Interactions of intergenic microRNAs with mRNAs of genes involved in carcinogenesis

miRNAs regulate gene expression by binding with mRNAs of many genes. Studying their effects on genes involved in oncogenesis is important in cancer diagnostics and therapeutics. The RNAHybrid 2.1 program was used to predict the strong miRNA binding sites (p < 0.0005) in target mRNAs. The program Finder 2.2 was created to verify 784 intergenic miRNAs (ig-miRNA) origin. Among 54 considered oncogenes and tumor suppressor genes, 47 genes are the best targets for ig-miRNAs. Accordingly, these genes are strongly regulated by 111 ig-miRNAs. Some miRNAs bind several mRNAs, and some mRNAs have several binding sites for miRNAs. Of the 54 mRNAs, 21.8%, 43.0%, and 35.2% of the miRNA binding sites are present in the 5'UTRs, CDSes, and 3'UTRs, respectively. The average density of the binding sites for miRNAs in the 5'UTR was 4.4 times and 4.1 times greater than in the CDS and the 3'UTR, respectively. Three types of interactions between miRNAs and mRNAs were identified, which differ according to the region of the miRNA bound to the mRNA: 1) binding occurs predominantly via the 3'-region of the miRNA; 2) binding occurs predominantly through the central region of the miRNA; and 3) binding occurs predominantly via the 5'-region of the miRNA. Several miRNAs effectively regulate only one gene, and this information could be useful in molecular medicine to modulate translation of the target mRNA. We recommend described new sites for validation by experimental investigation.     

How will telomeric complex be further contributed to our longevity? — The potential novel biomarkers of telomere complex counteracting both aging and cancer

With the smooth move towards the coming expected clinical reports of anticancer pharmaceutical molecules targeting telomeres and telomerase, and also with the exciting success in the extension of lifespan by regulating telomerase activity without increased onset of oncogenesis in laboratory mouse models (Garcia-Cao et al., 2006; Jaskelioff et al., 2011), we are convinced that targeting telomeres based on telomerase will be a potential approach to conquer both aging and cancer and the idea of longevity seems to be no more mysterious. More interestingly, emerging evidences from clinical research reveal that other telomeric factors, like specifi c telomeric binding proteins and nonspecific telomere associated proteins also show crucial importance in aging and oncogenesis. This stems from their roles in the stability of telomere structure and in the inhibition of DNA damage response at telomeres. Uncapping these proteins from chromosome ends leads to dramatic telomere loss and telomere dysfunction which is more abrupt than those induced by telomerase inactivation. Abnormal expression of these factors results in developmental failure, aging and even oncogenesis evidenced by several experimental models and clinical cases, indicating telomere specifi c proteins and its associated proteins have complimentary roles to telomerase in telomere protection and controlling cellular fate. Thus, these telomeric factors might be potential clinical biomarkers for early detection or even therapeutic targets of aging and cancer. Future studies to elucidate how these proteins function in telomere protection might benefit patients suffering aging or cancer who are not sensitive to telomerase mediation.     

Comparative Characteristics of Immunological,Clinical and Morphological Features of Human Lymphoid Tumors in Respect with Tumor Genesis and Progression

We describe three lymphoid tumors with the same immunophenotype characteristic for chronic lymphoid leukemia (CD19⁺/CD5⁺, clonality of the light immunoglobulin chains, CD23⁺ and CD10^–). However, clinical picture and morphology of neoplastic cells dictate different clinical forms of these cases: chronic lymphoid leukemia, large cell transformation of chronic lymphoid leukemia and diffuse large B-cell lymphoma. Taking into account that immunophenotype reflects the origin of tumor, while clinical outcome and morphological features of cells reflect the stage of tumor progression and/or pathway of tumor formation, we discuss the approach to natural classification of lymphoid tumors based on the process of their evolution.     

Ubiquitylation Pathways In Insulin Signaling and Organismal Homeostasis

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis.     

FOXO 蛋白的修饰与细胞凋亡和癌变

Fox 蛋白家族是 2000 年才发布统一命名的蛋白质家族 . 由于其在生物体内所起的重要作用,已迅速成为生命科学研究的热点 . 目前,已经发现其家族成员有 100 多种,其中, FOXO 亚家族在动物细胞的凋亡中起重要作用 . 细胞凋亡与动物的长寿、繁殖、代谢、肿瘤发生及免疫有重要关系,对 Forkhead (Fox) 蛋白分子的命名进行了回顾、对其分类与结构特征进行了总结,并重点对 FOXO 的化学修饰、活性调节及其在细胞凋亡和肿瘤发生中的作用进行了综述 .     

Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4‐phosphatase‐1

Akt is a crucial phosphoinositide 3-kinase (PI(3)K) effector that regulates cell proliferation and survival. PI(3)K-generated signals, PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂, direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3,4)P₂ is degraded by inositol polyphosphate 4-phosphatase-1 (4-ptase-1) forming PtdIns(3)P; however, the role of 4-ptase-1 in regulating the activation and function of Akt is unclear. In mouse embryonic fibroblasts lacking 4-ptase-1 (^−/−MEFs), the Akt-pleckstrin homology (PH) domain was constitutively membrane-associated both in serum-starved and agonist-stimulated cells, in contrast to ^+/+MEFs, in which it was detected only at the plasma membrane following serum stimulation. Epidermal growth factor (EGF) stimulation resulted in increased Ser⁴⁷³ and Thr³⁰⁸-Akt phosphorylation and activation of Akt-dependent signalling in ^−/−MEFs, relative to ^+/+MEFs. Significantly, loss of 4-ptase-1 resulted in increased cell proliferation and decreased apoptosis. SV40-transformed ^−/−MEFs showed increased anchorage-independent cell growth and formed tumours in nude mice. This study provides the first evidence, to our knowledge, that 4-ptase-1 controls the activation of Akt and thereby cell proliferation, survival and tumorigenesis.     

Ribosomal protein uS3 in cell biology and human disease: Latest insights and prospects

The conserved ribosomal protein uS3 in eukaryotes has long been known as one of the essential components of the small (40S) ribosomal subunit, which is involved in the structure of the 40S mRNA entry pore, ensuring the functioning of the 40S subunit during translation initiation. Besides, uS3, being outside the ribosome, is engaged in various cellular processes related to DNA repair, NF-kB signaling pathway and regulation of apoptosis. This review is devoted to recent data opening new horizons in understanding the roles of uS3 in such processes as the assembly and maturation of 40S subunits, ensuring proper structure of 48S pre-initiation complexes, regulation of initiation and ribosome-based RNA quality control pathways. Besides, we summarize novel results on the participation of the protein in processes beyond translation and consider biomedical implications of previously known and recently found extra-ribosomal functions of uS3, primarily, in oncogenesis.     

Identifying causal networks linking cancer processes and anti‐tumor immunity using Bayesian network inference and metagene constructs

Cancer arises from a deregulation of both intracellular and intercellular networks that maintain system homeostasis. Identifying the architecture of these networks and how they are changed in cancer is a pre‐requisite for designing drugs to restore homeostasis. Since intercellular networks only appear in intact systems, it is difficult to identify how these networks become altered in human cancer using many of the common experimental models. To overcome this, we used the diversity in normal and malignant human tissue samples from the Cancer Genome Atlas (TCGA) database of human breast cancer to identify the topology associated with intercellular networks in vivo. To improve the underlying biological signals, we constructed Bayesian networks using metagene constructs, which represented groups of genes that are concomitantly associated with different immune and cancer states. We also used bootstrap resampling to establish the significance associated with the inferred networks. In short, we found opposing relationships between cell proliferation and epithelial‐to‐mesenchymal transformation (EMT) with regards to macrophage polarization. These results were consistent across multiple carcinomas in that proliferation was associated with a type 1 cell‐mediated anti‐tumor immune response and EMT was associated with a pro‐tumor anti‐inflammatory response. To address the identifiability of these networks from other datasets, we could identify the relationship between EMT and macrophage polarization with fewer samples when the Bayesian network was generated from malignant samples alone. However, the relationship between proliferation and macrophage polarization was identified with fewer samples when the samples were taken from a combination of the normal and malignant samples. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:470–479, 2016     

Wnt基因与生物发育和肿瘤发生

Wnt基因所编码的蛋白质与许多生长因子一样具有分泌型生长因子的结构特点;分泌后能与细胞表面基质及其特异性受体Frizzled蛋白相互作用,通过其下游的一系列诸如Dsh(Dishevelled)、β-环形蛋白、GSK3(glycogen synthase kinase 3)、APC(adenomatous polyposis coli)等蛋白质的磷酸化与去磷酸化的过程来完成Wnt信号的传导,在脊椎动物至原虫的生物发育及肿瘤发生中具有重要作用.