核糖体蛋白与肿瘤

核糖体由核糖体蛋白和核糖体RNA组成,是蛋白质生物合成的重要场所.核糖体蛋白参与蛋白质的翻译过程,核糖体蛋白和核糖体RNA的表达紊乱将激活核糖体蛋白的核糖体外功能,该功能在肿瘤的发生发展过程中发挥重要作用.核糖体蛋白有望作为生物标志物或治疗靶点用于肿瘤的早期诊断和治疗中.     

核糖体蛋白家族在肿瘤发生、发展中作用的研究进展

核糖体是蛋白质合成场所,核糖体蛋白质是核糖体主要成分,但其性质不稳定,容易被核质蛋白酶降解,当细 胞核糖体亚单位合成增加时,细胞功能发生调节异常继而出现代谢紊乱,导致细胞异常增殖及功能障碍,甚至发生恶性转 化。肿瘤的发生、发展常伴有基因组不稳定,会导致编码核糖体蛋白基因改变,肿瘤周边区域乏氧和营养不足,治疗所使 用的化学药物和放射线都可能影响到核糖体合成,核糖体蛋白质失衡或者功能障碍都会导致核糖体压力,会刺激核糖体蛋 白质以游离核糖体的形式增多。快速生长和增殖的肿瘤细胞较体细胞需要更多的核糖体合成机制,促进核糖体合成。大量 研究证实了核糖体蛋白在肿瘤中表达异常,提示我们核糖体蛋白在人类疾病及肿瘤发生与发展中发挥着重要作用。核糖体 蛋白家族是人体细胞内合成蛋白质的主要成员,在遗传信息的传递过程中发挥着不可替代的作用,但是合成蛋白质传递遗 传信息并不是核糖体蛋白的唯一功能,其还发挥着蛋白质翻译以外的功能。目前的研究结果证明,核糖体蛋白家族通过调 控癌基因和抑癌基因表达,调控细胞周期和凋亡,促进血管生成,协同染色体基因发挥更加广泛作用,调节肿瘤增殖,浸润, 转移等恶性生物学行为。核糖体蛋白家族在肿瘤的发生与发展中发挥着重要作用,是促进肿瘤发生与发展的重要因素。     

铁死亡在泌尿系统肿瘤中的作用及其机制研究进展

铁死亡是近年来新发现的一种不同于凋亡、坏死和自噬的程序性细胞死亡。细胞内谷胱甘肽及谷胱甘肽过氧化物酶抗氧化防御系统调控异常及铁离子依赖性膜结构脂质过氧化的蓄积是铁死亡发生的主要病理生理改变。铁死亡参与包括肿瘤、缺血再灌注损伤及神经系统疾病等多种疾病的发生发展过程。近年来研究发现铁死亡与泌尿系统肿瘤密切相关,本文概述了铁死亡在泌尿系统肿瘤发生及进展中作用的相关调控分子机制,旨在为泌尿系统肿瘤的临床治疗提供新的方向。     

mTOR信号通路及其与肿瘤的联系

mToR是一种在细胞生长调控中处于核心地位的丝/苏氨酸蛋白酶。其相关信号通路复杂,且涉及面广泛,mToR可在多种因素的活化下参与基因转录、蛋白质翻译起始、核糖体生物合成、细胞凋亡等多项细胞功能。大量研究显示:mTOR信号通路调控异常与肿瘤发生密切相关,是肿瘤治疗的一个重要靶点。     

肿瘤代谢研究新进展

与正常细胞相比，肿瘤细胞因其基因或者表观遗传的改变，导致许多代谢通路发生紊乱。正常细胞发生恶化过程中，不仅糖代谢通路发生异常，线粒体生物合成、氨基酸代谢、脂代谢等其他代谢通路也会发生变化。这些代谢变化对肿瘤的发生发展以及临床靶向治疗具有重要的意义。     

DNA甲基转移酶在妇科肿瘤中的研究进展

大量研究表明，许多种类的肿瘤细胞都有异常的DNA甲基化行为，抑癌基因常常被过量地甲基化而失去活性，而基因的DNA序列并不发生改变。DNA甲基化是由DNA甲基转移酶（DNMT）催化并维持的。DNMT通过调节细胞内甲基化过程而参与肿瘤的发生与发展，在有5′端调控区胞嘧啶．鸟嘌呤（CpG）岛甲基化异常参与的肿瘤细胞中常表现为过度表达，其活性增高是肿瘤细胞具有特征的早期分子改变。     

活化T细胞核因子与肿瘤发生和发展的研究进展

活化T细胞核因子(nuclear factor of activated T cells,NFAT)是一组在哺乳动物细胞内广泛表达的转录因子,主要参与精密调控机体生长发育相关的、复杂的细胞内相互作用。近年来,越来越多的研究数据显示NFAT与人类肿瘤的发生、发展密切相关在多种肿瘤细胞及肿瘤微环境的复杂间质成分中,NFAT异常活化,促进肿瘤形成和浸润转移。本文旨在阐述目前研究发现的NFAT在肿瘤生物学中发挥的重要作用,涉及肿瘤的形成、生长、存活、恶性转化、侵袭转移和血管生成等过程,以及NFAT在肿瘤发生、发展中的作用机制,预测这些研究结果对于开辟新的肿瘤治疗途径有着重要的意义。     

RNA N7-甲基鸟苷甲基化修饰在肿瘤发生发展中的作用

N7-甲基鸟苷（m7G）是表观遗传学调控过程中最常见的RNA 修饰之一，在mRNA、核糖体RNA（rRNA）、转运RNA （tRNA）、miRNA 等多种RNA分子的加工和代谢中起着重要作用，进而参与细胞增殖、分化、凋亡和迁移等多种功能。越来越多的证据表明，m7G甲基化修饰参与肿瘤的发生发展。异常的m7G甲基化修饰通过调控癌基因和抑制基因的表达促进或抑制多种肿瘤的进展，m7G甲基化修饰及其调控因子可能是肿瘤诊断和治疗的潜在靶点。本文就m7G甲基化修饰的最新研究进展、检测方法及其在肿瘤发生发展中作用的分子机制进行评述。     

“辅助伴侣”分子MPP11和HSPA14与肿瘤发生发展及治疗的关系

组成核糖体相关复合物的MPP11和HSPA14,因其能够辅助“伴侣分子”完成新生肽链在核糖体从最初合成的线性结构到组装、正确折叠成三维构象的过程,又被称为“辅助伴侣”分子.近年来的研究表明,MPP11和HSPA14不仅能够发挥其“辅助伴侣”分子作用,也与细胞分化发育以及肿瘤发生发展存在紧密联系.本文通过就MPP11和HSPA14分子的结构、细胞内定位、生物学功能以及它们之间的相互作用、相互调控等方面进行综述,进一步揭示MPP11和HSPA14在肿瘤中的高表达,介导了肿瘤的发生发展过程,为后续肿瘤免疫治疗提供了新的方向.     

肿瘤相关巨噬细胞与长链非编码RNA在肿瘤发展中的研究进展

肿瘤相关巨噬细胞是肿瘤微环境重要组成部分，极化亚型影响肿瘤进展过程。长链非编码RNA(long non-coding RNA，lncRNA)不编码蛋白质，但是同样参与生物学过程，异常表达的lncRNA影响生理和病理进程，尤其对肿瘤发展有重要调控作用。癌症中一些异常表达的lncRNA直接或者间接影响巨噬细胞极化亚型调控肿瘤发展进程，lncRNA和巨噬细胞之间调节机制尚未清楚。lncRNA同肿瘤相关巨噬细胞可作为肿瘤潜在靶点和治疗中间物。本文将对在肿瘤中相互作用的肿瘤相关巨噬细胞与长链非编码RNA调控肿瘤进展过程进行综述。      

Targeted cancer therapy with ribosome biogenesis inhibitors: a real possibility?

The effects of many chemotherapeutic drugs on ribosome biogenesis have been underestimated for a long time. Indeed, many drugs currently used for cancer treatment – and which are known to either damage DNA or hinder DNA synthesis – have been shown to exert their toxic action mainly by inhibiting rRNA synthesis or maturation. Moreover, there are new drugs that have been proposed recently for cancer chemotherapy, which only hinder ribosome biogenesis without any genotoxic activity. Even though ribosome biogenesis occurs in both normal and cancer cells, whether resting or proliferating, there is evidence that the selective inhibition of ribosome biogenesis may, in some instances, result in a selective damage to neoplastic cells. The higher sensitivity of cancer cells to inhibitors of rRNA synthesis appears to be the consequence of either the loss of the mechanisms controlling the cell cycle progression or the acquisition of activating oncogene and inactivating tumor suppressor gene mutations that up-regulate the ribosome biogenesis rate. This article reviews those cancer cell characteristics on which the selective cancer cell cytotoxicity induced by the inhibitors of ribosome biogenesis is based.     

Ribosome biogenesis and control of cell proliferation: p53 is not alone

Cell growth is a prerequisite for cell proliferation, and ribosome biogenesis is a limiting factor for cell growth. In mammalian cells, the tumor suppressor p53 has been shown to induce cell-cycle arrest in response to impaired ribosome biogenesis. Recently, p53-independent mechanisms of cell-cycle arrest in response to alterations of ribosome biogenesis have been described. These findings provide a rational basis for the use of drugs that specifically impact ribosome biogenesis for the treatment of cancers lacking active p53 and extend the scenario of mechanisms involved in the relationship between cell growth and cell proliferation.     

核酸适配子及其在肿瘤标志物研究中的应用

适配子是应用指数富集的配体系统进化（SELEX）技术从单链随机寡核苷酸文库中筛选得到的能与靶标高特异性和高亲和力结合的单链寡核苷酸配体。以肿瘤标志物为靶标的核酸适配子不仅可以用于建立敏感而特异的肿瘤标志物检测新方法,也可用于捕获血液中的肿瘤细胞继而进行相关分析,还可携带药物对肿瘤进行靶向治疗,以及用于阻断靶分子的功能而实现肿瘤的生物治疗。肿瘤标志物的适配子筛选和应用是肿瘤研究的一个新领域。      

SNORA23 inhibits HCC tumorigenesis by impairing the 2?-O-ribose methylation level of 28S rRNA

Objective: The dysregulation of ribosome biogenesis is associated with the progression of numerous tumors, including hepatocellular carcinoma (HCC). Small nucle...     

Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability

Since chromosomal instability (CIN) is a hallmark of most cancer cells, it is essential to identify genes whose alteration results into this genetic instability. Using a yeast CIN indicator strain, we show that inactivation of the YMR131c/RRB1 gene, which is involved in early ribosome assembly and whose expression is induced when the spindle checkpoint is activated, alters chromosome segregation and blocks mitosis at the metaphase/anaphase transition. We demonstrate that RRB1 interacts with YPH1 (yeast pescadillo homologue 1) and other members of the Yph1 complex, RPL3, ERB1 and ORC6, involved in ribosome biogenesis and DNA replication. Transient depletion of the human homologues GRWD, Pescadillo, Rpl3, Bop1 and Orc6L resulted in an increase of abnormal mitoses with appearance of binucleate or hyperploid cells, of cells with multipolar spindles and of aberrant metaphase plates. If deregulation of proteins involved in ribosome biogenesis, commonly observed in malignant tumors, could contribute to cancer through an aberrant protein synthesis, our study demonstrates that alteration of proteins linking ribosome biogenesis and DNA replication may directly cause CIN.     

RNA helicase DDX5 is a p53-independent target of ARF that participates in ribosome biogenesis

The p19ARF tumor suppressor limits ribosome biogenesis and responds to hyperproliferative signals to activate the p53 checkpoint response. Although its activation of p53 has been well characterized, the role of ARF in restraining nucleolar ribosome production is poorly understood. Here we report the use of a mass spectroscopic analysis to identify protein changes within the nucleoli of Arf-deficient mouse cells. Through this approach, we discovered that ARF limited the nucleolar localization of the RNA helicase DDX5, which promotes the synthesis and maturation of rRNA, ultimately increasing ribosome output and proliferation. ARF inhibited the interaction between DDX5 and nucleophosmin (NPM), preventing association of DDX5 with the rDNA promoter and nuclear pre-ribosomes. In addition, Arf-deficient cells transformed by oncogenic RasV12 were addicted to DDX5, because reduction of DDX5 was sufficient to impair RasV12-driven colony formation in soft agar and tumor growth in mice. Taken together, our findings indicate that DDX5 is a key p53-independent target of the ARF tumor suppressor and is a novel non-oncogene participant in ribosome biogenesis.     

SNORA23 inhibits HCC tumorigenesis by impairing the 2′-O-ribose methylation level of 28S rRNA

Objective:The dysregulation of ribosome biogenesis is associated with the progression of numerous tumors, including hepatocellular carcinoma (HCC). Small nucleolar RNAs (snoRNAs) regulate ribosome biogenesis by guiding the modification of ribosomal RNAs (rRNAs). However, the underlying mechanism of this process in HCC remains elusive.Methods:RNA immunoprecipitation and sequencing were used to analyze RNAs targeted by ribosome proteins. The biological functions of SNORA23 were examined in HCC cells and a xenograft mouse model. To elucidate the underlying mechanisms, the 2′-O-ribose methylation level of rRNAs was evaluated by qPCR, and the key proteins in the PI3K/Akt/mTOR pathway were detected using Western blot.Results:Twelve snoRNAs were found to co-exist in 4 cancer cell lines using RPS6 pull-down assays. SNORA23 was downregulated in HCC and correlated with the poor prognoses of HCC patients. SNORA23 inhibited the proliferation, migration, and invasion of HCC cells both in vitro and in vivo. We also found that SNORA23 regulated ribosome biogenesis by impairing 2′-O-ribose methylation of cytidine⁴⁵⁰⁶ of 28S rRNA. Furthermore, SNORA23, which is regulated by the PI3K/Akt/mTOR signaling pathway, significantly inhibited the phosphorylation of 4E binding protein 1. SNORA23 and rapamycin blocked the PI3K/AKT/mTOR signaling pathway and impaired HCC growth in vivo.Conclusions:SNORA23 exhibited antitumor effects in HCC and together with rapamycin, provided a promising therapeutic strategy for HCC treatment.