人类肿瘤中17号染色体杂合性缺失的研究进展

染色体变化直接导致基因发生改变,使细胞生长失控,恶性增殖,最终形成肿瘤。17号染色体LOH是肿瘤最常见的染色体变化,了解其与肿瘤发生发展关系有助于阐明肿瘤发生的分子机制。     

人类肿瘤中17号染色体杂合性缺失的研究进展

染色体变化直接导致基因发生改变，使细胞生长失控，恶性增殖，最终形成肿瘤。17号染色体LOH是肿瘤最常见的染色体变化，了解其与肿瘤发生发展关系有助于阐明肿瘤发生的分子机制。     

脑肿瘤患者外周血淋巴细胞染色体不稳定性的研究

研究脑实体肿瘤染色体改变是探索神经系统肿瘤发病机制的一种重要方法,目前已取得了重大进展。关于脑肿瘤患者外周血淋巴细胞染色体改变则研究不多,且结果颇不一致。我们以未经放疗或化疗的脑肿瘤患者为研究对象,测定其染色体畸变率和微核率,试图了解染色体不稳定性与肿瘤发生的关系及其临床意义。     

染色体重排断裂点、脆性部位、癌基因与肿瘤发生

近年来,国内外关于肿瘤染色体重排、脆性部位及原癌基因的研究发展迅速,文献浩瀚。本文综合这几个方面的研究进展,对染色体重排、脆性部位与原癌基因激活及肿瘤发生的关系作一阐述。肿瘤细胞遗传学研究和分子遗传学研究的结合为肿瘤遗传基础的研究辰示了令人鼓舞的前景,使肿瘤细胞遗传学研究摆脱了徘徊不前的困境,提高到深入研究肿瘤染色体重排与原癌基因激活的关系这一新的高度,促进了对肿瘤发生机理的研究。     

肿瘤炎性微环境与树突状细胞研究进展

肿瘤免疫是近年来的研究热点,已知肿瘤微环境尤其是炎性微环境在促进肿瘤发生、发展过程中起重要作用。肿瘤浸润的树突状细胞（DC）多存在表型未成熟化、分布异常及功能障碍等现象,这可能是肿瘤诱导机体免疫耐受的重要机制之一。肿瘤炎性微环境可通过多种途径调节DC的分化和成熟,相关信号通路和分子机制正逐步得到阐明,此将为DC疫苗的研制和肿瘤免疫治疗提供新的希望。     

染色体乘客复合体在肿瘤中的研究进展

染色体乘客复合体（CPC）是近年来研究发现的一组十分重要的调控细胞分裂的高度保守复合物之一。CPC主要由酶蛋白Aurora B激酶、着丝粒中心蛋白INCENP、Survivin 和Borealin/Dasra B等蛋白分子组成,经研究发现是一种与肿瘤发生发展联系密切的调控因子。本文综述了染色体乘客复合体相关的研究进展,阐述了Aurora B、INCENP、Survivin 和Borealin/Dasra B蛋白分别在不同肿瘤中的表达情况和作用机制,为肿瘤寻找新的治疗方法提供一定的理论依据。     

3号染色体短臂上的等位基因丢失是肾细胞癌透明细胞型的特征

染色体某些部位上基因的丢失与许多人和动物肿瘤的发生有关,肿瘤抑制基因的潜在作用已成为人类肿瘤发生和演化研究的热门主题。对于人的肾细胞癌(RCC)来讲,以前的细胞遗传学研究表明,染色体3p的重排不仅发生在遗传型RCC,而且也发生在散发型RCC。近来,RFLP分析在分子水平上为RCC染色体3p重要位点的丢失又提供了证据。最近,有人采用染色体移位方法证明正     

端粒、端粒酶和肿瘤发生的关系

端粒是真核生物染色体的天然末端 ,它对染色体的稳定起重要作用。其长度缩短或丢失可导致细胞死亡或恶变。端粒酶是一种特殊的核糖核蛋白逆转录酶 ,它的活性可以自身 RNA为模板合成端粒 DNA加到染色体末端 ,以维持端粒长度 ,使细胞永生。端粒及端粒酶与肿瘤发生的关系成为近年来的研究热点。端粒酶可望成为肿瘤治疗领域的新的靶分子。本文就这一领域里的新进展作一综述     

共济失调毛细血管扩张症高肿瘤发生率分子机制的研究进展

共济失调毛细血管扩张症(ataxia-telangiectasia,AT)是一种常染色体隐性遗传病,其主要表现为易患癌症、基因组不稳定性、辐射敏感性、渐进性小脑退变及免疫缺陷等。本文主要综述ATM(ATmutated)在染色体不稳定性、辐射敏感性、细胞周期调控及凋亡中的作用机制,从而对AT病人的肿瘤高发生率分子机制进行探讨。     

脆性组氨酸三联体(FHIT)基因

人类第3号染色体上的基因座在不同的肿瘤组织中出现高频率的杂合性丢失(LOH),提示该部位可能是抑癌基因潜伏的位点。最近克隆的脆性组氨酸三联体基因(fragile histidine triad,FHIT)可能是定位于染色体3p14.2的一个抑癌基因,该基因在肿瘤组织中广泛地缺失为研究肿瘤发生机制提供了新线索。     

CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction

Chromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitization to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitization might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT-specific multidrug sensitization is associated with enhanced autophagosome-lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2(+) breast cancer cell lines. Live cell microscopy analysis revealed that CERT depletion induces LAMP2-dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over-expressed in HER2(+) breast cancer and CERT protein expression acts as an independent prognostic variable and predictor of outcome in adjuvant chemotherapy-treated patients with primary breast cancer. These data suggest that the induction of LAMP2-dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following paclitaxel exposure to limit the acquisition of CIN and intra-tumour heterogeneity.     

Chromosomes and cancer cells

Two prominent features of cancer cells are abnormal numbers of chromosomes (aneuploidy) and large-scale structural rearrangements of chromosomes. These chromosome aberrations are caused by genomic instabilities inherent to most cancers. Aneuploidy arises through chromosomal instability (CIN) by the persistent loss and gain of whole chromosomes. Chromosomal rearrangements occur through chromosome structure instability (CSI) as a consequence of improper repair of DNA damage. The mechanisms that cause CIN and CSI differ, but the phenotypic consequences of aneuploidy and chromosomal rearrangements may overlap considerably. Both CIN and CSI are associated with advanced stage tumors with increased invasiveness and resistance to chemotherapy, indicating that targeted inhibition of these instabilities might slow tumor growth. Here, we review recent efforts that define the mechanisms and consequences of CIN and CSI.     

53BP1在宫颈鳞状细胞癌及其癌前病变中的表达

目的探讨53BP1在宫颈鳞状细胞癌及其癌前病变中的表达,阐明53BP1在宫颈鳞状细胞癌发生中的作用。方法应用免疫组化EnVision法检测10例正常宫颈组织、20例宫颈鳞状上皮内瘤变1级(cervical intraepithelial neoplasm 1,CIN1)、20例CIN2、20例CIN3和20例宫颈鳞状细胞癌中53BP1的表达。结果正常宫颈组织中仅有2例53BP1呈局灶性表达,阳性率为20%,而53BP1蛋白在CIN1～3和宫颈癌组织中阳性率均为100%,差异有统计学意义(P<0.01)。53BP1在正常宫颈组织和CIN1中弥漫阳性率均为0,而在CIN2、CIN3和宫颈癌组织中弥漫阳性率分别为55%、70%和100%,53BP1在CIN2、CIN3和宫颈癌组织中的弥漫阳性表达明显高于正常宫颈组织和CIN1(P<0.01)。53BP1蛋白弥漫阳性表达在CIN2与CIN3之间差异无显著性(P=0.327)。宫颈癌中53BP1蛋白弥漫阳性表达明显高于CIN3和CIN2,差异有统计学意义(P=0.020;P=0.001)。结论 53BP1表达水平可作为基因组不稳定性的标记物,基因组不稳定性在宫颈癌发生过程中可能是一早期事件。     

Persistent increase in chromosome instability in lung cancer: possible indirect involvement of p53 inactivation

Karyotype and fluorescence in situ hybridization analyses have demonstrated the frequent presence of an altered static state of the number of chromosomes (ie, aneuploidy) in lung cancer, but it has not been directly established whether aneuploidy is in fact associated with a persistent increase in the rate of chromosomal losses and gains (ie, chromosome instability, or CIN). The study presented here used a panel of 10 lung cancer cell lines to provide for the first time direct evidence that CIN is a common feature in lung cancer cell lines in association with the presence of significant aneuploidy. In addition, we found that the CIN phenotype correlates well with the presence of p53 mutations. However, human papilloma virus 16-E6-directed inactivation of p53 in a representative non-CIN lung cancer cell line did not result in the induction of CIN, at least up to the 25th generation, suggesting that inactivation of p53 itself is unlikely to directly induce CIN in lung cancer cells. Interestingly, however, significant CIN could be induced in conjunction with the generation of aneuploid populations when the mitotic spindle formation was transiently abrogated in p53-inactivated cells. These results suggest that inactivation of p53 may allow lung cancer cells to go through an inappropriate second division cycle under certain forms of mitotic stresses, which would result in the induction of the CIN phenotype in conjunction with the generation of aneuploidy.     

Cyclin E and chromosome instability in colorectal cancer cell lines.

Aims/Background: The development of colorectal cancer depends on at least two distinct pathways involving genetic instability, namely: chromosome instability (CIN) and microsatellite instability. Cyclin E is involved in aneuploidy and several cancer types show an abnormal number of chromosomes. METHODS: Cyclin E protein and mRNA values were analysed in human fetal skin fibroblasts and five colorectal cancer cell lines. RESULTS: Cells with an aberrant number of chromosomes had higher cyclin E mRNA values and a significant increase in protein concentrations. CONCLUSIONS: These data suggest that cyclin E regulation is altered in aneuploid cells and is an important factor in the CIN pathway.     

KIF11 silencing and inhibition induces chromosome instability that may contribute to cancer

Understanding the aberrant pathways that contribute to oncogenesis and identifying the altered genes involved in these pathways is a critical first step to develop effective strategies to better combat cancer. Chromosome instability (CIN) is an aberrant phenotype that occurs in ～80% of all cancer types and is associated with aggressive tumors, the acquisition of multidrug resistance and poor patient prognosis. Despite these associations however, the aberrant genes and molecular defects underlying CIN remain poorly understood. KIF11 is an evolutionarily conserved microtubule motor protein that functions in centrosome and chromosome dynamics in mitosis. Interestingly, the yeast ortholog of KIF11, namely CIN8 is a CIN gene and thus aberrant KIF11 expression and function is suspected to underlie CIN. In support of this possibility, KIF11 is somatically altered in a large number of cancer types. Using a complementary biochemical and genetic approach we examined whether KIF11 silencing with siRNAs or inhibition with monastrol was able to convert two distinct and karyotypically stable cell lines into karyotypically unstable cell lines. Indeed, quantitative imaging microscopy and flow cytometry revealed that KIF11 silencing induced increases in nuclear areas, micronucleus formation, DNA content and chromosome numbers relative to controls that was also observed following KIF11 inhibition. Collectively, this study identifies and validates KIF11 as an evolutionarily conserved CIN gene, and further suggests that aberrant expression and function may contribute to the pathogenesis of a subset of cancers.     

Distinct telomere length regulation in premalignant cervical and endometrial lesions: implications for the roles of telomeres in uterine carcinogenesis

Mouse models show that progressive shortening of telomeres with ageing causes chromosomal instability, which can lead to the initiation of cancer. However, it is unclear what roles telomere shortening plays in human carcinogenesis. The present study has investigated the involvement of telomere dynamics in uterine carcinogenesis. Using telomere-FISH (telo-FISH) assays, telomere lengths in premalignant and malignant cervical and endometrial lesions were measured and compared with chromosomal arm loss or gain. Telo-FISH signals were visualized with Cy3-labelled telomere-specific probes and presented as telomere intensity (TI). Early-stage cervical intraepithelial neoplasias (CINs), especially CIN2, had significantly shorter telomeres than corresponding normal squamous epithelia (p = 0.019), together with increased rates of chromosomal arm loss/gain (p < 0.001). Cervical cancers had relatively short telomeres, but they also showed greater heterogeneity than other sampled tissues, including those with long telomeres. In contrast, there was no significant difference between the telomere length of normal endometrium and of endometrial hyperplasia and endometrial cancer. There was no significant difference in the rate of chromosomal arm loss/gain between normal endometrium and endometrial hyperplasia. These findings suggest that progressive shortening of telomeres occurs in CIN, in association with chromosomal instability, which may play critical roles in cervical carcinogenesis. In contrast, endometrial hyperplasias have relatively stable telomeres without widespread chromosome alteration, implying that endometrial carcinogenesis involves mechanisms distinct from those of cervical carcinogenesis, possibly including microsatellite instability.     

DNA amplification and chromosomal translocations are accompanied by chromosomal instability: analysis of seven human colon cancer cell lines by comparative genomic hybridization and spectral karyotyping

Genetic instability in human cancers is classified as chromosomal instability (CIN) or microsatellite instability (MIN). DNA amplification and translocations are observed frequently in various cancers. We used comparative genomic hybridization (CGH) and spectral karyotyping (SKY) to study seven human colon cancer cell lines and investigate the relations among genetic instability, DNA amplification, and chromosomal translocations. DNA amplification was found in five cell lines (COLO320DM, COLO201, WiDr, CoCM-1, and CACO-2), and all were aneuploid. In these five cell lines, segments of chromosomes were translocated to other chromosomes. In contrast, cell lines with MIN, DLD-1, and LoVo did not show DNA amplification. The LoVo cells with MIN were considered near diploid and contained translocations. These findings suggest that DNA amplification and chromosomal translocations are accompanied by CIN.     

High frequency of copy-neutral LOH in MUTYH-associated polyposis carcinomas

Genetic instability is known to drive colorectal carcinogenesis. Generally, a distinction is made between two types of genetic instability: chromosomal instability (CIN) and microsatellite instability (MIN or MSI). Most CIN tumours are aneuploid, whereas MSI tumours are considered near-diploid. However, for MUTYH-associated polyposis (MAP) the genetic instability involved in the carcinogenesis remains unclear, as near-diploid adenomas, aneuploid adenomas and near-diploid carcinomas have been reported. Remarkably, our analysis of 26 MAP carcinomas, using SNP arrays and flow sorting, showed that these tumours are often near-diploid (52%) and mainly contain chromosomal regions of copy-neutral loss of heterozygosity (LOH) (71%). This is in contrast to sporadic colon cancer, where physical loss is the main characteristic. The percentage of chromosomal gains (24%) is comparable to sporadic colorectal cancers with CIN. Furthermore, we verified our scoring of copy-neutral LOH versus physical loss in MAP carcinomas by two methods: fluorescence in situ hybridization, and LOH analysis using polymorphic markers on carcinoma fractions purified by flow sorting. The results presented in this study suggest that copy-neutral LOH is an important mechanism in the tumorigenesis of MAP.     

Chromosomal aberrations and microsatellite instability of malignant peripheral nerve sheath tumors: a study of 10 tumors from nine patients

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon soft tissue neoplasm with a poor prognosis, occurring sporadically or associated with neurofibromatosis type 1 (NF1); however, the histogenesis of MPNST remains unclear, especially in sporadic tumors. There are two major forms of genomic instability in human cancer: chromosomal instability (CIN) and microsatellite instability (MSI). An inverse relationship has recently been demonstrated between CIN and MSI in colorectal cancers. CIN and MSI are suggested to be individual pathways, which are involved in the pathogenesis and which may lead to specific clinical and pathological characteristics. To elucidate the chromosomal aberration as a consequence of CIN and MSI status of MPNST, we karyotyped 10 MPNSTs from nine patients, and examined the MSI of seven microsatellite markers using high-resolution fluorescence microsatellite analysis; 2 out of 10 cases (20%) had normal karyotypes, and 8 out of 10 cases (80%) revealed structural and numerical chromosomal aberrations. Three of the 10 cases (30%) showed near triploidy. The most frequent aberration was -22 (40%), followed by +2, +14, -13, -17, and -18 (30% each). An MSI-low status was observed in 30% of cases; the remaining cases showed microsatellite stability. These findings suggest that chromosomal aberration as a consequence of CIN has a greater role in the pathogenesis of MPNST than does that due to MSI.