恶性肿瘤中MNX1反义RNA 1的作用及机制研究进展

正长链非编码RNA (long non-coding RNA,lncRNA)是一类广泛存在于细胞核和细胞质内、长度在200 nt以上、缺少开放阅读框、不参与或很少参与蛋白质编码、主要从蛋白编码基因的反义链及间隔区转录出来的RNA~([1-6])。已有大量研究证实,lnc RNA涉及调控多种生物学功能,比如细胞增殖、凋亡及血管生成~([7-9])。表达异常的lnc RNA与诸多肿瘤的发生发展密切相关~([10-11])。     

长链非编码RNA MEG3 调控作用相关的信号通路研究进展

正随着基因组学的不断发展,越来越多的研究表明lncRNA表达水平的改变与疾病的发展和状态有明显的联系,尤其在肿瘤中发挥举足轻重的作用~([1])。LncRNA是长度大于200个核苷酸的转录RNA,保守性低,在体内通过控制蛋白质的合成、RNA的成熟和转运以及改变染色体结构从而使转录基因沉默等机制发挥调控作用~([2])。MEG3是一类重要的lncRNA,具有肿瘤抑制作用~([3]),有望成为肿瘤诊断的生物标志物和肿瘤治疗的靶点,以下就MEG3在肿瘤及多种相关疾病关系密切的信号通路的作用及其机制作一综述。     

长链非编码RNA在急性髓系白血病中调控机制的研究进展

<正>长链非编码RNA(long non-coding RNA,lncRNA)是指长度大于200个核苷酸的非编码RNA,起初它被认为是基因组转录的"噪音",即RNA聚合酶Ⅱ转录的副产物,并不具有生物学功能~([1-2])。但随着研究的深入,人们发现lncRNA参与了X染色体沉默、表观遗传调控、转录激活与干扰、细胞分化调节等多个关键的调控过程~([3-5])。研究表明,lncRNA的异常,包括     

长链非编码RNA在神经发生中的调控作用

<正>基因组计划的研究成果表明,哺乳动物基因组中仅仅只有不到1%的序列能够转录为mRNA,剩下大部分基因组序列转录为之前被称为"转录噪音"的非编码RNA(noncoding RNA,ncRNA)~([1])。而lncRNA是ncRNA家族中最大的一类~([2])。近几年来,随着二代测序技术的广泛应用,lncRNA的神秘面纱才逐渐被揭开。许多研究表明,lncRNA虽然不编码蛋白质,但它有多种功能,包括招募转录因子来调控基因     

牛磺酸上调基因1对肿瘤发生发展的调控作用

<正>基因的失调控(异常表达)是肿瘤发生发展的重要原因(诱因)业已被学术界所公认,而在这一过程中非编码RNA(non-coding RNA,ncRNA)起到了极为重要的调控作用~([1-2])。小RNA(small RNA;包括微小RNA,microRNA,miRNA,miR)和长链非编码RNA(long non-coding RNA,lncRNA)均属于ncRNA~([3-4])。     

长链非编码RNA对神经干细胞的调控作用及其机制

正长链非编码RNA(LncRNA)作为一种重要的细胞功能调控因子引起越来越多广泛的关注。它是一种长度在200-100000 nt之间的RNA分子,位于细胞核或细胞质内,不编码蛋白质。在基因组转录产物中,lncRNA所占数量比例远远超过编码RNA的比例,与DNA、RNA、蛋白质相互作用参与细胞内多种调控过程,在生命活动调控网络中有极其重要的作用。lncRNA目前是遗传学研究的热点之一。近年来许多研究表明,lncRNA在神经干细胞的自我更新、增殖和分化中     

长链非编码RNA与运动障碍疾病

长链非编码RNA(Long non-coding RNA,lncRNA)是一类长度超过200个核苷酸的不具有蛋白质编码功能的RNA,研究发现它们参与调控神经元的发育与再生,在中枢退行性疾病中差异表达。LncRNA通过影响附近蛋白质基因的编码调控其生物学功能,而运动障碍疾病与中枢基底神经节神经元内蛋白质基因的异样表达有关,本文综述近期有关lncRNA及其相关蛋白质基因在运动障碍疾病发病机制中的研究进展。     

长链非编码RNA通过ceRNA在乳腺癌中的调控机制

长链非编码RNA(long non-coding RNA,lncRNA)是一种长度大于200 nt的不具有编码蛋白质功能的RNA。lncRNA在多种肿瘤中存在差异性表达,通过转录调控、转录后调控等方式影响肿瘤的增殖、侵袭、转移、耐药等。多项研究表明,lncRNA可通过竞争性内源性RNA(competing endogenous RNA,ceRNA)机制与miRNA相互作用,并影响其它RNA、蛋白的表达,影响疾病进程;提示lncRNA可能是一种肿瘤标志物和潜在的治疗靶点。该文现就lncRNA通过ceRNA调控乳腺癌的研究进展进行综述。     

长链非编码RNA调控肿瘤细胞凋亡的研究进展

长链非编码RNA(long non-coding RNA,lncRNA)是一类长度>200个核苷酸、通常不编码蛋白质的RNA。近年研究表明,lncRNA在肿瘤的的发展过程中发挥抑癌或促癌作用,参与细胞增殖、凋亡等过程。本综述简要介绍lncRNA的生物学功能及其调控细胞凋亡的研究进展。     

长链非编码RNA OIP5-AS1在肿瘤中的研究进展

长链非编码RNA(long non-coding RNA,lncRNA)与肿瘤的发生发展密切相关.LncRNA反义Opa反应蛋白5RNA(Opa interacting protein 5-antisense RNA 1,OIP5-AS1)在多种肿瘤中不仅异常表达,还发挥癌基因的作用,是潜在的肿瘤治疗靶点,并有望成为肿...     

LncRNA TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis

Background

Long noncoding RNAs (lncRNAs) have been considered as significant regulators in many cancer progression, such as proliferation, invasion and other path of evolution. Nevertheless, we have not had a grasp of the role of lncRNA TP73-AS1 in gastric cancer (GC).

Regulating p73 isoforms in human tumours

Although mutations in the TP73 gene are extremely rare in human tumours, altered expression is common. In some tumours, most notably leukaemias and lymphomas, expression of TP73 is reduced, suggesting a tumour suppressor role. In contrast, TP73 is over-expressed in many other tumour types, implying that it has oncogenic functions in human tumourigenesis. These conflicting scenarios can be reconciled by the observations that the TP73 gene produces p53-like isoforms (TAp73) and anti-p53 isoforms (DeltaTAp73). Thus, loss of TAp73 or over-expression of DeltaTAp73 should each promote oncogenic transformation, and the balance of expression of the opposing isoforms is the crucial factor. The mechanisms that regulate expression of TP73 isoforms are therefore of great interest. Recent data provide evidence for interacting roles of ZEB1, p300, and a polymorphic 73 bp deletion in intron 1 of the human TP73 gene in this process. Importantly, alterations to the proposed regulatory pathway for controlling TP73 isoform expression in colorectal cancer are associated with adverse clinico-pathological characteristics. Because p73 is also associated with tumour chemosensitivity, these new findings should provide prognostic information and have the potential to guide future therapeutic decisions.     

Intronic deletion affecting a negative regulatory region of TP73 is related to breast and colorectal carcinomas

The TP73 gene encodes a nuclear protein that has high homology with TP53. TP73 is rarely mutated in human cancer. The presence of a 1-kb regulatory fragment within the first intron of TP73 was recently reported. This fragment exerts silencer activity on TP73 mediated by ZEB. We searched for possible mutations in this negative regulatory region in 45 colorectal and 43 breast cancer patients and in 34 healthy donors. The study was carried out using the SSCP method, and the allelic variants detected were sequenced. The expression of TP73 was analyzed by quantitative RT-PCR, and loss of heterozygosity (LOH) was assessed by microsatellite study. In several samples, we identified an allele variant that corresponds to a deletion of 73 bp in tumor tissues and normal counterparts, localized between -489 and -417 from the ATG start site of exon 2. Among the 88 tumor samples, 35 (40%) showed at least 1 allele with the cited deletion, versus 7 of the 34 (21%) healthy donors (P = 0.045). When we classified the patients according to the number of variations into homozygous or heterozygous groups, the significance was clearer (P = 0.03). No LOH was detected in the heterozygous cases. There was a positive quantitative correlation between the expression of TP73 and the presence of the allelic variant (P = 0.029). These data suggest that this allelic variant is common in breast and colorectal cancers and that it could alter the expression of the TP73 gene with an additive effect.     

Expression of long non-coding RNA ZEB1-AS1 in esophageal squamous cell carcinoma and its correlation with tumor progression and patient survival

Background: LncRNA ZEB1-AS1 has been identified as a tumor oncogene in hepatocellular carcinoma. However, the clinical significance in esophageal squamous cell carcinoma (ESCC) is still unknown. The aim of this study was to explore ZEB1-AS1 expression levels and evaluated its clinical significance in ESCC patients. Methods: LNCRNA ZEB1-AS1 expression was determined by quantitative real-time PCR (QRT-PCR) in 87 pairs of ESCC specimens and adjacent non-tumor tissues. Then, the association of ZEB1-AS1 expression with clinicopathological factors or survival of ESCC patients were determined. Results: LNCRNA ZEB1-AS1 was found up-regulated in ESCC tissues compared to adjacent non-tumor tissues. Increased lncRNA ZEB1-AS1 expression was significantly associated with tumor grade, depth of invasion, and lymph node metastasis. Kaplan-Meier analysis revealed that ESCC patients with high ZEB1-AS1 expression had a poorer overall survival and disease-free survival. Furthermore, multivariate analysis suggested that ZEB1-AS1 expression was identified as an independent prognostic factor in patients with ESCC. Conclusion: These results indicated that lncRNA ZEB1-AS1 was associated with tumor progression and could be an independent prognostic factor for ESCC patients.     

Methylation status of TP73 in meningiomas

Deletions at 1p are frequent in meningioma and represent a genetic marker associated with the genesis of atypical WHO grade II forms. Previous mutational analysis of TP73, a structurally and functionally TP53 homologous gene located at 1p36.33, failed to demonstrate a significant rate of sequence variations linked to gene inactivation in meningiomas with 1p loss. As an alternative, TP73 may be inactivated through aberrant 5' CpG island methylation, a primary mechanism participating in the inactivation of tumor suppressor genes during tumorigenesis. We determined the methylation status of the TP73 gene in a series of 60 meningiomas (33 grade I, 24 grade II, and 3 grade III samples), including tumors with deletion at 1p (n=30) and with intact 1p (n=30). Aberrant methylation was detected in 10 cases (33%) with 1p deletion and in 3 tumors (10%) with retention of alleles at this chromosome arm. The distribution of the 13 cases of methylation according to malignancy grade was 7 grade I, 5 grade II, and 1 grade III tumor. Accordingly, although TP73 aberrant methylation was more frequent in meningiomas with 1p deletion (P<0.05), no association with the grade of malignancy could be established. These findings, together with the previously reported increased TP73 expression in malignant meningiomas suggest that opposing functions of this gene may characterize distinct subsets of tumors: suppressed or reduced expression as a result of CpG methylation in some grade I-grade II tumors, and enhanced expression in some more malignant forms.     

TP53 family members and human cancers

Based on gene sequence homologies, a p53 (TP53) gene family become apparent with the addition of the most recently identified p63 (TP73L; formerly TP63) and p73 (TP73) genes to the already known p53. The p53 gene encodes for a unique protein eliciting well-known tumor suppressor gene (TSG) properties that mediate cellular response to DNA damage, e.g., cell cycle arrest or apoptosis. In contrast, both homologues specify an array of isoforms different in their N- and C-terminal domains. Transactivating isoforms, such as TAp63/p73, show TSG properties similar to p53, while isoforms lacking N-terminal transactivating domain such as DeltaNp63/p73, induce a functional block against p53 as well as TAp63/p73 activities. Both p63/p73 types of isoforms are involved in development: p63 is critical for epithelial stem cell renewal and epithelial homeostasis, and p73 is involved in neurogenesis and natural immune response. These facts support interdependent functions for the p53 family members, which appear linked together in a complex and tight regulation network to fulfill cellular functions related to DNA damage and tissue homeostasis maintenance. The lack of p63/p73 mutations in human cancers rule out a typical TSG role for either of the p53 homologues. Nonetheless, p63 and p73 genes seem strongly involved in malignancy acquisition and maintenance process because of: 1) their tissue identities, and 2) their close interplay activities within the p53 family members, and primarily through the negative regulatory role played by DeltaNp63/p73 isoforms for cell death control and differentiation.     

Frequent allelic imbalance suggests involvement of a tumor suppressor gene at 1p36 in the pathogenesis of human lung cancers

The short arm of chromosome 1 is among the most frequently affected regions in various types of common adult cancers as well as in neuroblastoma. In a previous study of ours, frequent allelic imbalance at the TP73 locus at 1p36 was noted in lung cancer despite the absence of TP73 mutations. This suggested the possible existence of an as yet unidentified tumor suppressor gene on 1p. Our initial attempt using the candidate gene approach did not yield any somatic mutations in the 14-3-3sigma gene (official gene symbol, SFN), a mediator of G2 arrest by TP53. Detailed deletion mapping of the telomeric region of 1p was thus carried out as an initial step toward positional cloning. We used seven polymorphic markers in addition to TP73 to examine 61 primary lung cancers. Allelic imbalance at one or more loci of 1p36 was observed in 30 of the 61 cases, whereas D1S508 at 1p36.2 exhibited the highest frequency (45%) of allelic imbalance among the 1p36 markers examined. In contrast, two proximal markers at 1p32-34 showed significantly less frequent (11-14%) allelic imbalance. Consequently, the present study identified the shortest region of overlap between D1S507 and TP73, which included the most frequently affected marker, D1S508. In addition, several cases exhibited allelic imbalance confined to a subtelomeric region distal to D1S2845 at 1p36.3. The present findings warrant future studies to identify the putative tumor suppressor gene(s) at 1p36 to gain a better understanding of the molecular pathogenesis of lung cancer. Genes Chromosomes Cancer 28:342-346, 2000.     

Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of nonastrocytic tumors, we analyzed promoter methylation status of 10 tumor-associated genes in a series of 41 oligodendrogliomas (22 World Health Organization [WHO] grade II; 13 WHO grade III; 6 WHO grade II-III oligoastrocytomas) and 7 WHO grade II-III ependymomas, as well as 2 nonneoplastic brain samples, by a methylation-specific polymerase chain reaction. Aberrant CpG island methylation was detected in 9 of 10 genes analyzed, and all but one sample displayed anomalies in at least one gene. The frequencies of hypermethylation for the 10 genes were as follows, in oligodendrogliomas and ependymomas, respectively: 80% and 28% for MGMT; 70% and 28% for GSTP1; 66% and 57% for DAPK; 44% and 28% for TP14(ARF); 39% and 0% for THBS1; 24% and 28% for TIMP3; 24% and 14% for TP73; 22% and 0% for TP16(INK4A); 3% and 14% for RB1; and 0% in both neoplasms for TP53. No methylation of these genes was detected in normal brain tissue samples. We conclude that a high frequency of aberrant methylation of the 5' CpG island of the MGMT, GSTP1, TP14(ARF), THBS1, TIMP3, and TP73 genes is observed in nonastrocytic neoplasms. This aberration seems to occur early in the carcinogenesis process (it is already present in the low-grade forms), although in some instances (DAPK, THBS1, and TP73) it appears also associated with the genesis of anaplastic forms.