scholarly journals 2041 The cell-cell adhesion component PLEKHA7 regulates the pro-tumorigenic MIR17HG long non-coding RNA in colon epithelial cells

2018 ◽  
Vol 2 (S1) ◽  
pp. 30-30
Author(s):  
Mary C. Bridges ◽  
Joyce Nair-Menon ◽  
Antonis Kourtidis
Keyword(s):  
Colon Cancer ◽  
Epithelial Cells ◽  
Cell Transformation ◽  
Adherens Junctions ◽  
Mature Mirnas ◽  
Epithelial Tissue ◽  
Mrna Levels ◽  
Rna Seq ◽  
Non Coding Rna ◽  
And Function

OBJECTIVES/SPECIFIC AIMS: The goal of this study is to test the hypothesis that the adherens junctions of colon epithelial cells regulate lncRNAs levels and function via the microprocessor and RISC complexes to suppress expression of pro-tumorigenic markers and aberrant cell behavior. METHODS/STUDY POPULATION: To test this hypothesis, we used colon epithelial cancer cell lines. We performed RNA-seq following knockdown of PLEKHA7, a key component of the adherens junctions, to identify changes in lncRNA expression and downstream mRNA levels. We confirmed junctional localization of affected lncRNAs from the RNA-seq and those that we found in our preliminary study by using in situ hybridization (ISH). RESULTS/ANTICIPATED RESULTS: RNA-seq identified junction-associated lncRNAs whose expression levels are regulated by PLEKHA7. The top upregulated lncRNA upon PLEKHA7 depletion was MIR17HG, an oncogenic host transcript of a cluster of miRNAs. These mature miRNAs also co-precipitate with PLEKHA7. PLEKHA7 knockdown results in increased levels of MIR17HG, but only a subset of its hosted miRNAs (miR-19a,b). Notably, miR-19a and mir-19b are highly upregulated in colon cancer. Our data suggest that 2 PLEKHA7-associated miRNAs, miR-203a and miR-372, mediate suppression MIR17HG. Re-expression of PLEKHA7 in aggressive colon cancer cells that lack PLEKHA7 suppressed expression of MIR17HG, as well as anchorage independent growth of these cells. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data point towards a novel mechanism of lncRNA regulation that tethers epithelial tissue integrity with pro-tumorigenic cell transformation. Reducing elevated MIR17HG levels, is a potential therapeutic approach to suppress the tumorigenic behavior of cells that have lost their junctional integrity and homeostasis. identify a network of miRNA-mRNA-lncRNA interactions that could be exploited for further mechanistic studies, as well as for diagnostic and therapeutic purposes in the future.

scholarly journals Machine learning reduced gene/non-coding RNA features that classify Schizophrenia patients accurately and highlight insightful gene clusters

2020 ◽  
Author(s):  
Yichuan Liu ◽  
Hui-Qi Qu ◽  
Xiao Chang ◽  
Lifeng Tian ◽  
Joseph Glessner ◽  
...  
Keyword(s):  
Machine Learning ◽  
Neurodevelopmental Disorder ◽  
Wnt Signaling Pathway ◽  
Gene Clusters ◽  
Differentially Expressed ◽  
Cell Junction ◽  
Mrna Levels ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Non Coding Rnas

AbstractSchizophrenia (SCZ) is a chronic and severely disabling neurodevelopmental disorder that affects people worldwide. RNA-seq has been a powerful method to detect the differentially expressed genes/non-coding RNAs in patients; however, due to overfitting problems differentially expressed targets (DETs) cannot be used properly as biomarkers. In this study, dorsolateral prefrontal cortex (dlpfc) RNA-seq data from 254 individuals’ was obtained from the CommonMind consortium and analyzed with machine learning methods, including random forest, forward feature selection (ffs), and factor analysis, to reduce the numbers of gene/non-coding RNA feature vectors to overcome overfitting problem and explore involved functional clusters. In 2-fold shuffle testing, the average predictive accuracy for SCZ patients was 67% based on coding genes, and the 96% based on long non-coding RNAs (lncRNAs). Coding genes were further clustered into 14 factors and lncRNAs were clustered into 45 factors to represent the underlying features. The largest contribution factor for coding genes contains number of genes critical in neurodevelopment and previously reported in relation with various brain disorders. Genomic loci of lncRNAs were more insightful, enriched for genes critical in synapse function (p=7.3E-3), cell junction (p=0.017), neuron differentiation (p=8.3E-3), phosphorylation (8.2E-4), and involving the Wnt signaling pathway (p=0.029). Taken together, machine learning is a powerful algorithm to reduce functional biomarkers in SCZ patients. The lncRNAs capture the characteristics of SCZ tissue more accurately than mRNA as the formers regulate every level of gene expression, not limited to mRNA levels.

scholarly journals PIN1 Is an E2F Target Gene Essential for Neu/Ras-Induced Transformation of Mammary Epithelial Cells

2002 ◽  
Vol 22 (15) ◽  
pp. 5281-5295 ◽  
Author(s):  
Akihide Ryo ◽  
Yih-Cherng Liou ◽  
Gerburg Wulf ◽  
Masafumi Nakamura ◽  
Sam W. Lee ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Mammary Epithelial Cells ◽  
Cell Transformation ◽  
Mammary Tumorigenesis ◽  
Mammary Epithelial ◽  
Oncogenic Signaling ◽  
And Function

ABSTRACT Oncogenes Neu/HER2/ErbB2 and Ras can induce mammary tumorigenesis via upregulation of cyclin D1. One major regulatory mechanism in these oncogenic signaling pathways is phosphorylation of serines or threonines preceding proline (pSer/Thr-Pro). Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer/Thr-Pro bonds, Pin1 can regulate the conformation and function of certain phosphorylated proteins. We have previously shown that Pin1 is overexpressed in breast tumors and positively regulates cyclin D1 by transcriptional activation and posttranslational stabilization. Moreover, in Pin1 knockout mice, mammary epithelial cells fail to undergo massive proliferation during pregnancy, as is the case in cyclin D1 null mice. These results indicate that Pin1 is upregulated in breast cancer and may be involved in mammary tumors. However, the mechanism of Pin1 overexpression in cancer and its significance in cell transformation remain largely unknown. Here we demonstrate that PIN1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2F. Furthermore, overexpression of Pin1 not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary epithelial cells. In contrast, inhibition of Pin1 suppresses Neu- and Ras-induced transformed phenotypes, which can be fully rescued by overexpression of a constitutively active cyclin D1 mutant that is refractory to the Pin1 inhibition. Thus, Pin1 is an E2F target gene that is essential for the Neu/Ras-induced transformation of mammary epithelial cells through activation of cyclin D1.

scholarly journals E–N-cadherin heterodimers define novel adherens junctions connecting endoderm-derived cells

2011 ◽  
Vol 195 (5) ◽  
pp. 873-887 ◽  
Author(s):  
Beate K. Straub ◽  
Steffen Rickelt ◽  
Ralf Zimbelmann ◽  
Christine Grund ◽  
Caecilia Kuhn ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Adherens Junctions ◽  
Tumor Biology ◽  
Intercellular Junctions ◽  
Pivotal Role ◽  
Major Portion ◽  
Tissue Development ◽  
Cadherin Switch ◽  
And Function ◽  
E Cadherin

Intercellular junctions play a pivotal role in tissue development and function and also in tumorigenesis. In epithelial cells, decrease or loss of E-cadherin, the hallmark molecule of adherens junctions (AJs), and increase of N-cadherin are widely thought to promote carcinoma progression and metastasis. In this paper, we show that this “cadherin switch” hypothesis does not hold for diverse endoderm-derived cells and cells of tumors derived from them. We show that the cadherins in a major portion of AJs in these cells can be chemically cross-linked in E–N heterodimers. We also show that cells possessing E–N heterodimer AJs can form semistable hemihomotypic AJs with purely N-cadherin–based AJs of mesenchymally derived cells, including stroma cells. We conclude that these heterodimers are the major AJ constituents of several endoderm-derived tissues and tumors and that the prevailing concept of antagonistic roles of these two cadherins in developmental and tumor biology has to be reconsidered.

scholarly journals A Comprehensive Profile of Mature MicroRNA in the Pig

2017 ◽  
Author(s):  
Xiliang Wang ◽  
David K.C. Cooper ◽  
Zhiming Cai ◽  
Lisha Mou
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Mature Mirnas ◽  
Human Diseases ◽  
Meat Production ◽  
Biological Processes ◽  
Non Coding Rna ◽  
Mature Microrna ◽  
And Function ◽  
Posttranscriptional Level

The pig is an important source of meat production and provides a valuable model for certain human diseases. MicroRNA (miRNA), which is non-coding RNA and regulates gene expression at the posttranscriptional level, plays a critical role in various biological processes. Studies on identification and function of mature miRNAs in multiple pig tissues are increasing, yet the literature is limited. Therefore, we reviewed current research to determine the miRNAs expressed in specific pig tissues that are involved in carcass values (including muscle and adipocytes), reproduction (including pituitary, testis, and ovary), and development of some solid organs (e.g., brain, lung, kidney, and liver). We also discuss the possible regulating mechanisms of miRNA. Finally, as pig organs are suitable candidates for xenotransplantation, biomarkers of their miRNA in xenotransplantation were evaluated.

scholarly journals Expression and Regulation Profile of Mature MicroRNA in the Pig: Relevance to Xenotransplantation

2017 ◽  
Author(s):  
Zongpei Song ◽  
David K. C. Cooper ◽  
Zhiming Cai ◽  
Lisha Mou
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Mature Mirnas ◽  
Human Diseases ◽  
Meat Production ◽  
Biological Processes ◽  
Non Coding Rna ◽  
Mature Microrna ◽  
And Function ◽  
Posttranscriptional Level

The pig is an important source of meat production and provides a valuable model for certain human diseases. MicroRNA (miRNA), which is non-coding RNA and regulates gene expression at the posttranscriptional level, plays a critical role in various biological processes. Studies on identification and function of mature miRNAs in multiple pig tissues are increasing, yet the literature is limited. Therefore, we reviewed current research to determine the miRNAs expressed in specific pig tissues that are involved in carcass values (including muscle and adipocytes), reproduction (including pituitary, testis, and ovary), and development of some solid organs (e.g., brain, lung, kidney, and liver). We also discuss the possible regulating mechanisms of miRNA. Finally, as pig organs are suitable candidates for xenotransplantation, biomarkers of their miRNA in xenotransplantation were evaluated.

scholarly journals An alternative mode of epithelial polarity in the Drosophila midgut

2018 ◽  
Author(s):  
Jia Chen ◽  
Aram-Christopher Sayadian ◽  
Nick Lowe ◽  
Holly E. Lovegrove ◽  
Daniel St Johnston
Keyword(s):  
Epithelial Cells ◽  
Adherens Junctions ◽  
Epithelial Polarity ◽  
Alternative Mode ◽  
Epithelial Tissues ◽  
Occluding Junctions ◽  
Discs Large ◽  
And Function ◽  
Adhesion Complex

AbstractApical-basal polarity is essential for the formation and function of epithelial tissues, whereas loss of polarity is a hallmark of tumours. Studies in Drosophila have identified conserved polarity factors that define the apical (Crumbs, Stardust, Par-6, aPKC), junctional (Baz/Par-3) and basolateral (Scribbled, Discs large, Lgl) domains of epithelial cells (1, 2). Because these conserved factors mark equivalent domains in diverse vertebrate and invertebrate epithelial types, it is generally assumed that this system organises polarity in all epithelia. Here we show that this is not the case, as none of these canonical factors are required for the polarisation of the endodermal epithelium of the Drosophila adult midgut. Furthermore, unlike other Drosophila epithelia, the midgut forms occluding junctions above adherens junctions, as in vertebrates, and requires the integrin adhesion complex for polarity (3, 4). Thus, Drosophila contains two types of epithelia that polarise by different mechanisms. Since knock-outs of canonical polarity factors often have little effect on the polarity of vertebrate epithelia, this diversity of polarity mechanisms is likely to be conserved in other animals (5-8).

scholarly journals Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer

2020 ◽  
Vol 21 (7) ◽  
pp. 2559 ◽  
Author(s):  
Joyce Nair-Menon ◽  
Amanda C. Daulagala ◽  
Dean M. Connor ◽  
Lauren Rutledge ◽  
Trevor Penix ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Epithelial Cells ◽  
Cancer Cell ◽  
Adherens Junctions ◽  
Mirna Biogenesis ◽  
Cell Contact ◽  
Rnai Machinery ◽  
The Core

The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells. Here, we demonstrate that the localization of the core RNAi components is specific and predominant at apical areas of cell-cell contact of human normal colon epithelial tissues and normal primary colon epithelial cells. Importantly, the apical junctional localization of RNAi proteins is disrupted or lost in human colon tumors and in poorly differentiated colon cancer cell lines, correlating with the dysregulation of the adherens junction component PLEKHA7. We show that the restoration of PLEKHA7 expression at adherens junctions of aggressively tumorigenic colon cancer cells restores the junctional localization of RNAi components and suppresses cancer cell growth in vitro and in vivo. In summary, this work identifies the apical junctional localization of the RNAi machinery as a key feature of the differentiated colonic epithelium, with a putative tumor suppressing function.

scholarly journals Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells

2017 ◽  
Vol 28 (15) ◽  
pp. 2023-2034 ◽  
Author(s):  
Tomohito Higashi ◽  
Ann L. Miller
Keyword(s):  
Epithelial Cells ◽  
Tight Junctions ◽  
Barrier Function ◽  
Hot Spots ◽  
Adherens Junctions ◽  
New Model ◽  
Open Questions ◽  
And Function ◽  
Molecular Components

Tricellular contacts are the places where three cells meet. In vertebrate epithelial cells, specialized structures called tricellular tight junctions (tTJs) and tricellular adherens junctions (tAJs) have been identified. tTJs are important for the maintenance of barrier function, and disruption of tTJ proteins contributes to familial deafness. tAJs have recently been attracting the attention of mechanobiologists because these sites are hot spots of epithelial tension. Although the molecular components, regulation, and function of tTJs and tAJs, as well as of invertebrate tricellular junctions, are beginning to be characterized, many questions remain. Here we broadly cover what is known about tricellular junctions, propose a new model for tension transmission at tAJs, and discuss key open questions.

Characterization of Prostatic Epithelial Cells in Organotypic Culture

1982 ◽  
Vol 40 ◽  
pp. 256-257
Author(s):  
Louis Terracio ◽  
William H.J. Douglas
Keyword(s):  
Epithelial Cells ◽  
Monolayer Culture ◽  
Organotypic Culture ◽  
Epithelial Tissue ◽  
Organotypic Cultures ◽  
3 Dimensional ◽  
Prostatic Epithelium ◽  
And Function ◽  
Sponge Matrix

Cell cultures of prostatic epithelial tissue provide a model allowing the study of a single factor on prostatic epithelium without the complicating influences of the stroma. Investigators have developed methods of establishing prostatic epithelium in monolayer culture that maintain good differentiated structure and function, however, even these systems do not maintain the histological organization or columnar polarity of the epithelial cells and thus leave something to be desired. Work by Moscona and Douglas et al., have shown that epithelial cells cultured on a 3-dimensional collagen sponge matrix (GELFOAM, UPJOHN CO.) are capable of reaggregating to form histological structures similar to those found in the intact organ (e.g. alveolar-like structures in the lung, thus they are called organotypic cultures). Engle jat ell., have shown that this superior morphology is also reflected in an increased response of these cells to hormones ini vitro and thus reflects an increase in the retention of differentiated function.

scholarly journals Machine Learning Reduced Gene/Non-Coding RNA Features That Classify Schizophrenia Patients Accurately and Highlight Insightful Gene Clusters

2021 ◽  
Vol 22 (7) ◽  
pp. 3364
Author(s):  
Yichuan Liu ◽  
Hui-Qi Qu ◽  
Xiao Chang ◽  
Lifeng Tian ◽  
Jingchun Qu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Dorsolateral Prefrontal Cortex ◽  
Predictive Accuracy ◽  
Gene Clusters ◽  
Differentially Expressed ◽  
Mrna Levels ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Dorsolateral Prefrontal ◽  
Non Coding Rnas

RNA-seq has been a powerful method to detect the differentially expressed genes/long non-coding RNAs (lncRNAs) in schizophrenia (SCZ) patients; however, due to overfitting problems differentially expressed targets (DETs) cannot be used properly as biomarkers. This study used machine learning to reduce gene/non-coding RNA features. Dorsolateral prefrontal cortex (dlpfc) RNA-seq data from 254 individuals was obtained from the CommonMind consortium. The average predictive accuracy for SCZ patients was 67% based on coding genes, and 96% based on long non-coding RNAs (lncRNAs). Machine learning is a powerful algorithm to reduce functional biomarkers in SCZ patients. The lncRNAs capture the characteristics of SCZ tissue more accurately than mRNA as the former regulate every level of gene expression, not limited to mRNA levels.

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