、miR-125b和miR-504等可直接调控p53的表达与活性,参与TP53信号通路的调节,还有一些miRNAs则通过调节p53上下游基因,发挥重要的生物学功能.其中,最具有代表性的是miR-34家族,它们受p53直接调控并参与TP53信号通路,通过靶向抑制多个TP53信号通路关键分子的表达,发挥抑瘤作用.此外,它们还可以通过抑制沉默信息调节子,增强p53的活性,反馈调节TP53信号通路.miRNAs与TP53之间调控网络的研究,是对TP53抑瘤机制的重要补充.     

lats基因在细胞周期和肿瘤发生中的作用

lats基因(large tumor suppressor gene)最早在果蝇中发现,在小鼠和人中均有同源基因.该基因的功能从果蝇到人是高度保守的.lats基因的功能包括:作为肿瘤抑制基因,其突变会导致肿瘤的发生;磷酸化的Lats与Cdc2结合,参与细胞周期的调控;通过细胞-细胞间的通讯,可能参与生物体个体大小的调控机制.从果蝇到人lats基因功能的研究,提供了以果蝇作为模式生物研究哺乳动物基因功能的方法.     

Antitumor activity of L-asparaginase from Yersinia pseudotuberculosis

The cytotoxic activity of L-asparaginases from Yersinia pseudotuberculosis and from Erwinia carotovora were investigated in vitro using human T-lymphoblastic leukemia (Jurkat and Molt-4) and also solid tumor cell lines MCF-7 (human breast adenocarcinoma), LnCap (human prostate carcinoma), NGUK1 (rat Gasser node neurinoma). E.coli L-asparaginase produced by Medak (Germany) was used as a reference preparation. The data obtained indicate that Y. pseudotuberculosis L-asparaginase significantly inhibits growth of leukemic and solid tumor cells. Its antitumor activity is comparable to that of the reference preparation of L-asparaginase (Medak). These results suggest that the recombinant L-asparaginase can be used for the development of new preparations for the therapy of different types of tumors.