微量元素铁与肿瘤发生及发展的关系

目的 铁既是生命所必须的,但又与肿瘤的发生、发展密切相关,其机制并不明确.本文旨在总结微量元素铁与肿瘤发生、增殖、转移的关系及其机制.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“铁,肿瘤”为关键词,检索1990-2016年的相关文献.纳入标准:(1)细胞实验、动物模型、人群研究中微量元素铁与肿瘤发生、发展的关系;(2)氧化应激损伤、炎症反应、免疫应答、信号通路异常在微量元素铁与肿瘤关系中的作用.根据纳入标准,符合分析的文献共70篇.结果 大量研究发现,铁过载与肿瘤的发生及发展密切相关,铁通过诱导氧化损伤、促进炎症因子的产生、降低免疫系统对肿瘤的监视等机制增加肿瘤的发病风险,铁还可以改变正常信号转导通路促进肿瘤增殖与转移.最近这些年许多参与铁代谢的蛋白被发现,靶向铁的治疗可能作为肿瘤治疗的新策略,但是其需要更多的临床资料来证实.结论 通过对铁元素与肿瘤发生及发展关系的研究,能够给肿瘤的预防及治疗提供新的思路与方法.     

E2F基因与肿瘤放射敏感性研究进展

目的 肿瘤放射敏感性是影响肿瘤放射治疗效果的重要原因.在众多影响放射敏感性的因素中,细胞周期、细胞凋亡和DNA损伤修复发挥重要作用.E2F基因家族通过编码E2Fs转录因子家族,调控细胞周期、细胞凋亡等生命活动.本研究旨在总结E2F基因与肿瘤细胞放射敏感性的关系的研究进展.方法 应用PubMed、CNKI等数据库,以“E2F,放疗敏感性,辐射敏感性”等为关键词,检索1990-12-2017-05的中英文文献,共检索到英文文献1 560篇,中文文献634篇.纳入标准:(1)E2F的结构其对细胞周期,细胞凋亡,DNA损伤调控的相关研究;(2)肿瘤细胞辐射敏感性影响因素的临床、基础研究;(3)E2F基因与肿瘤放射敏感性关系的基础研究.排除标准:(1)讨论与辐射敏感性因素关系不紧密的研究;(2)探究不与E2F基因相互作用的基因和细胞因子的研究.符合分析的文献126篇,72篇纳入分析.结果 E2F基因通过PRb/E2F通路调控G1/S期转变,进而调控细胞周期进程.细胞DNA损伤后,E2F1通过p53依赖型和非p53依赖型方式诱导细胞凋亡,成为肿瘤放射治疗的潜在靶点.结论 探究E2F基因与肿瘤放射敏感性的关系将可能成为未来提高肿瘤放射敏感性的重要思路.     

Forkhead家族转录因子FoxM1与肿瘤

目的 随着分子生物学和分子肿瘤学的深入研究,运用肿瘤发生发展中的关键分子做为诊断标志和治疗靶点已成为肿瘤诊治的新趋势.本研究旨在分析Forkhead家族转录因子FoxM1介导肿瘤发生发展的机制及其在分子诊断和靶向干预中的价值.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“FoxM1和肿瘤”为关键词,检索2011-03-2016-02的所有相关文献,共检索到英文文献383篇,中文文献97篇.纳入标准:(1)FoxM1介导肿瘤发生发展的机制;(2)FoxM1与肿瘤分子诊断及靶向干预.根据纳入标准,符合分析的文献44篇.结果 FoxM1通过调控细胞周期G1/S和G2/M期促转化分子Skp2、Cksl、C myc和细胞周期调节分子Cdc25A、Cdc25B、Cyclin D1、p27kip1和p21cip1等表达,影响细胞有丝分裂、细胞周期、DNA损伤修复、细胞增殖与分化等生物学过程.FoxM1过表达导致细胞异常增殖、新生血管形成、上皮间质转化、维持干细胞特性、代谢异常和细胞逃逸衰老等生物学表征,促进细胞恶性转化,参与肿瘤发生发展.FoxM1还可调节多种肿瘤细胞对药物敏感性与耐药性.基于FoxM1的恶性肿瘤诊断系统对多种早期癌症的诊断具有良好价值.以FoxM1为靶点的抗肿瘤化合物通过抑制肿瘤细胞中过度表达的FoxM1成为临床治疗的潜在的新策略.结论 FoxM1过表达促进肿瘤发生发展,检测FoxM1分子有助于肿瘤早期识别,抑制FoxM1可以靶向干预肿瘤的发生发展,FoxM1是肿瘤诊疗的潜在靶标.     

内质网应激调节顺铂引起的肿瘤细胞凋亡

目的:总结国内外关于内质网应激在化疗药物顺铂诱导肿瘤细胞死亡中的作用及研究进展.方法:应用Medline和CNKI期刊全文数据库系统,以"肿瘤抑制因子p53、DNA损伤应激反应、细胞凋亡、内质网应激"为关键词,检索2000-2010年的相关文献,共检索到英文文献1256篇和中文文献32篇.纳入标准:1)肿瘤抑制因子p53的调节及其引发的细胞凋亡分子机制;2)内质网应激的发生条件及内质网应激反应的分子调控;3)内质网应激在肿瘤细胞治疗中对凋亡的影响.根据纳入标准,符合分析的文献21篇.结果:内质网应激与肿瘤抑癌基因p53蛋白及其细胞凋亡作用有重要关系.传统的化疗药物对某些肿瘤细胞有耐药性,内质网应激相关调控可能会增加化疗药物对肿瘤细胞的杀伤作用.结论:抑制肿瘤细胞的内质网应激状态为肿瘤的治疗提供了一个新的思路.     

乳腺癌TGF-β信号通路相关转录因子研究进展

目的 总结与转化生长因子β(transforming growth factor-β,TGF-β)信号通路相关的转录因子在乳腺癌发生发展过程中的作用,分析它们与TGF-β信号通路之间的网络调控机制.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“乳腺癌、转录因子和TGF-β”等为关键词,检索2011-01-01-2015-12 31的相关文献.纳入标准:(1)乳腺癌侵袭转移;(2)转录因子与TGF-β信号通路存在联系.剔除标准:(1)未阐明转录因子与TGF-β信号通路作用的具体机制;(2)实验设计不严谨.符合纳入标准的英文文献146篇,中文文献35篇,根据剔除标准剔除英文文献50篇,中文文献34篇,最后纳入分析文献88篇.结果 TGF-β信号通路是一条极为重要的细胞内信号转导途径,能调控细胞增殖、分化、迁移、粘附及凋亡等生理活动.在乳腺癌中,TGF-β信号通路起着双重作用,即在肿瘤发生的早期阶段,TGF-β信号通路起着一种预防性或肿瘤抑制的作用,但随着肿瘤的发展,TGF-β能够通过影响肿瘤微环境、增强侵袭性及抑制免疫细胞功能来促进肿瘤细胞的转移.多个转录因子c-Myc、p53、C/EBPβ、14-3-3ξ、Blimp-1、Oct-4和Nanog、Foxq1、TBX3、FOXM1、GATA3、HOXB9、Six1、Pokemon、Snail、Slug和SOX4已证实与TGF-β信号通路发生相互作用,共同参与调控乳腺癌发生发展过程.结论 乳腺癌发生过程中转录因子与TGF-β信号通路形成复杂的调控网络,对乳腺癌的进程起着双向调节作用.     

Nodal信号调控与肿瘤的研究现状

目的:总结Nodal及其信号调控与肿瘤发生、发展的关系,并探讨针对Nodal的抑制策略在肿瘤治疗中的应用价值.方法:以“Nodal、信号通路和肿瘤”等为关键词,检索2000-01-2011-12 PubMed及CNKI期刊全文数据库.纳入标准:1)Nodal结构及生物学作用;2)胚胎发育及肿瘤发生中Nodal信号调控的区别;3)Nodal与肿瘤恶性度的相关性;4)抑制Nodal信号通路的肿瘤治疗策略可行性.根据纳入标准,符合分析的文献40篇.结果:Nodal在肿瘤组织重新高表达,其信号参与了肿瘤发生、血管生成和侵袭转移等进程,并受到其他信号通路的调控.Nodal在肿瘤的发生、发展中扮演重要角色,但其机制有待明确.结论:深入探究Nodal在胚胎发育和肿瘤发生过程中功能上的区别及相似之处,阐明Nodal相关信号通路及其中的关键分子,可能会为恶性肿瘤的临床诊治提供新靶点和新思路.     

肿瘤与microRNA的DNA甲基化相关性研究进展

目的:总结国内外关于microRNA (miRNA)的DNA甲基化在各肿瘤中的研究进展.方法:应用PubMed及CNKI全文数据库检索系统,以“miRNA、DNA甲基化和肿瘤”为检索词,检索2004-04-2012-05的相关文献,共检索到英文文献401篇,中文文献40篇.文献纳入标准:1)miRNA的生物学特性;2)DNA甲基化的作用机制及与肿瘤的关系;3)miRNA的DNA甲基化与肿瘤发生发展的关系.根据纳入标准符合分析的文献27篇.结果:miRNA在肿瘤发生发展中可发挥癌基因和抑癌基因的作用,DNA甲基化是肿瘤发生的一个重要因素.20％受甲基化调控的miRNA在上游5 kb范围内有CpG岛,miRNA的DNA甲基化与CpG岛有密切关系.miR-34、miR-124、miR-9和miR-127的DNA甲基化在各种肿瘤中频繁发生,多数通过靶向调节癌基因或抑癌基因而在肿瘤发生发展中发挥作用.结论:miRNA的DNA甲基化在人类肿瘤中广泛存在,甲基化miRNA可能作为肿瘤早期诊断、治疗、转移和预后的分子标志.     

EGFR相关的DNA修复及放射抗拒机制研究现状

目的:总结国外关于表皮生长因子受体(EGFR)通过各种信号通路调节DNA修复导致辐射抗拒相关机制的研究进展.方法:应用PubMed数据库系统,以“表皮生长因子受体、信号通路、DNA损伤修复、放射抗拒”为关键词检索2005-01-2011-12的相关文献,共检索到英文文献198篇.纳入标准:1)EGFR的表达;2)辐射抗拒和DNA损伤修复机制;3)EGFR和辐射诱导的DNA损伤修复;4)EGFR信号通路调控DNA损伤修复导致放射抗拒的可能机制.根据纳入标准,纳入分析22篇文献.结果:EGFR过表达与放化疗抗拒相关.它可以通过联接DNA蛋白激酶催化亚单位(DNA-PKcs)来调节放疗诱导的DNA损伤的修复.EGFR及其对DNA修复能力之间的分子连接可能通过该受体的一个或多个下游信号通路介导.结论:EGFR作为调节DNA损伤修复机制的信号通路与放射抗拒之间存在相关性,靶向于其中激活的信号通路可以为改善放射抗拒提供新的治疗思路.     

微小RNA的DNA甲基化与肿瘤发生发展相关性的研究进展

目的:总结国内外关于微小RNA DNA甲基化在肿瘤发生发展过程的作用及其进行靶向调控的研究现状.方法:应用Medline及CNKI期刊全文数据库检索系统,以"肿瘤、微小RNA、DNA甲基化"为关键词,检索1993-01-2010-01的相关文献,共检索到英文文献62篇和中文文献2篇.纳入标准:1)微小RNA的起源和特点;2)微小RNA与DNA甲基化的关系;3)微小RNA DNA甲基化与肿瘤发生发展的关系;4)微小RNA DNA甲基化与肿瘤预后的关系.根据纳入标准符合分析文献23篇.结果:DNA甲基化可能是一种导致miRNA在肿瘤中表达沉默并影响其靶基因的表达和功能,进而影响肿瘤生物学行为的重要方式.结论:微小RNA DNA甲基化是肿瘤发生发展的重要机制之一,为肿瘤的诊断及治疗提供了新的方法.     

DNA损伤应答通路研究现状

目的：分析不同DNA损伤诱导的细胞DNA修复和凋亡通路,以及相关因子在其中所起作用。方法：应用PubMed及CNKI全文数据库检索系统,以“DNA损伤、细胞凋亡和DNA修复”等为关键词,检索200601—201112的相关文献,共检索到1826篇,中文文献579篇。纳入标准：1）细胞对DNA损伤的监测;2）DNA损伤触发的DNA修复;3）DNA损伤触发的细胞凋亡。根据纳入标准符合分析的文献21篇。结果：细胞的DNA损伤应答是复杂的过程,DSBs或DNA复制阻滞是最常见DNA损伤性结构改变,其能启动多种信号通路,涉及的损伤识别因子主要有MRN、P13激酶ATM及ATR等,最终触发细胞周期抑制、DNA损伤修复或诱导细胞凋亡。结论：细胞能够识别具有潜在致死性的DNA损伤,进而激活特异的损伤通路以抑制细胞周期,增强DNA修复或诱导细胞凋亡。而因子p53和NF—KB的促细胞凋亡和促细胞存活双重作用对细胞的凋亡或者存活起决定作用。     

Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence

Data accumulating during the last two decades suggest that tumorigenesis is held in check by two major intrinsic failsafe mechanisms; apoptosis and cellular senescence. While apoptosis is a programmed cell death process, cellular senescence, which is the focus of this article, is defined as irreversible cell cycle arrest. This process is triggered either by telomere erosion or by acute stress signals including oncogenic stress induced by overactive oncogenes or underactive tumor suppressor genes. The outcome of this is often replication overload and oxidative stress resulting in DNA damage. Oncogenic stress induces at least three intrinsic pathways, p16/pRb-, Arf/p53/p21- and the DNA damage response (DDR)-pathways, that induce premature senescence if the stress exceeds a threshold level. Oncogene-induced senescence (OIS) is frequently observed in premalignant lesions both in animal tumor models and in human patients but is essentially absent in advanced cancers, suggesting that malignant tumor cells have found ways to bypass or escape senescence. This review focuses on cell-autonomous mechanism by which certain oncogenes, tumor suppressor genes and components of the DDR/DNA-repair machinery suppress senescence – mechanisms that are exploited by tumor cells to evade senescence and continue to multiply. In this way, tumor cells become addicted to the continuous activity of senescence suppressor proteins. However, some senescence pathways, although under suppression, may remain intact and can be re-established if senescence suppressor proteins are inactivated or if senescence inducers are reactivated. This can hopefully form the basis for a “pro-senescence therapy” strategy to combat cancer in the future.     

α-Catulin knockdown induces senescence in cancer cells

Cellular senescence functions as a tumor suppressor that protects against cancer progression. α-Catulin, an α-catenin-related protein, is reported to have tumorigenic potential because it regulates the nuclear factor-κB (NF-κB) pathway, but little is known about its clinical relevance and the mechanism through which it regulates cancer progression. Here, we found that α-catulin mRNA levels were significantly upregulated in cancer cell lines and clinical oral squamous cell carcinomas, which positively correlated with tumor size (P=0.001) and American Joint Committee on Cancer (AJCC) stage (P=0.004). α-Catulin knockdown in the OC2 and A549 cancer cell lines dramatically decreased cell proliferation and contributed to cellular senescence, and inhibited OC2 xenograft growth. Mechanistic dissection showed that α-catulin depletion strongly induced the DNA-damage response (DDR) in both cell lines, via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53. Global gene expression analysis revealed that α-catulin knockdown altered cell-cycle regulation and DDR pathways at the presenescent stage as well as significantly downregulate several crucial genes related to mitotic chromosome condensation, DDR and DNA repair systems, which suggests that its depletion-induced cellular senescence might be caused by chromosome condensation failures, severe DNA damage and impaired DNA repair ability. Our study provides evidence that α-catulin promotes tumor growth by preventing cellular senescence and suggests that downregulating α-catulin may be a promising therapeutic approach for cancer treatment.     

SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells

SV40 virus has emerged as a potential cofactor with asbestos in the development of diffuse malignant mesothelioma, but its precise role in the pathogenesis of this tumor is unclear. SV40 large T antigen is known to inactivate cellular proteins involved in DNA damage and senescence, including p53 and pRb. We hypothesize that SV40 oncoproteins will sensitize mesothelial cells to DNA damage induced by asbestos or chemotherapeutic agents. SV40 oncoprotein expression in murine mesothelial cell lines enhanced spontaneous and asbestos-induced double-strand breaks, indicated by gamma-H2AX foci, and potentiated micronucleus formation. Mesothelial cells exposed to asbestos or bleomycin for 96 h acquired senescent-like morphology and displayed elevated senescence-associated beta-galactosidase activity, reduced bromodeoxyuridine (BrdUrd) incorporation, and reduced colony formation. SV40 oncoprotein expression abrogated the senescent phenotype, and transfected cell lines showed an increase in both BrdUrd incorporation and colony formation after prolonged DNA damage. Murine mesothelial cell lines lacking wild-type p53 due to a point mutation or gene rearrangement also failed to senesce in response to asbestos or chemotherapeutic agents. In addition, stress-induced senescence in human mesothelial cell lines was impaired by SV40 oncoprotein expression (MeT-5A), p53 small interfering RNA, or spontaneous p53 mutation (REN). These studies suggest that exposure to DNA-damaging agents can induce senescence in both murine and human mesothelioma cell lines and suggest a major, although not exclusive, role for p53 in this response. SV40 virus may contribute to mesothelioma progression by impairing stress-induced senescence, in part through p53 inactivation, thereby favoring survival and proliferation of mesothelial cells that have sustained DNA damage.     

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

Cellular senescence is important for the maintenance of tissue homeostasis, and has recently been shown to pose a natural barrier to tumorigenesis. The E3 ubiquitin ligase, E6AP, has been linked to a number of protein regulators of the cell cycle as well as the cellular stress response. We therefore explored the role of E6AP in the cellular response to stress. We found that mouse embryo fibroblasts (MEFs) lacking E6AP escape replicative senescence, as well as Ras-induced senescence associated with impaired markers. E6AP-deficient MEFs exhibit a range of transformed phenotypes: these include the ability to grow under stress conditions (such as low serum and DNA damage), enhanced proliferation, anchorage independent growth and enhanced growth of xenografts in mice. The transformed phenotype of E6AP-deficient MEFs is associated with lower basal and stress-induced accumulation of p53. Overall, our study implicates E6AP as an important regulator of the cellular response to stress, in particular through the regulation of replicative and oncogene-induced senescence.     

Short telomeres limit tumor progression in vivo by inducing senescence

Telomere maintenance is critical for cancer progression. To examine mechanisms of tumor suppression induced by short telomeres, we crossed mice deficient for the RNA component of telomerase, mTR(-/-), with Emu-myc transgenic mice, an established model of Burkitt's lymphoma. Short telomeres suppressed tumor formation in Emu-myc transgenic animals. Expression of Bcl2 blocked apoptosis in tumor cells, but surprisingly, mice with short telomeres were still resistant to tumor formation. Staining for markers of cellular senescence showed that pretumor cells induced senescence in response to short telomeres. Loss of p53 abrogated the short telomere response. This study provides in vivo evidence for the existence of a p53-mediated senescence mechanism in response to short telomeres that suppresses tumorigenesis.     

Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor

ABSTRACT: BACKGROUND: Cellular senescence represents a tumor suppressive response to a variety of aberrant and oncogenic insults. We have previously described a transgenic mouse model of Cyclin D1-driven senescence in pineal cells that opposes tumor progression. We now attempted to define the molecular mechanisms leading to p53 activation in this model, and to identify effectors of Cyclin D1-induced senescence. Results: Senescence evolved over a period of weeks, with initial hyperproliferation followed by cell cycle arrest due to ROS production leading to activation of a DNA damage response and the p53 pathway. Interestingly, cell cycle exit was associated with repression of the Cyclin-dependent kinase Cdk2. This was followed days later by formation of heterochromatin foci correlating with RB protein hypophosphorylation at Cdk4-dependent sites. In the absence of the Cdk4-inhibitor p18Ink4c, cell cycle exit was delayed but most cells eventually showed a senescent phenotype. However, tumors later arose from this premalignant, largely senescent lesion. We found that the p53 pathway was intact in tumors arising in a p18Ink4c-/- background, indicating that the two genes represent distinct tumor suppressor pathways. Upon tumor progression, both p18Ink4c-/- and p53-/- tumors showed increased Cdk2 expression. Inhibition of Cdk2 in cultured pre-tumorigenic and tumor cells of both backgrounds resulted in decreased proliferation and evidence of senescence. Conclusion: Our findings indicate that the p53 and the RB pathways play temporally distinct roles in senescence induction in Cyclin D1-expressing cells, and that Cdk2 inhibition plays a role in tumor suppression, and may be a useful therapeutic target.     

Many roads lead to oncogene-induced senescence

Oncogene-induced senescence is a mechanism of tumor suppression that restricts the progression of benign tumors. Important advances have been made toward elucidating the mechanisms that regulate this response; however, there is presently no unified model that integrates all current findings. DNA damage, replicative stress, reactive oxygen species, heterochromatin formation and negative feedback signaling networks have all been proposed to play an integral role in promoting senescence in response to various oncogenic insults. In all cases, these signals have been shown to function through Rb and p53, but utilize different intermediaries. Thus, it appears that senescence is not triggered by a single, linear series of events, but instead is regulated by a complex signaling network. Accordingly, multiple proteins may cooperate to establish a senescence response, but the limiting signal(s) may be dictated by the initiating genetic alteration and/or tissue type. This review will focus on integrating current models and will highlight data that provide new insight into the signals that function to suppress human tumor development.