Identification of Putative Metastasis Suppressor MicroRNA in Human Breast Cancer PDF Download
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Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 41
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Book Description
Metastases are responsible for>90% of human cancer deaths; yet, our knowledge regarding the molecular regulation of metastasis remains fragmentary. MicroRNAs are short RNAs that suppress their targets post-transcriptionally, leading to modulation of diverse biological processes. MicroRNAs are well suited to regulate metastasis due to their capacity to concomitantly inhibit numerous target genes. We have identified a microRNA, miR-31, whose levels correlated inversely with metastatic recurrence in human breast cancer patients. Expression of miR-31 in otherwise-aggressive breast tumor cells impeded metastasis. We deployed a novel microRNA sponge strategy to stably inhibit miR-31; this allowed otherwise-non-aggressive breast cancer cells to metastasize. These phenotypes were achieved via pleiotropic modulation of a cohort of clinically relevant metastasis-promoting genes, which were over represented among the>200 mRNAs predicted to be direct targets of miR-31. In fact, we discovered that miR-31-evoked concurrent regulation of three such effectors - integrin alpha5, radixin, and RhoA - was sufficient to explain this microRNA's impacts on metastasis. Together, these findings provide insights into metastasis that may prove useful in the diagnosis and/or treatment of breast cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 41
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Book Description
Metastases are responsible for>90% of human cancer deaths; yet, our knowledge regarding the molecular regulation of metastasis remains fragmentary. MicroRNAs are short RNAs that suppress their targets post-transcriptionally, leading to modulation of diverse biological processes. MicroRNAs are well suited to regulate metastasis due to their capacity to concomitantly inhibit numerous target genes. We have identified a microRNA, miR-31, whose levels correlated inversely with metastatic recurrence in human breast cancer patients. Expression of miR-31 in otherwise-aggressive breast tumor cells impeded metastasis. We deployed a novel microRNA sponge strategy to stably inhibit miR-31; this allowed otherwise-non-aggressive breast cancer cells to metastasize. These phenotypes were achieved via pleiotropic modulation of a cohort of clinically relevant metastasis-promoting genes, which were over represented among the>200 mRNAs predicted to be direct targets of miR-31. In fact, we discovered that miR-31-evoked concurrent regulation of three such effectors - integrin alpha5, radixin, and RhoA - was sufficient to explain this microRNA's impacts on metastasis. Together, these findings provide insights into metastasis that may prove useful in the diagnosis and/or treatment of breast cancer.
Author: César López-Camarillo
Publisher: CRC Press
ISBN: 1466576766
Category : Science
Languages : en
Pages : 428
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Book Description
MicroRNA (miRNA) biology is a cutting-edge topic in basic as well as biomedical research. This is a specialized book focusing on the current understanding of the role of miRNAs in the development, progression, invasion, and metastasis of diverse types of cancer. It also reviews their potential for applications in cancer diagnosis, prognosis, and therapeutic targets as well as the potential use in translational medicine. Chapters present comprehensive and expert perspectives on the roles of miRNAs in most common cancers from bench to bedside applications and are written by an international team of renowned experts in the field.
Author: Miao Sun
Publisher:
ISBN: 9781303229190
Category :
Languages : en
Pages : 146
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Book Description
Elucidating targets of physiological metastasis suppressors can highlight key signaling pathways leading to tumor invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP), I developed an integrated approach based on statistical analysis of tumor gene expression data combined with experimental validation. In the first part of the thesis, I utilized this approach to identify and validate two novel signaling pathways targeted by RKIP that promote HMGA2-driven metastasis in human breast cancer. RKIP induces and HMGA2 inhibits expression of miR-200b, and miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2 ) via down-regulation of HMGA2, but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. The RKIP/LOX/SDC2 signature is prognostic for metastasis-free survival in ER-negative breast cancer patients. To further identify critical downstream targets of HMGA2 in human breast cancer, I did gene and microRNA expression array analyses of human breast cancer cells with depleted HMGA2 expression. In the second part of the thesis, I show that TET1 and HOXA9 are important effectors of HMGA2. Depletion of HMGA2 induces TET1 expression. TET1 binds and demethylates its own promoter as well as the promoters of HOXA genes, stimulating TET1 and HOXA gene expression. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts, and a gene signature based upon HMGA2, TET1, and HOXA9 expression is prognostic for overall survival in breast cancer patients. These results implicate the HMGA2-TET1-HOXA9 signaling pathway in the epigenetic regulation of breast cancer and highlight the importance of targeting methylation as a potential therapeutic strategy.
Author: Frank J Slack
Publisher: World Scientific
ISBN: 1908978473
Category : Science
Languages : en
Pages : 299
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Book Description
MicroRNAs have recently emerged as key regulators of gene expression during development and are frequently misexpressed in human disease states, in particular cancer. These 22-nucleotide-long transcripts act to promote or repress cell proliferation, migration and apoptosis during development, all of which are processes that go awry in cancer. Thus, microRNAs have the ability to behave like oncogenes or tumor suppressors. In addition, their small size and molecular properties make them amenable as targets and therapeutics in cancer treatment. This book goes into detail on how microRNAs represent a paradigm shift in thinking about gene regulation during development and disease, and provide the oncologist with a potentially powerful new battery of agents to diagnose and treat cancer./a
Author: Tissa Thomas Manavalan
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 314
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Book Description
MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level by repressing translation or stimulating mRNA degradation. In this study, I tested the hypothesis that miRNAs are differentially expressed in antiestrogen-sensitive MCF-7 versus -resistant L Y2 human breast cancer cells. Microarray analyses identified 97 miRNAs that are differentially expressed between two estrogen receptor alpha (ERa) -positive human breast cancer cell lines: endocrine-sensitive MCF-7 versus -resistant L Y2 cells under basal conditions. Opposite expression of miRs-lOa,-21, -22, -12Sb, -181, -200a, -200b, -200c, -221, and -222 was confirmed between MCF-7 and L Y2 cells. The ER antagonist ICI 182,780 (fulvestrant or Faslodex) generally blocked the effect of estradiol E2 and 4-hydroxytamoxifen (4-OHT) regulated miRs, i.e.. , miR-lOa, miR-21, miR-22, miR-200a, miR-221, and miR-222, indicating that these responses in MCF-7 cells are ER-mediated. Time dependent variation in basal (ethanol, the vehicle), E2, and 4-0HT regulation of the top 8 miRNAs was detected in MCF-7 cells. Bioinformatic analyses to impute the biological significance of the identified miRNAs by identifying their computationally predicted target genes in the human genome using TargetScan, Pic Tar, and the Sanger miRBase Targets databases was performed. Thirty six putative mRNA targets were identified. Agreement in the direction of anticipated regulation was detected for 12 putative targets. These miRNAs showing opposite expression between these two breast cancer cell lines may be involved in endocrine resistance. MiR-200 family includes two clusters i.e. miR-200 a/200 b/ 429 and miR-200c/141 encoded on chromosome 1 and chromosome 12, respectively. Lower miR-200a, miR-200 b and miR-200c expression was observed in estrogen-independent LCC1 and endocrine-resistant LCC2, LCC9, and LY2 compared to the parental, endocrine-sensitive MCF-7 human breast cancer cell line. ZEB 1 protein was found to be expressed in endocrine-resistant LY2 cells but not in endocrine-sensitive MCF-7 cells. L Y2 cells did not express E-cadherin, a ZEB 1 target which is a marker for epithelial phenotype. This is the first demonstration that L Y2 cells have undergone EMT as part of their endocrine-resistant phenotype. Concomitant with miR-200 decrease, there was an increase in ZEB 1 mRNA expression m L Y2 cells. Overexpression of miR-200b or miR-200c in LY2 cells changed the cellular morphology from a mesenchymal to an epithelial appearance and sensitized cells to inhibition by 4-0HT and fulvestrant. These studies indicate that reduced expression of miR-200 and a corresponding increase in ZEB 1 protein is an indicator of endocrine-resistance in breast cancer cells.
Author: Scott John Valastyan
Publisher:
ISBN:
Category :
Languages : en
Pages : 301
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Book Description
In these studies, the microRNA miR-31 was identified as a potent inhibitor of breast cancer metastasis. miR-31 expression levels were inversely associated with the propensity to develop metastatic disease in human breast cancer patients. Additionally, various functional analysis revealed that miR-31 expression was both necessary and sufficient to impede breast cancer metastasis. These effects did not involve confounding influences on primary tumor development; instead, miR-31 exerted its anti-metastatic activities by impinging upon at least three distinct steps of the invasion-metastasis cascade: local invasion, one or more early post intravasation events, and metastatic colonization. At a mechanistic level, miR-31 impaired metastasis via the pleiotropic suppression of a cohort of target genes that otherwise operate to promote metastasis, including integrin a5, radixin, and RhoA. Significantly, the concomitant re-expression of integrin a5, radixin, and RhoA sufficed to override the full spectrum of miR-31'7s anti-metastatic activities. Moreover, the concurrent short hairpin RNA-conferred knockdown of endogenous integrin a5, radixin, and RhoA levels closely phenocopied the known consequences of ectopic miR-31 expression on metastasis. Integrin a5, radixin, and RhoA were found to act during at least partially unique steps of the invasion-metastasis cascade downstream of miR-31. Notably, the temporally controlled re-activation of miR-31 in already-established metastases elicited metastatic regression. These anti-metastatic therapeutic responses were attributable to the capacity of acutely re-expressed miR-31 to induce both cell cycle arrest and apoptosis; such effects arose specifically within the context of the foreign microenvironment present at a metastatic locus. When taken together, these findings provide mechanistic insights concerning the regulation of breast cancer metastasis and suggest that miR-31 may represent a clinically useful prognostic biomarker and/or therapeutic target in certain aggressive human carcinomas. In addition, a novel experimental system for the unbiased identification of metastasisrelevant genes was described. The utility of this system was demonstrated in an initial proof-of-concept screen, which implicated RhoJ as a previously unappreciated modulator of cell motility. Collectively, these observations imply that the single-cell clone-based screening methodology outlined herein may represent a generally useful means by which to enumerate novel regulators of various metastasis-relevant processes.
Author: Helge Großhans
Publisher: Springer
ISBN: 9781441978240
Category : Science
Languages : en
Pages : 160
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Book Description
Given this pervasiveness and importance of miRNA-mediated gene regulation, it should come as little surprise that miRNAs themselves are also highly regulated. However, the recent explosion of knowledge on this topic has been remarkable, providing a primary motivation for publication of this book. As miRNAs are transcribed by RNA polymerase II, the enzyme that also generates mRNAs, it was perhaps not unexpected that miRNA transcription would be subject to regulation, and we have willfully mitted this aspect from this monograph. However, what has been unexpected is the extent of post-transcriptional regulation of miRNAs that is illustrated in this book.
Author: Bin Wang
Publisher: CRC Press
ISBN: 9814411647
Category : Medical
Languages : en
Pages : 468
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Book Description
In the past few decades there has been incredible growth in "bionano"-related research, which has been accompanied by numerous publications in this field. Although various compilations address topics related to deoxyribonucleic acid (DNA) and protein, there are few books that focus on determining the structure of ribonucleic acid (RNA) and using RNA as building blocks to construct nanoarchitectures for biomedical and healthcare applications. RNA Nanotechnology is a comprehensive volume that details both the traditional approaches and the latest developments in the field of RNA-related technology. This book targets a wide audience: a broad introduction provides a solid academic background for students, researchers, and scientists who are unfamiliar with the subject, while the in-depth descriptions and discussions are useful for advanced professionals. The book opens with reviews on the basic aspects of RNA biology, computational approaches for predicting RNA structures, and traditional and emerging experimental approaches for probing RNA structures. This section is followed by explorations of the latest research and discoveries in RNA nanotechnology, including the design and construction of RNA-based nanostructures. The final segment of the book includes descriptions and discussions of the potential biological and therapeutic applications of small RNA molecules, such as small/short interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and ribozymes.
Author: Ulf Schmitz
Publisher: Springer Science & Business Media
ISBN: 9400755902
Category : Medical
Languages : en
Pages : 352
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Book Description
This edited reflects the current state of knowledge about the role of microRNAs in the formation and progression of solid tumours. The main focus lies on computational methods and applications, together with cutting edge experimental techniques that are used to approach all aspects of microRNA regulation in cancer. We are sure that the emergence of high-throughput quantitative techniques will make this integrative approach absolutely necessary in the near future. This book will be a resource for researchers starting out with cancer microRNA research, but is also intended for the experienced researcher who wants to incorporate concepts and tools from systems biology and bioinformatics into his work. Bioinformaticians and modellers are provided with a general perspective on microRNA biology in cancer, and the state-of-the-art in computational microRNA biology.
Author: Wafik S. El-Deiry
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 222
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Book Description
This volume presents the entire breadth of translational cancer research and brings together members of academia and industry in the expectation of accelerating interactions and progress in the field. A variety of key topics are presented, beginning with discovery of molecular targets and pathways (oncogene, cell survival, tumor suppression, cell death), host-neoplasm interactions (cell adhesion, matrix proteases), early detection, monitoring progression, understanding tumor progression and metastasis, immune surveillance, in vivo molecular imaging, animal models, drug discovery including chemistry, high-throughput assays, mechanism determination, target validation, therapeutic window and some progress in clinical trials for more advanced agents and targets.
