Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain ...largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA.
As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in ...neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified
. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.
In this paper, we tackle the problem of constructing a differentially private synopsis for two-dimensional datasets such as geospatial datasets. The current state-of-the-art methods work by ...performing recursive binary partitioning of the data domains, and constructing a hierarchy of partitions. We show that the key challenge in partition-based synopsis methods lies in choosing the right partition granularity to balance the noise error and the non-uniformity error. We study the uniform-grid approach, which applies an equi-width grid of a certain size over the data domain and then issues independent count queries on the grid cells. This method has received no attention in the literature, probably due to the fact that no good method for choosing a grid size was known. Based on an analysis of the two kinds of errors, we propose a method for choosing the grid size. Experimental results validate our method, and show that this approach performs as well as, and often times better than, the state-of-the-art methods. We further introduce a novel adaptive-grid method. The adaptive grid method lays a coarse-grained grid over the dataset, and then further partitions each cell according to its noisy count. Both levels of partitions are then used in answering queries over the dataset. This method exploits the need to have finer granularity partitioning over dense regions and, at the same time, coarse partitioning over sparse regions. Through extensive experiments on real-world datasets, we show that this approach consistently and significantly outperforms the uniform-grid method and other state-of-the-art methods.
TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to ...malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.
A probabilistic password model assigns a probability value to each string. Such models are useful for research into understanding what makes users choose more (or less) secure passwords, and for ...constructing password strength meters and password cracking utilities. Guess number graphs generated from password models are a widely used method in password research. In this paper, we show that probability-threshold graphs have important advantages over guess-number graphs. They are much faster to compute, and at the same time provide information beyond what is feasible in guess-number graphs. We also observe that research in password modeling can benefit from the extensive literature in statistical language modeling. We conduct a systematic evaluation of a large number of probabilistic password models, including Markov models using different normalization and smoothing methods, and found that, among other things, Markov models, when done correctly, perform significantly better than the Probabilistic Context-Free Grammar model proposed in Weir et al., which has been used as the state-of-the-art password model in recent research.
Based on the theory of commitment and trust, this paper constructs an online consumer purchase decision model, empirically studies the common values, online trust, commitment and purchase decision, ...and explores the influence mechanism and path of online consumer purchase decision. The results show that common values of shopping platforms and online consumers have a significant positive impact on trust and commitment, among which the common value orientation of mutual trust and commitment compliance has the most significant impact, which reflects the core content of common values. Secondly, the confidentiality of buyer information, common value of ethics, accurate disclosure of information, and finally the attitude to solve problem;The establishment of online trust has a significant positive impact on commitment, and both online trust and commitment are positively related to purchase decision. In terms of research methods, the theory of commitment and trust is introduced into the study of online consumption on Chinese shopping platforms, which expands the scope of application of the theory of commitment and trust. The trust of online consumers is generated by their own shopping experience. The conclusion of this study provides a decision-making basis for the innovation of marketing model and has theoretical reference value.
This study was designed to explore the role of versican in the development of hepatocellular carcinoma (HCC). Ectopic expression of the versican 3′‐untranslated region (3′‐UTR) was studied as a ...competitive endogenous RNA for regulating miRNA functions. We used this approach to modulate the expression of versican and its related proteins in 3′‐UTR transgenic mice and in the liver cancer cell line HepG2, stably transfected with the 3′‐UTR or a control vector. We demonstrated that transgenic mice expressing the versican 3′‐UTR developed HCC and increased expression of versican isoforms V0 and V1. HepG2 cells transfected with versican 3′‐UTR displayed increased proliferation, survival, migration, invasion, colony formation, and enhanced endothelial cell growth, but decreased apoptosis. We found that versican 3′‐UTR could bind to miRNAs miR‐133a, miR‐199a*, miR‐144, and miR‐431 and also interacted with CD34 and fibronectin. As a consequence, expression of versican, CD34, and fibronectin was up‐regulated by ectopic transfection of the versican 3′‐UTR, which was confirmed in HepG2 cells and in transgenic mice as compared with wild‐type controls. Transfection with siRNAs targeting the versican 3′‐UTR abolished the effects of the 3′‐UTR. Taken together, these results demonstrate that versican V0 and V1 isoforms play important roles in HCC development and that versican mRNAs compete with endogenous RNAs in regulating miRNA functions.—Fang, L., Du, W. W., Yang, X., Chen, K., Ghanekar, A., Levy, G., Yang, W., Yee, A. J., Lu, W.‐Y., Xuan, J. W., Gao, Z., Xie, F., He, C., Deng, Z., Yang, B. B. Versican 3′‐untranslated region (3′‐UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. FASEB J. 27, 907–919 (2013). www.fasebj.org
► Versican V2 isoform promotes angiogenesis by modulating the activities of endothelial cells. ► Fibronectin is up-regulated by V2 isoform and mediated V2 function. ► Our study suggests that V2 could ...be a potential target for intervention of tumor angiogenesis.
Versican is a proteoglycan expressed in the extracellular matrix, where it regulates a variety of cell activities and affects tumor development. With alternative splicing, there are four versican isoforms, denoted V0, V1, V2 and V3. The V2 isoform is highly expressed in the mature brain but its function in the mature brain has not yet been elucidated. Since brain tumors are among the most angiogenic of human tumors, we investigated whether or not the V2 isoform plays a role in angiogenesis and found that the glioblastoma cell line U87 stably transfected with V2 formed tumors containing extensive vasculature. Although the V2-expressing cells grew slowly, they survived well in serum-free medium. They also displayed high adhesive ability to endothelial cells and facilitated tube-like structure formation. Importantly, fibronectin was up-regulated by V2 and mediated V2 function. Thus, versican V2 could be a potential target for intervention of brain tumor angiogenesis.
Angiogenesis and invasion are essential processes for solid tumor growth and dissemination. The tumor development process can be dependent on the activation of a series of signaling pathways, ...including growth factor-activated pathways. MicroRNAs have been shown to be critical for tumorigenesis, but their roles in cancer angiogenesis, invasion and other signaling pathways important for tumor development are still unclear in the context of tumor biology. We investigated the role of microRNA miR-98 in regulating tumor growth, invasion, and angiogenesis using a highly aggressive breast cancer model in vitro and in vitro. We found that the expression of miR-98 inhibited breast cancer cell proliferation, survival, tumor growth, invasion, and angiogenesis. Conversely, inhibition of endogenous miR-98 promoted cell proliferation, survival, tumor growth, invasion, and angiogenesis. It appeared that miR-98 inhibited angiogenesis by modulating endothelial cell activities including cell spreading, cell invasion and tubule formation. Interestingly, miR-98 reduced the expression of ALK4 and MMP11, both of which were potential targets of miR-98. Transfection of an anti-miR-98 construct increased the expression of both targets. We confirmed that mir-98 targeted the 3'-untranslated regions of ALK4 and MMP11. Finally, ALK4- and MMP11-specific siRNAs inhibited breast cancer cell proliferation, survival, and angiogenesis. Rescue experiments with ALK4 and MMP11 constructs reversed the anti-proliferative, anti-invasive and anti-angiogenic effects of miR-98. Our findings define a regulatory role of miR-98 in tumor angiogenesis and invasion through repressed ALK4 and MMP11 expression.
We performed in vitro and in vivo experiments to investigate the role of the circular RNA circSKA3 in tumor development. We examined the effects of circSKA3 on mediating breast cancer metastasis. ...In vitro, we found that the circular RNA circSKA3 was transferred between breast cancer cells, which were decreased by inhibiting exosome secretion. In vivo, circSKA3-containing exosomes potentiated tumor development and invasion that were inhibited by blocking exosome transmission. The ascites isolated from tumor-bearing mice or breast cancer patients showed high levels of circSKA3 and integrin β1. Single-cell culture and single-cell PCR showed that circSKA3 was heterogeneously expressed, the cells expressing higher levels of circSKA3 had a higher potential to form large colonies. This property was similar to c-myc, but circSKA3 expression had no correlation with c-myc levels. The effects of circSKA3 on cell migration and invasion appeared to predominate c-myc functions. By releasing circSKA3-containing exosomes to cancer cells expressing lower levels of circSKA3, the large colonies could regulate the activities of small colonies, enhancing the tumor-forming capacity of the entire population. Thus, we provide evidence that the transmission of circular RNAs in tumor-derived exosomes may allow for the maintenance of advantageous invasive sub-clones in breast cancer.
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The circRNA circSKA3 can be transferred between breast cancer cells by exosome secretion. circSKA3 is heterogeneously expressed. circSKA3-containing exosomes potentiate tumor development and invasion that are inhibited by blocking exosome transmission. The ascites from tumor-bearing mice or cancer patients contains high levels of circSKA3 and integrin β1 in the exosomes.
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