植物花粉发育miRNAs研究进展

作为一类内源性的负调控因子,植物miRNAs通过沉默靶基因或者翻译抑制来调控基因的表达。到目前为止,用高通量测序技术、miRNA微阵列技术以及实时荧光定量PCR等方法已经鉴定出许多与植物花粉发育有关的miRNAs。越来越多的证据表明,这些miRNAs选择性地存在于花粉发育的各个时期并发挥着特异的调控功能。该文对近年来花粉发育中与miRNAs相关的研究作一综述,介绍了与之相关的研究方法及参与调控花粉发育过程的miRNAs,为深入探索miRNAs调控植物花粉发育的分子机制、通过人工miRNAs技术构建作物雄性不育系以及推动杂种优势的利用提供研究策略。     

MicroRNA与胚胎神经发育

胚胎神经发育过程中,众多基因时空性表达及其表达产物相互作用形成精确的调控,其中某些基因表达质或量的改变会引起胚胎发育异常,导致先天畸形的发生.这一精确的基因表达调控过程是在转录及转录后等不同水平进行的.MicroRNAs(miRNAs),是这个基因调控大家族中新的成员.目前研究表明miRNAs在神经干细胞的不同发育阶段和哺乳动物脑发育过程中有不同的表达模式,这表明miRNAs可能在胚胎神经发育过程中起作用.本文就miRNAs在胚胎神经发育过程中的表达及功能作一综述.     

MicroRNA与肿瘤及其耐药性的研究进展

MicroRNAs(miRNAs)是一类非编码的内源性小RNA分子,能影响mRNA的稳定性和/或翻译,在细胞增殖、分化、凋亡、基因调控及疾病的发生,尤其是肿瘤中扮演着重要的角色.miRNAs可广泛参与肿瘤的发生和发展,具有与原癌基因或肿瘤抑制基因相似的作用.新近的研究表明,miRNAs可能与肿瘤的多药耐药关系密切.本文从miRNAs的生物学特性、生理功能、作用机制、与肿瘤及多药耐药的关系等研究进展予以综述.     

MicroRNAs在心血管自噬中的调节作用

自噬作为一种进化上高度保守的细胞降解途径,其调节异常与心血管疾病的发生、发展密切相关.研究显示,在心血管系统中,基础水平自噬对维持心肌正常收缩和传导至关重要,而在缺血/再灌注损伤和心力衰竭等心血管病理状态下,自噬水平明显增强.细胞自噬是一种多基因参与的复杂过程,近年来越来越多的证据表明,microRNAs(miRNAs)在心血管系统发育、正常生理功能维持以及不同心血管疾病(cardiovascular disease,CVDs)自噬中具有重要调节作用.本文通过对miRNAs与CVDs自噬调节方面的进展进行归纳,针对miRNAs对CVDs自噬的潜在机制进行总结,望为心血管疾病的诊断和治疗提供新的方向.     

microRNA层面上癌症的公共机制

microRNAs(miRNA)是一类内源性的非编码小RNA。已有研究表明miRNAs的靶基因中有不少癌症的相关基因。为了全面研究miRNA与癌症的关系,作者将19种癌症的相关基因集合分别富集到494个miRNAs靶基因集合上,得到各类癌症所富集的miRNAs。结果发现19种癌症仅集中地富集在144个miRNAs上,由此验证了癌症在miRNAs上的公共机制。在此基础上,作者对癌症富集较多的8个miRNAs做了进一步研究,结果发现这8个miRNAs均为高度保守的miRNAs,且它们的靶基因集合一致富集在基因本体论(gene ontology,GO)的基本生物学过程上,并与转录因子活性以及蛋白激酶活性相关。另一方面,在基于miRNA构建的癌症网络中,前列腺癌与乳腺癌,结肠癌与乳腺癌之间共享较多的miRNAs,表明了这些癌症在miRNA层面上存在密切的关系。     

疱疹病毒microRNAs功能的研究进展

自2004年首次发现EB病毒能够编码microRNAs(miRNAs)以来,在疱疹病毒α、β、γ三个亚科已发现超过470个miRNAs。miRNAs为内源性非编码小分子RNA,长度18-25个核苷酸,通过靶向基因转录本调控基因的表达。疱疹病毒miRNAs不仅靶向病毒潜伏到裂解复制的关键基因,也调节多个宿主基因。目前的研究数据表明疱疹病毒编码的miRNAs调节病毒的潜伏感染与裂解复制、免疫识别、细胞凋亡及肿瘤生成等生物学过程。本文旨在总结疱疹病毒miRNAs的靶基因及其功能,为深入剖析疱疹病毒的致病机制提供理论支持。     

干细胞研究的新途径:miRNAs

微小RNA(microRNAs,miRNAs)是一类内源性的非编码单链RNA,能够通过与靶mRNA特异性的碱基配对而导致靶mRNA降解或抑制其翻译,从而对基因进行转录后调控。干细胞的自我更新和多向分化过程依赖于广泛而多样的调控机制,miRNAs正是这些调控机制中非常重要的一类分子。研究发现,干细胞的自我更新功能需要多种miRNAs的参与来维持;干细胞的分化也是多种miRNAs参与调控的结果。miRNAs可以作为干细胞研究的一个新的切入点。     

综述: 衰老相关microRNAs研究进展

microRNAs(miRNAs)是一类长度约22个核苷酸的非编码RNA.这是一种广泛存在于真核生物中的内源性单链小分子RNA,miRNAs通过部分碱基对互补方式与靶基因结合,在转录和转录后水平调节靶基因表达.最近研究发现,miRNAs可以靶向多个衰老相关信号通路,在线虫、果蝇、小鼠和人类的衰老过程中发挥了重要的调控作用.本文总结了近年来与衰老相关的miRNAs的研究进展,首先介绍衰老相关的信号通路,然后重点介绍与线虫和哺乳动物衰老有关的miRNAs,以及这些miRNAs如何调控衰老相关信号通路,从而影响细胞、组织和整个机体的衰老进程和衰老相关性疾病,最后展望该领域未来的研究方向.     

基于数据挖掘分析microRNAs在冠状动脉支架内再狭窄中的调控机制

目的:通过寻找支架内再狭窄相关的循环microRNAs(miRNAs)及其作用靶基因,阐释miRNAs在经皮冠状动脉介入治疗的同时带来的支架内再狭窄(ISR)中的网络调控作用及机制。方法:由美国NCBI的GEO公共数据平台下载GSE60959中的miRNAs芯片数据,通过GeneSpringGX芯片分析软件分析得到ISR患者和对照组之间差异表达的循环miRNAs;采用miRNAs靶基因预测算法TargetScan和miRanda预测差异表达miRNAs的靶基因,通过DAVID平台和KEGG数据库分析得到靶基因所参与的信号通路;用GSE46560的mRNA芯片数据分析得到ISR患者较非ISR患者循环mRNAs差异表达谱,用来验证miRNAs调控ISR所作用的靶基因;采用Cytoscape软件构建基于miRNAs-信号通路、miRNAs-靶基因的共表达网络。结果:与对照组相比,ISR组存在131个差异表达循环miRNAs,其中上调41个。前5个上调miRNAs分别是miR-1183、miR-512-5p、miR-187-5p、miR-144-3p和miR-1225-5p。5个miRNAs的预测靶基因共6587个,信号通路富集分析显示这些基因主要参与的信号通路包括MAPK signaling pathway、ErbB signaling pathway、Wnt signaling pathway、Focal adhesion、Neurotrophin signaling pathway和Regulation of actin cytoskeleton。进一步对mRNAs芯片进行差异分析显示,与对照组相比,ISR患者差异循环mRNAs共171个,其中最可能受上述5个miRNAs调控的基因共43个。构建的共表达网络显示,miR-512-5p是作用靶基因和参与信号通路最多的miRNAs。结论:ISR患者循环miRNAs和mRNAs表达谱均存在改变,多个差异表达miRNAs通过作用于多个靶mRNAs,进而影响多个信号通路的活性,最终对ISR的发生、发展形成网络调控作用。     

衰老相关microRNAs研究进展

microRNAs(miRNAs)是一类长度约22个核苷酸的非编码RNA.这是一种广泛存在于真核生物中的内源性单链小分子RNA,miRNAs通过部分碱基对互补方式与靶基因结合,在转录和转录后水平调节靶基因表达.最近研究发现,miRNAs可以靶向多个衰老相关信号通路,在线虫、果蝇、小鼠和人类的衰老过程中发挥了重要的调控作用.本文总结了近年来与衰老相关的miRNAs的研究进展,首先介绍衰老相关的信号通路,然后重点介绍与线虫和哺乳动物衰老有关的miRNAs,以及这些miRNAs如何调控衰老相关信号通路,从而影响细胞、组织和整个机体的衰老进程和衰老相关性疾病,最后展望该领域未来的研究方向.     

Epigenetics in esophageal cancers

Esophageal cancers are a challenging upper gastrointestinal tract tumor entity for interdisciplinary oncology. For the two main histotypes, namely esophageal squamous cell carcinomas and Barrett’s adenocarcinomas, several genetic aberrations have been shown to contribute to carcinogenesis and progression as well as to represent potential novel targets for therapeutic intervention. This is paralleled by growing insight into epigenetic alterations of esophageal cancers. Studies involving the analyses of human tissue specimens predominantly describe altered patterns of miRNA expression, DNA methylation patterns, and histone marks levels. This review provides a critical update on this increasing knowledge of epigenetic alteration in esophageal cancers by specifically focusing on the translational aspects of epigenetic analyses from human tissue specimens.     

Malignant Potential of Gastrointestinal Cancers Assessed by Structural Equation Modeling

Background

Parameters reported in pathologic reviews have been failing to assess exactly the malignant potential of gastrointestinal cancers. We hypothesized that malignant potential could be defined by common latent variables (hypothesis I), but there are substantial differences in the associations between malignant potential and pathologic parameters according to the origin of gastrointestinal cancers (hypothesis II). We shed light on these issues by structural equation modeling.

Materials and Methods

We conducted a cross-sectional survey of 217 esophageal, 192 gastric, and 175 colorectal cancer patients who consecutively underwent curative surgery for their pathologic stage I cancers at Keiyukai Sapporo Hospital. Latent variables identified by factor analysis and seven conventional pathologic parameters were introduced in the structural equation modeling analysis.

Results

Because latent variables were disparate except for their number, ''three'' in the examined gastrointestinal cancers, the first hypothesis was rejected. Because configural invariance across gastrointestinal cancers was not approved, the second hypothesis was verified. We could trace the three significant paths on the causal graph from latent variables to lymph node metastasis, which were mediated through depth, lymphatic invasion, and matrilysin expression in esophageal cancer, whereas only one significant path could be traced in both gastric and colorectal cancer. Two of the three latent variables were exogenous in esophageal cancer, whereas one factor was exogenous in the other gastrointestinal cancers. Cancer stemness promoted viability in esophageal cancer, but it was suppressed in others.

Conclusion

These results reflect the malignant potential of esophageal cancer is higher than that of the other gastrointestinal cancers. Such information might contribute to refining clinical treatments for gastrointestinal cancers.     

Oridonin-induced mitochondria-dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways

Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported for its antitumor activity on several cancers. However, its effect on human esophageal cancer remains unclear. In this study, we demonstrated that oridonin could inhibit the growth of human esophageal cancer cells both in vitro and in vivo. Oridonin not only suppressed the proliferation, but also induced cell cycle arrest and mitochondrial-mediated apoptosis in KYSE-30, KYSE-150, and EC9706 cells with dose-dependent manner. Further mechanism studies revealed that oridonin led cell cycle arrest in esophageal cancer cells via downregulating cell cycle-related proteins, such as cyclin B1 and CDK2, while upregulating p53 and p21. Oridonin also increased proapoptotic protein Bax and reduced antiapoptotic protein Bcl-2, as well as the increased expression of cleaved caspase-3, -8, and -9. In addition, oridonin treatment could significantly inhibit the PI3K/Akt/mTOR and Ras/Raf signaling pathway. In vivo results further demonstrated that oridonin treatment markedly inhibited tumor growth in the esophageal cancer xenograft mice model. Taken together, these results suggest that oridonin may be a potential anticancer agent for the treatment of esophageal cancer.     

Roles of cancer stem cells in gastrointestinal cancers

Cancer stem cells (CSCs) are the main cause of tumor growth, invasion, metastasis and recurrence. Recently, CSCs have been extensively studied to identify CSC-specific surface markers as well as signaling pathways that play key roles in CSCs self-renewal. The involvement of CSCs in the pathogenesis of gastrointestinal (GI) cancers also highlights these cells as a priority target for therapy. The diagnosis, prognosis and treatment of GI cancer have always been a focus of attention. Therefore, the potential application of CSCs in GI cancers is receiving increasing attention. This review summarizes the role of CSCs in GI cancers, focusing on esophageal cancer, gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer. In addition, we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers, which may provide better guidance for clinical treatment of GI cancers.     

Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus

Hedgehog (Hh) signaling is frequently activated in human cancer, including esophageal cancer. Most esophageal cancers are diagnosed in the advanced stages, therefore, identifying the very alterations that drive esophageal carcinogenesis may help designing novel strategies to diagnose and treat the disease. Analysis of Hh signaling in precancerous lesions is a critical first step in determining the significance of this pathway for carcinogenesis. Here we report our data on Hh target gene expression in 174 human esophageal specimens [28 esophageal adenocarcinomas (EAC), 19 Barrett’s esophagus, 103 cases of esophageal squamous cell carcinoma (ESCC), and 24 of squamous dysplastic lesions], and in two rat models of esophageal cancer. We found that 96% of human EAC express Hh target genes. We showed that PTCH1 expression is the most reliable biomarker. In contrast to EAC, only 38% of ESCC express Hh target genes. We found activation of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees (21% and 58% respectively). Expression of Hh target genes is frequently detected in severe squamous dysplasia/ carcinoma in situ (p=0.04) and Barrett’s esophagus (p=0.01). Unlike EAC, sonic hedgehog (Shh) expression was rare in ESCCs. Consistent with the human specimen data, we found a high percentage of Hh signaling activation in precancerous lesions in rat models. These data indicate that Hh signaling activation is an early molecular event in the development of esophageal cancer, particularly EAC.     

Acetaldehyde-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the FASAY (functional analysis of separated alleles in yeast)

Chronic alcohol consumption is a major risk factor for upper aero-digestive tract cancers, including cancer of the esophagus. Whereas alcohol as such is not thought to be directly carcinogenic, acetaldehyde, its first metabolite, has been proven genotoxic and mutagenic in the HPRT gene. As mutations in the tumour suppressor gene TP53 are the most common genetic alterations involved in human cancers, especially esophageal tumours, the aim of this work was to establish the mutational pattern induced by acetaldehyde in vitro on the TP53 gene, and to compare this pattern with that found in human alcohol-related tumours. For this purpose, we used a functional assay in yeast, the FASAY (functional analysis of separated alleles in yeast), after in vitro exposure of human normal fibroblasts AG1521 to acetaldehyde. We noted 35 mutations, of which 32 were single-nucleotide substitutions including 2 nonsense and 30 missense mutations. The pattern showed that the main mutations were G>A transitions (n=23, of which 14 in CpG sites), followed by G>T transversions (n=4), A>G transitions (n=2) and A>T transversions (n=2). Other mutations were one-base insertion and two deletions, leading to frameshifts. Eleven mutations (31%) were located in TP53 hot-spots in codons 245, 248, 249 and 273. Finally, we compared this pattern with that found for esophageal cancers in humans. These results support the notion that acetaldehyde plays a role in TP53 mutations in esophageal cancers. The key feature of this approach is that mutagenesis is directly studied in a key gene in human carcinogenesis, allowing direct comparison of mutational patterns with those in human tumours.     

Circulating microRNAs as diagnostic and therapeutic biomarkers in gastric and esophageal cancers

Gastric and esophageal cancers are as main cancers of the gastrointestinal (GI) tract, which are associated with poor diagnosis and survival. Several efforts were made in the past few decades to finding effective therapeutic approaches, but these approaches had several problems. Finding new biomarkers is a critical step in finding new approaches for the treatment of these cancers. Finding new biomarkers that cover various aspects of the diseases could provide a choice of suitable therapies and better monitoring of patients with these cancers. Among several biomarkers tissue specific and circulating microRNAs (miRNAs) have emerged as powerful candidates in the diagnosis of gastric and esophageal cancers. MiRNAs are small noncoding single‐stranded RNA molecules that are found in the blood and regulate gene expression. These have numerous characteristics that make them suitable for being used as ideal biomarkers in cancer diagnosis. Research has indicated that the level and profile of miRNA in serum and plasma are very high. They are potentially noninvasive and sensitive enough to detect tumors in their primary stages of infection. Multiple lines of evidence indicate that the presence, absence, or deregulation of several circulating miRNAs (i.e., let‐7a, miR‐21, miR‐93, miR‐192a, miR‐18a, and miR‐10b for gastric cancer, and miR‐21, miR‐375, miR‐25‐3p, miR‐151a‐3p, and miR‐100‐3p for esophageal cancer) are associated with initiation and progression of gastric and esophageal cancers. The aim of this review is to highlight the recent advances in the roles of miRNAs in diagnosis and treatment of gastric and esophageal cancers.     

Irisin immunohistochemistry in gastrointestinal system cancers

Cancer is the leading cause of morbidity and mortality worldwide. Some studies have shown that high heat kills cancer cells. Irisin is a protein involved in heat production by converting white into brown adipose tissue, but there is no information about how its expression changes in cancerous tissues. We used irisin antibody immunohistochemistry to investigate changes in irisin expression in gastrointestinal cancers compared to normal tissues. Irisin was found in human brain neuroglial cells, esophageal epithelial cells, esophageal epidermoid carcinoma, esophageal adenocarcinoma and neuroendocrine esophageal carcinoma, gastric glands, gastric adenosquamous carcinoma, gastric neuroendocrine carcinoma, gastric signet ring cell carcinoma, neutrophils in vascular tissues, intestinal glands of colon, colon adenocarcinoma, mucinous colon adenocarcinoma, hepatocytes, hepatocellular carcinoma, islets of Langerhans, exocrine pancreas, acinar cells and interlobular and interlobular ducts of normal pancreas, pancreatic ductal adenocarcinoma, and intra- and interlobular ducts of cancerous pancreatic tissue. Histoscores (area × intensity) indicated that irisin was increased significantly in gastrointestinal cancer tissues, except liver cancers. Our findings suggest that the relation of irisin to cancer warrants further investigation.     

microRNA-10b confers cisplatin resistance by activating AKT/mTOR/P70S6K signaling via targeting PPARγ in esophageal cancer

It is well known that the acquisition of chemoresistance is a major obstacle for the effective treatment of human cancers. It is reported that microRNAs (miRNAs) are implicated in chemotherapy resistance of various malignancies. miR-10b was previously proved as an oncogene in multiple malignancies, including esophageal cancer. However, its biological significance in regulating cisplatin (DDP) resistance in esophageal cancer is still elusive. Here, we observed that miR-10b expression was upregulated and peroxisome proliferator-activated receptor-γ (PPARγ) expression was downregulated in esophageal cancer tumor tissues and cells. PPARγ was proved as a functional target of miR-10b. Moreover, suppression of miR-10b enhanced the chemosensitivity of esophageal cancer cells to DDP in vitro and in vivo. In addition, PPARγ-mediated DDP sensitivity was weakened by miR-10b overexpression. Furthermore, miR-10b-activated AKT/mTOR/p70S6K signaling pathway through targeting PPARγ. Inactivation of AKT/mTOR/p70S6K by AKT inhibitor (GSK690693) attenuated miR-10b-induced DDP resistance in esophageal cancer cells. Taken together these observation, miRNA-10b-mediated PPARγ inhibition enhanced DDP resistance by activating the AKT/mTOR/P70S6K signaling in esophageal cancer, suggesting a potential target to improve therapeutic response of patients with esophageal cancer to DDP.