脑膜瘤WHO 分级及其基因学研究进展

脑膜瘤是颅内第二大常见肿瘤。WHO根据组织学及肿瘤生物学将脑膜瘤分为3级。目前,随着脑膜瘤研究的深入及肿瘤分子生物学的发展,脑膜瘤在基因学方面的研究越来越受到重视。其中包括原癌基因的激活和抑癌基因的失活。现阶段,比较公认的与肿瘤包括脑膜瘤形成有关的原癌基因主要有c-myc基因、bcl-2基因、Survivin基因及mdm2基因等,抑癌基因主要有p53基因、p73基因、NF-2基因及p16基因等。这些基因通过不同的机制发生不同的改变最终参与了不同级别脑膜瘤的发生和发展。现就其研究进展做一综述。     

p16表达异常与肿瘤关系的研究进展

作为一种抑癌基因,p16能通过阻遏细胞周期而抑制细胞增殖,p16基因失活亦是肿瘤发生发展与侵袭转移的重要因素。导致p16失活的原因主要包括基因缺失或突变,以及基因启动子甲基化所致的表观遗传性表达抑制。但在部分肿瘤组织中,p16表达显著性上调,这可能是致癌因素激活p16基因表达的结果。本文简要综述近年来p16基因表达与肿瘤相关性的研究进展。     

细胞代谢异常与肿瘤发生发展

细胞代谢的改变是肿瘤的一个重要特征,其与肿瘤的发生发展互为因果。肿瘤代谢改变是一个复杂的过程,原癌基因激活、抑癌基因失活以及信号通路的异常活化在转录和翻译后修饰等多个水平上调节代谢酶或代谢调控蛋白,通过影响其活性、亚细胞定位、稳定性、自噬等多种机制引起细胞代谢流的改变。由于代谢异常在肿瘤发生发展中的关键作用,通过干预肿瘤细胞代谢特异靶点、修正细胞的代谢异常成为预防肿瘤发生和治疗肿瘤的新思路。     

宫颈癌中相关基因启动子高甲基化研究进展

本文主要从分子水平介绍了在宫颈癌发生发展过程中抑癌基因的甲基化的作用.以往认为人乳头状病毒高危型的的感染是导致宫颈癌发生的主要因素.随着科技的发展,宫颈癌组织中抑癌基因的甲基化越来越备受关注.既往认为基因内突变和染色体物质缺失是肿瘤抑制基因失活的主要原因.但是,启动子CPG岛异常甲基化导致的基因失活在肿瘤发生发展过程中起着非常重要的作用现已确切证明,DNA甲基化是肿瘤抑制基因失活的第三种机制,而且在某些情况下是抑癌基因失活的惟一机制.对宫颈癌组织中的对相关抑癌基因甲基化的筛选并作为标记应用在检测宫颈癌中,这在防止宫颈癌的发生起到重大作用,还可有望作为宫颈癌治疗疗效检测的一项手段.     

泛素蛋白连接酶MDM2活性及稳定性调控的研究进展

泛素蛋白连接酶MDM2(Murine double minute 2)具有癌基因活性, MDM2高表达会导致抑癌基因p53失活而诱发肿瘤, 但在至少7%的肿瘤中p53基因正常而mdm2异常扩增, 表明MDM2还具有其他底物分子, 以p53不依赖的方式促进肿瘤的发生。鉴于MDM2的重要作用, 文章在基因水平、转录水平、翻译后修饰水平、相互作用分子的调节等方面系统总结了目前对MDM2调控的主要研究机制及其进展。     

抑癌基因p53与肿瘤研究的最新进展

p53基因是迄今为止已发现的与人类肿瘤发生相关性最高的抑癌基因,其主要生物学功能是通过调控DNA修复、细胞周期停滞和诱导细胞凋亡,维持基因组和细胞稳定,抑制肿瘤生长;肿瘤血管再生、微小RNA（microRNA,miRNA）及肿瘤干细胞是近几年来肿瘤发生机理研究领域的热点,本文综述了p53基因在肿瘤血管再生、miRNA、肿瘤干细胞中作用的最新研究进展及其在肿瘤治疗中的应用。     

DNA损伤修复反应的双刃剑效应在肿瘤与衰老发生发展中的作用

人类生存环境中的有害物质、机体正常代谢产生的氧化自由基、端粒缩短或端粒酶活性改变、原癌基因激活或抑癌基因失活等均可造成DNA损伤。通过启动DNA损伤修复反应,激活p53/p21或p16/Rb信号转导途径可以引发细胞周期阻滞,为修复破损的DNA赢得时间,避免不完整的DNA信息继续传递下去。过度的细胞周期阻滞将引起不可逆的细胞增殖停滞并最终引起细胞衰老,而当损伤的DNA没有完全修复就无限制的进入细胞周期时,将会诱发肿瘤的形成。肿瘤和衰老的发生机制是相互对立、相互交织的,而DNA损伤修复反应是联系二者的纽带。     

抑癌基因研究进展

肿瘤的发生与原癌基因的激活及／或抑癌基因的缺失或灭活关系密切,尤其是抑癌基因的研究成为近几年来肿瘤发生方面的研究热点。本文从抑癌基因的定义,发现过程,已发现的抑癌基因及几种重要抑癌基因的功能等方面作以综述。     

肺癌相关抑癌基因的研究进展

肺癌是当前最常见的恶性肿瘤之一,其发病率和死亡率均逐年升高。肺癌对人类健康的危害日益加重,因此对肺癌诊断和治疗的要求更加迫切。肺癌的发生、发展涉及复杂的生物学过程,主要包括抑癌基因的失活和原癌基因的激活,因此深入了解与肺癌相关的基因的作用和机制很有必要。随着分子生物学的迅速发展,人们对肺癌中相关发病基因有了更深刻的认识,现就肺癌相关的抑癌基因(如p53、Rb、p16、LKB1、PTEN、4.1B/DAL-1、GPRC5A、GATA、PTPRO)作一简要概述。     

错配修复基因与涎腺肿瘤的关系

错配修复(mismatch repair,MMR)是DNA复制后的一种修复机制,对维持基因组稳定起重要作用.错配修复基因功能缺陷是继癌基因激活、抑癌基因失活之后又一肿瘤的发生、发展机制,错配修复基因的异常表达与全身多种肿瘤相关.涎腺肿瘤为口腔颌面部常见肿瘤之一,具有与其他系统肿瘤相似的组织学类型,多来源于肌上皮.近年来,有关涎腺肿瘤与错配修复基因的关系正逐步成为研究热点,本文就错配修复基因的组成、作用机制以及与涎腺肿瘤发生、发展的关系作一综述.     

Ras Regulates Rb via NORE1A

Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.     

HCCR-1, a novel oncogene,encodes a mitochondrial outer membrane protein and suppresses the UVC-induced apoptosis

Background  

The Human cervical cancer oncogene (HCCR-1) has been isolated as a human oncoprotein, and has shown strong tumorigenic features. Its potential role in tumorigenesis may result from a negative regulation of the p53 tumor suppressor gene.     

deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo

TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, DeltaNp73, is upregulated in breast and gynecological cancers. We further showed that DeltaNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of DeltaNp73, this can only be directly shown in primary cells. We report here that DeltaNp73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. DeltaNp73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, DeltaNp73 rescues Ras-induced senescence. Moreover, DeltaNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of DeltaNp73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of DeltaNp73. Taken together, DeltaNp73 behaves as an oncogene that targets p53 that might explain why DeltaNp73 upregulation may be selected for during tumorigenesis of human cancers.     

Targeting p53 for Novel Anticancer Therapy

Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the “guardian of the genome,” is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients.