肿瘤抑制蛋白p33ING1b在消化系统肿瘤中的研究进展

肿瘤抑制蛋白p33ING1b为生长抑制基因-1(ING1)的主要表达产物,它在细胞增殖和细胞周期调控、细胞衰老、DNA损伤修复、细胞凋亡和核染色质重塑中发挥重要作用。其表达异常与肿瘤的发生发展密切相关。本文就肿瘤抑制蛋白p33ING1b在消化系统肿瘤中的研究进展做一综述。     

软组织肉瘤表观遗传学研究进展

软组织肉瘤是一组起源于间叶组织的恶性肿瘤，在成人恶性肿瘤中约占1%，但是其亚类繁多并且部分软组织肉瘤恶性程度较高，5年生存率为50%~60%。在不断探索软组织肉瘤发病机制的过程中，研究发现除了基因组变化可以致瘤，表观遗传学的改变与肿瘤的发生、发展也有着密切的联系。与遗传学不同，表观遗传学不涉及基因核苷酸序列的变化，主要通过DNA甲基化、组蛋白修饰、非编码RNA调控及染色质重塑等方式发生可遗传的基因表达。软组织肉瘤发生、发展过程中涉及的表观遗传学机制可以为临床诊断和治疗用药提供更多新思路。本文将对软组织肉瘤的表观遗传学研究进展进行综述。      

ING1基因与肿瘤关系的研究进展

肿瘤的发生是一个多基因参与的多步骤的复杂过程,肿瘤抑制基因可能是抑制肿瘤发生的重要保护机制。ING1是1996年发现的一个候选抑癌基因,定位于人染色体13q33～34。ING1mRNA有ING1a、ING1b和ING1c三种变位剪接形式,分别编码三种不同的蛋白质:p47ING1a、p33ING1b和p24ING1c,其中p33ING1b是目前肿瘤研究的热点。ING1蛋白在正常细胞主要位于细胞核内,部分肿瘤细胞则在细胞质表达较多。ING1具有调控细胞周期、诱导细胞凋亡和DNA损伤修复的作用。其中,p33ING1通过调控细胞周期负向调节细胞生长而p47ING1a过表达则对细胞生长无明显影响。p33ING1b过量表达可以促进p21WAF1表达,协同p53引起细胞周期阻滞从而抑制肿瘤细胞生长。ING1基因可能是通过乙酰化依赖通路的活性调节来改变基因的表达,参与多种过程的调控。ING1编码的蛋白通过组蛋白乙酰转移酶(HATs)和组蛋白去乙酰化酶(HDACs)参与染色质的重塑,在DNA损伤修复方面发挥重要作用。ING1基因与脑瘤、肝癌和胃癌等多种肿瘤的发生发展有关。ING1基因的结构特点、生物学功能与肿瘤的发生发展密切相关。     

ING1基因与肿瘤关系的研究进展

肿瘤的发生是一个多基因参与的多步骤的复杂过程，肿瘤抑制基因可能是抑制肿瘤发生的重要保护机制。ING1是1996年发现的一个候选抑癌基因，定位于人染色体13q33～34。ING1mRNA有ING1a、ING1b和ING1c三种变位剪接形式，分别编码三种不同的蛋白质：p47^ING1a．p33^ING1b和p24^ING1c，其中p33^ING1b是目前肿瘤研究的热点。ING1蛋白在正常细胞主要位于细胞核内，部分肿瘤细胞则在细胞质表达较多。ING1具有调控细胞周期、诱导细胞凋亡和DNA损伤修复的作用。其中，p33^ING1通过调控细胞周期负向调节细胞生长而p47^ING1a过表达则对细胞生长无明显影响。p33^ING1b过量表达可以促进p21^WAF1表达，协同p53引起细胞周期阻滞从而抑制肿瘤细胞生长。ING1基因可能是通过乙酰化依赖通路的活性调节来改变基因的表达，参与多种过程的调控。ING1编码的蛋白通过组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）参与染色质的重塑，在DNA损伤修复方面发挥重要作用。ING1基因与脑瘤、肝癌和胃癌等多种肿瘤的发生发展有关。ING1基因的结构特点、生物学功能与肿瘤的发生发展密切相关。     

人类癌症中长链非编码RNA与miRNA相互作用的研究进展

人类基因组中大部分为非编码区,转录产生非编码RNA（ncRNA）。这些ncRNA可以在表观遗传学水平及转录后水平调控癌基因和抑癌基因的表达,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。微小RNA（miRNA） 和长链非编码RNA（lncRNA） 是ncRNA的两个重要分类。其中,lncRNA通过多种机制在不同水平进行基因表达调控,发挥其生物学功能,这些机制包括基因印迹、染色质重塑、细胞周期调控、选择性剪接、mRNA降解和翻译调控等。近年来,miRNA和lncRNA在癌症发生发展中相互作用的分子机制引起了人们的注意。本文主要就这两者在癌症发生发展过程中的相互作用机制及研究方法进行综述。     

FHIT基因与肿瘤

脆性组氨酸三联体(FHIT)基因是一种定位于人类染色体3p14.2上的抑癌基因,在多种器官中都有表达,其包含的脆性位点FRA3B,是基因组中最脆弱的部分.FHIT可促进细胞凋亡,抑制细胞增殖和细胞癌变.FHIT基因高度甲基化、基因缺失、FRA3B脆性位点的改变以及蛋白合成过程中的异常,可导致FHIT基因功能缺失,促进多种肿瘤的发生与发展.将野生型FHIT导入FHIT表达降低或表达缺失的肿瘤细胞中可促进肿瘤细胞凋亡.FHIT基因与其他基因联合治疗可能为肿瘤的治疗提供新的方向.     

肿瘤抑制基因ARHI的生物学功能及研究进展

肿瘤是一种基因病,抑癌基因在抵御肿瘤发生、发展中起着重要作用。ARHI(aplysia ras hom olog I)/NOEY2 是一个新发现的抑癌基因,是 ras/rap超家族成员之一,与 ras家族有50%~60%的同源性,位于人染色体1p31,属小GTP结合蛋白,是该家族第1个被报道的肿瘤抑制基因。ARHI基因编码的蛋白在人类多种组织表达,其中正常卵巢的ARHI表达最高。ARHI是一个印迹基因,印迹机制可能与其CpG岛的差异甲基化有关。ARHI 参与细胞周期调控可能作用于cyclin D1 ,使其不能与 CDK结合形成活性激酶,从而使细胞停止于 G1 期。AR HI可能通过依赖caspase和 calpain两条途径参与信号通路传导诱发细胞凋亡。该基因的异常表达跟多种肿瘤的发生、发展有关。ARHI基因参与了乳腺癌的发生和发展,该基因的表达缺失可能与乳腺癌的转移机制有关。卵巢癌、乳腺癌存在广泛的1p31缺失,其中 ARHI 基因是最常见的一个缺失区域。ARHI基因和蛋白在胰腺癌组织中有较高比例的缺失,提示该基因和蛋白在胰腺癌的发生中起一定作用。ARHI基因在膀胱癌、肝癌、前列腺癌等其他肿瘤中也有不同程度的表达异常。     

肿瘤抑制基因ARHI的生物学功能及研究进展

肿瘤是一种基因病，抑癌基因在抵御肿瘤发生、发展中起着重要作用。ARHI(aplysia ras homolog I)／NOEY2是一个新发现的抑癌基因．是ras/rap超家族成员之一．与ras家族有50％～60％的同源性．位于人染色体1p31，属小GTP结合蛋白，是该家族第1个被报道的肿瘤抑制基因。ARHI基因编码的蛋白在人类多种组织表达，其中正常卵巢的ARHI表达最高。ARHI是一个印迹基因．印迹机制可能与其CpG岛的差异甲基化有关。ARHI参与细胞周期调控可能作用于cyclin D1，使其不能与CDK结合形成活性激酶，从而使细胞停止于G1期。ARHI可能通过依赖caspase和calpain两条途径参与信号通路传导诱发细胞凋亡。该基因的异常表达跟多种肿瘤的发生、发展有关。ARHI基因参与了乳腺癌的发生和发展，该基因的表达缺失可能与乳腺癌的转移机制有关。卵巢癌、乳腺癌存在广泛的1p31缺失，其中ARHI基因是最常见的一个缺失区域。ARHI基因和蛋白在胰腺癌组织中有较高比例的缺失，提示该基因和蛋白在胰腺癌的发生中起一定作用。ARHI基因在膀胱癌、肝癌、前列腺癌等其他肿瘤中也有不同程度的表达异常。     

miR-485-5p在恶性肿瘤中的研究进展

MicroRNAs(miRNAs)是一类长度约22个核苷酸的非编码RNA,在基因表达调控中,参与多种重要的生理和病理过程。miRNAs能够特异性结合靶基因序列,抑制基因的转录或翻译,从而抑制基因在转录或转录后水平上的表达。miRNAs作为肿瘤抑制因子或促进因子在癌症发生发展中经常失调。最近的研究发现miR-485-5p在多种癌症中表达下调,并调控肿瘤细胞生长、增殖、侵袭和迁移。miR-485-5p在肿瘤诊断、治疗及预后相关方面可作为具有潜在价值的肿瘤标志物,并有望成为临床肿瘤靶向治疗的新的治疗靶点。本文围绕miR-485-5p在肝癌、胃癌、乳腺癌及其他恶性肿瘤中的研究进展展开综述并对其未来应用和发展进行展望。     

印迹基因H 19在宫颈癌中的表达及意义

宫颈癌又称宫颈浸润癌，其发病率居妇女肿瘤中第2位。近年来流行病学调查发现，宫颈癌发病年龄渐趋年轻化，且发病率有上升趋势。H19基因与以往发现的p53、Rb基因一样均为抑癌基因，是一种人类发育印迹基因。在许多肿瘤细胞株研究中发现，H19基因的缺失和突变率为65％，超过了p53基因50％的突变率。H19基因在肿瘤的发生、发展过程中扮演着非常重要的角色，是继p53基因之后在肿瘤分子生物学上又一重大发现。本研究应用限制性转录多态性酶切位点法（RFLP法）检测该基因在32例宫颈癌中的表达，以探讨其在宫颈癌发生、发展中的作用。     

CHD5, a new member of the chromodomain gene family,is preferentially expressed in the nervous system

Chromatin remodeling is one of the mechanisms by which gene expression is regulated developmentally. Chromatin structure is controlled at least in part by post-translational modification of histones, as well as by chromodomain proteins. We have identified a novel gene encoding a protein with chromatin remodeling, helicase and DNA-binding motifs. This gene, called CHD5, is the fifth member of the CHD gene family identified in humans. This gene is most homologous to CHD3 and CHD4, which encode proteins that are part of the nucleosome remodeling and histone deacetylation (NuRD) complex. CHD5 is preferentially expressed in total brain, fetal brain, and cerebellum. It is also moderately expressed in the adrenal gland, but expression is undetectable in almost all other tissues examined. CHD5 maps within a small region of deletion on 1p36.3 in human neuroblastomas, a common pediatric tumor. We examined a panel of neuroblastoma cell lines for CHD5 expression, which was consistently low or undetectable in all these lines. Expression was also examined in a panel of 137 primary neuroblastomas, and low expression was highly correlated with 1p deletion, MYCN amplification, advanced stage, and unfavorable histology. These findings suggest that this gene may play a role in the development of the nervous system, and it may also play a role in the pathogenesis of neural tumors.     

Rsf-1/HBXAP在常见消化系统肿瘤中的表达及意义

染色质重塑因子1（ remodeling and spacing factor-1,Rsf-1;又名Hepatitis B X-antigen associat-ed protein,HBXAP）,位于11q13.5,属于人类核心组蛋白及染色质组装相关因子家族一员,是一个促癌基因,研究发现其在乳腺癌、胃癌、大肠癌、肺癌、肝癌、卵巢癌等肿瘤组织中高表达,并且与患者预后有很大的关系。下调Rsf-1基因表达和相应抗癌药物的联合应用可能成为肿瘤治疗的新策略。肿瘤组织中Rsf-1高表达病例的临床预后效果比Rsf-1低表达的差。Rsf-1在早期消化系统肿瘤中的敏感性比其他肿瘤标志物高,是否能作为早期诊断消化系统肿瘤的最佳标志物,有待于进一步研究。     

Mutation and Methylation Analysis of the Chromodomain-Helicase-DNA Binding 5 Gene in Ovarian Cancer

Chromodomain, helicase, DNA binding 5 (CHD5) is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a diverse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer samples by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 samples with normal CHD5 and in 2 of 3 samples with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 samples as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04). The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer; however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36.     

Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness

Though prostate cancer is often indolent, it is nonetheless a leading cause of cancer death. Defining the underlying molecular genetic alterations may lead to new strategies for prevention or treatment. Towards this goal, we performed array-based comparative genomic hybridization (CGH) on 86 primary prostate tumors. Among the most frequent alterations not associated with a known cancer gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Expression of CHD1 was significantly reduced in tumors with deletion (P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4) and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2 and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers, and indicate a possible novel role of altered chromatin remodeling in prostate tumorigenesis.     

The 5p12 breast cancer susceptibility locus affects MRPS30 expression in estrogen‐receptor positive tumors

Genome‐wide association studies have identified numerous loci linked to breast cancer susceptibility, but the mechanism by which variations at these loci influence susceptibility is usually unknown. Some variants are only associated with particular clinical subtypes of breast cancer. Understanding how and why these variants influence subtype‐specific cancer risk contributes to our understanding of cancer etiology. We conducted a genome‐wide expression Quantitative Trait Locus (eQTL) study in a discovery set of 287 breast tumors and 97 normal mammary tissue samples and a replication set of 235 breast tumors. We found that the risk‐associated allele of rs7716600 in the 5p12 estrogen receptor‐positive (ER‐positive) susceptibility locus was associated with elevated expression of the nearby gene MRPS30 exclusively in ER‐positive tumors. We replicated this finding in 235 independent tumors. Further, we showed the rs7716600 risk genotype was associated with decreased MRPS30 promoter methylation exclusively in ER‐positive breast tumors. In vitro studies in MCF‐7 cells carrying the protective genotype showed that estrogen stimulation decreased MRPS30 promoter chromatin availability and mRNA levels. In contrast, in 600MPE cells carrying the risk genotype, estrogen increased MRPS30 expression and did not affect promoter availability. Our data suggest the 5p12 risk allele affects MRPS30 expression in estrogen‐responsive tumor cells after tumor initiation by a mechanism affecting chromatin availability. These studies emphasize that the genetic architecture of breast cancer is context‐specific, and integrated analysis of gene expression and chromatin remodeling in normal and tumor tissues will be required to explain the mechanisms of risk alleles.     

卵巢癌表遗传学研究进展

表遗传学的分子机制包括DNA甲基化、组蛋白修饰、染色质改型和RNA干涉等,它们在基因转录调控过程中起重要作用。DNA甲基化和组蛋白乙酰化是表遗传学调控基因表达的两种主要方式,DNA低甲基化和组蛋白乙酰化可促进基因表达,DNA高甲基化和组蛋白去乙酰化可抑制基因表达,DNA甲基化和组蛋白乙酰化相互影响。DNA甲基化在卵巢癌的发生、发展中起重要作用,若干肿瘤抑制基因启动子区异常甲基化与卵巢癌的形成密切相关,包括RASSF1A、BRCA1、p16、hMLH1和CDH1等。多个抑癌基因异常甲基化作为一种分子生物学指标可能用于卵巢癌临床诊断、肿瘤分型及预后判断,而且DNA甲基化异常可能用于卵巢癌化疗疗效判断。DNA去甲基化制剂及组蛋白脱乙酰基酶抑制剂可能用于卵巢癌的临床治疗。     

EMSY links breast cancer gene 2 to the 'Royal Family'

Although the role of the breast cancer gene 2 (BRCA2) tumor suppressor gene is well established in inherited breast and ovarian carcinomas, its involvement in sporadic disease is still uncertain. The recent identification of a novel BRCA2 binding protein, EMSY, as a putative oncogene implicates the BRCA2 pathway in sporadic tumors. Furthermore, EMSY's binding to members of the 'Royal Family' of chromatin remodeling proteins may lead to a better understanding of the physiological function of BRCA2 and its role in chromatin remodeling.     

Prognostic value and clinicopathologic correlation of p53 gene mutations and nuclear DNA content in human lung cancer: A prospective study

The aim of this prospective study was to determine whether use of a combination of biomarkers, p53 and nuclear DNA content, led to improved prognosis and Clinicopathologic correlation in human non-small cell lung cancer. Nineteen patients undergoing curative resection of primary non-small cell lung cancer were evaluated. Resected tumors were studied by polymerase chain reaction/single strand conformation polymorphism analysis (p53 gene mutations), flow cytometry (nuclear DNA content and cell cycle analysis), and immunohistochemically (p53 oncoprotein). Histologically normal lung was used as an internal control for each patient. Minimum postoperative follow-up was 4 years. p53 gene mutations (5/19 tumors; 26%), tumor ploidy (5/19 diploid), patterns of immunoreactivity, or combination of biomarkers did not appear to correlate with clinicopathologic findings or clinical outcome. Two of three patients with associated second primary malignancies, had squamous cell diploid tumors with p53 gene mutations. We conclude that p53 gene mutations and tumor ploidy may represent different biologic markers for human nonsmall cell lung cancer. Although trends in improved predictive accuracy were not seen when both markers were incorporated into the tumor analysis, flow cytometry and molecular analysis of the p53 gene may identify patients at increased risk of the development of a second primary maligmancy. © 1994 Wiley-Liss, Inc.     

Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.     

Highly penetrant,rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5

Recent data suggest the SWI/SNF chromatin remodeling complex may also act as a tumor suppressor. Utilizing a reversibly inactivating conditional allele, we demonstrate that loss of Snf5/Ini1/Baf47/SmarcB1, a core subunit of SWI/SNF, results in highly penetrant cancer predisposition with 100% of mice developing mature CD8(+) T cell lymphoma or rare rhabdoid tumors with a median onset of only 11 weeks. Notably, while loss of Snf5 predisposes to aggressive cancers, it is also required for survival of virtually all nonmalignant cells in vivo. Reversible gene targeting demonstrates a critical and specific role for Snf5 in tumor suppression, provides a novel system in which to explore the genetic pathways involved in tumor suppression by Swi/Snf, and should be of wide use in evaluating other essential tumor suppressor genes.