长链非编码RNA在肝细胞肝癌发病中的作用及其机制研究进展

肝细胞肝癌(HCC)是肝癌中最常见的病理类型,患者病死率高。对HCC发生发展机制的认知局限是其不良预后的重要原因。长链非编码RNA(LncRNA)是基因调控的重要组成部分,可通过表观遗传、转录调节和转录后调节等方式调控肝癌细胞的发生发展。近年来,LncRNA在肝癌发生发展中作用的研究逐渐深入,这为HCC早期诊断、病情控制和预后评估提供了新的方法和思路。本文就LncRNA在HCC中的研究进展作一综述。     

Maspin plays an essential role in early embryonic development

Maspin (Mp) is a member of the serpin family with inhibitory functions against cell migration, metastasis and angiogenesis. To identify its role in embryonic development in vivo, we generated maspin knockout mice by gene targeting. In this study, we showed that homozygous loss of maspin expression was lethal at the peri-implantation stage. Maspin was specifically expressed in the visceral endoderm after implantation; deletion of maspin interfered with the formation of the endodermal cell layer, thereby disrupting the morphogenesis of the epiblast. In vitro, the ICM of the Mp(-/-) blastocysts failed to grow out appropriately. Data from embryoid body formation studies indicated that the Mp(-/-) EBs had a disorganized, endodermal cell mass and lacked a basement membrane layer. We showed that the embryonic ectoderm lineage was lost in the Mp(-/-) EBs, compared with that of the Mp(+/+) EBs. Re-expression of maspin partially rescued the defects observed in the Mp(-/-) EBs, as evidenced by the appearance of ectoderm cells and a layer of endoderm cells surrounding the ectoderm. In addition, a maspin antibody specifically blocked normal EB formation, indicating that maspin controls the process through a cell surface event. Furthermore, we showed that maspin directly increased endodermal cell adhesion to laminin matrix but not to fibronectin. Mp(+/-) endodermal cells grew significantly slower than Mp(+/+) endodermal cells on laminin substrate. We conclude that deletion of maspin affects VE function by reducing cell proliferation and adhesion, thereby controlling early embryonic development.     

The chicken as a model for embryonic development

The traditional strength of chicken embryos for studying development is that they are readily manipulated. This has led to some major discoveries in developmental biology such as the demonstration that the neural crest gives rise to almost the entire peripheral nervous system and the identification of signalling centres that specify the pattern of structures in the central nervous system and limb. More recently with the burgeoning discovery of developmentally important genes, chicken embryos have provided useful models for testing function. Uncovering the molecular basis of development provides direct links with clinical genetics. In addition, since many genes that have crucial roles in development are also expressed in tumours, basic research on chickens has implications for understanding human health and disease. Now that the chicken genome has been sequenced and genomic resources for chicken are becoming increasingly available, this opens up opportunities for combining these new technologies with the manipulability of chicken embryos and also exploiting comparative genomics.     

长链非编码RNA在动脉粥样硬化中的作用

动脉粥样硬化是一种致病因素多样、病理机制复杂的心血管疾病。近年研究发现,长链非编码RNA在动脉粥样硬化的发生、发展过程中发挥重要的调控作用。通过调节脂代谢、糖尿病、肥胖等危险因素,参与血管内皮功能、血管新生、免疫炎症等病理机制,影响动脉粥样硬化的疾病进程。本文就长链非编码RNA在动脉粥样硬化中的研究现状,综述其对疾病危险因素及病理机制的调控作用。     

长链非编码RNA在血液系统肿瘤中作用的研究进展

随着分子生物学技术的飞速发展,人们对于长链非编码RNA(Long non-coding RNA,lncRNA)的研究越来越深入。lncRNA不仅在生物体正常生物活动中不可或缺,还在许多疾病尤其是肿瘤中扮演重要角色。已有的研究表明多种lncRNA与血液系统肿瘤密切相关,具有影响抑癌基因p15表达、p53蛋白功能,以及与miRNA相互作用参与疾病等功能。本文综述了血液系统肿瘤相关的lncRNA并着重介绍与p15、p53、miRNA有关的lncRNA以及它们的相互作用在疾病中发挥的功能,以期能够全面了解血液系统肿瘤相关lncRNA的作用特点,为血液系统肿瘤的研究、诊断以及治疗提供新的思路。     

长链非编码RNA在胃癌中的研究进展

长链非编码RNA(Long non-coding RNA,lncRNA)是一类长度大于200个核苷酸的转录本,其转录本没有或少有蛋白质编码功能,参与调控多种生物生理功能。lncRNA可在表观遗传学、转录及转录后等多层面调控基因表达,对个体生长发育及肿瘤发生、发展过程至关重要。近年来,有诸多的研究发现lncRNA参与胃癌的发生、发展及转移等多个过程,且与患者的预后相关。对lncRNA在胃癌增殖、凋亡、侵袭和转移中的调控作用进行了综述,以期为胃癌临床诊断与治疗提供新的思路。     

Structural architecture of the human long non-coding RNA, steroid receptor RNA activator

While functional roles of several long non-coding RNAs (lncRNAs) have been determined, the molecular mechanisms are not well understood. Here, we report the first experimentally derived secondary structure of a human lncRNA, the steroid receptor RNA activator (SRA), 0.87 kB in size. The SRA RNA is a non-coding RNA that coactivates several human sex hormone receptors and is strongly associated with breast cancer. Coding isoforms of SRA are also expressed to produce proteins, making the SRA gene a unique bifunctional system. Our experimental findings (SHAPE, in-line, DMS and RNase V1 probing) reveal that this lncRNA has a complex structural organization, consisting of four domains, with a variety of secondary structure elements. We examine the coevolution of the SRA gene at the RNA structure and protein structure levels using comparative sequence analysis across vertebrates. Rapid evolutionary stabilization of RNA structure, combined with frame-disrupting mutations in conserved regions, suggests that evolutionary pressure preserves the RNA structural core rather than its translational product. We perform similar experiments on alternatively spliced SRA isoforms to assess their structural features.     

The chicken RaxL gene plays a role in the initiation of photoreceptor differentiation

The paired type homeodomain gene, Rax, was previously identified as a key molecule in early eye formation in mice and humans. We report the expression patterns of two Rax family members from chicken, Rax and RaxL, and on the function of RaxL in photoreceptor development. Both Rax and RaxL are expressed in early retinal progenitor cells, with Rax being expressed at a significantly higher level than RaxL. At the time that photoreceptors begin to form, RaxL appears at a relatively high level in a subset of cells within the zone of proliferating progenitor cells. Subsequently, it is expressed in cells migrating to the photoreceptor layer, where it is highly expressed during the initial, but not late, stages of photoreceptor differentiation. To test the function of RaxL, a putative dominant-negative allele of RaxL comprising a fusion of the engrailed repressor domain and a region of RaxL (EnRaxLDeltaC) was introduced in vivo into the early chick eye using a retroviral vector. EnRaxLDeltaC, but not the dominant negative Rax (EnRaxDeltaC), caused a significant reduction in expression of early markers of photoreceptor cells. Examination of the transactivation activity of RaxL on a reporter construct bearing a canonical photoreceptor-specific enhancer element showed that RaxL exhibited significant activation activity, and that this activity was severely diminished in the presence of EnRaxLDeltaC. The effect on photoreceptor gene expression in vivo was specific in that other cell types were unaffected, as was general proliferation in the retina. The reduction in numbers of cells expressing photoreceptor markers was probably due to decreased survival of developing photoreceptor cells, as there was increased apoptosis among cells of the retina expressing dominant-negative RaxL. We propose that RaxL plays a role in the initiation of differentiation, and also possibly commitment, of photoreceptor cells in the chicken retina.     

The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen

Our previous studies in both mouse and human identified the Bapx1 homeobox gene, a member of the NK gene family, as one of the earliest markers for prechondrogenic cells that will subsequently undergo mesenchymal condensation, cartilage production and, finally, endochondral bone formation. In addition, Bapx1 is an early developmental marker for splanchnic mesoderm, consistent with a role in visceral mesoderm specification, a function performed by its homologue bagpipe, in Drosophila. The human homologue of Bapx1 has been identified and mapped to 4p16.1, a region containing loci for several skeletal diseases. Bapx1 null mice are affected by a perinatal lethal skeletal dysplasia and asplenia, with severe malformation or absence of specific bones of the vertebral column and cranial bones of mesodermal origin, with the most severely affected skeletal elements corresponding to ventral structures associated with the notochord. We provide evidence that the failure of the formation of skeletal elements in Bapx1 null embryos is a consequence of a failure of cartilage development, as demonstrated by downregulation of several molecular markers required for normal chondroblast differentiation (&agr; 1(II) collagen, Fgfr3, Osf2, Indian hedgehog, Sox9), as well as a chondrocyte-specific alpha1 (II) collagen-lacZ transgene. The cartilage defects are correlated with failed differentiation of the sclerotome at the time when these cells are normally initiating chondrogenesis. Loss of Bapx1 is accompanied by an increase in apoptotic cell death in affected tissues, although cell cycling rates are unaltered.