Roles of the MicroRNA MiR-31 in Tumor Metastasis and an Experimental System for the Unbiased Discovery of Genes Relevant for Breast Cancer Metastasis PDF Download
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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: 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: Cesar Lopez-Camarillo
Publisher: CRC Press
ISBN: 1466576774
Category : Medical
Languages : en
Pages : 426
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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 th
Author: William Kong
Publisher:
ISBN:
Category :
Languages : en
Pages : 280
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Book Description
ABSTRACT: Recent statistics reveal breast cancer as the most common cancer among women and accounts for approximately 41,000 mortalities per year. In diagnosis, features such as stage, grade, lymph node metastasis are important prognostic indicators that help guide physicians and oncologist towards optimal patient care. Presence of established pathological markers such as ER, PR, and Her2/neu status would indicate ideal adjuvant therapy situation. Although treatment of these types of breast cancer is well established, cancer that lack all three receptors, "triple negatives" or "basal like" do not respond to adjuvant therapy and are considered more aggressive in that patients tend to recur early and experience visceral metastasis. Although scientists have uncovered numerous molecular biology mechanisms in search of an understanding in cancer, leading to development of fields such as apoptosis or growth pathways; cell cycle; angiogenesis; metastasis; and more recently cancer stem cells, much work remains as cancer is still not eradicated. MicroRNAs (miRNAs) are post transcriptional regulators of gene expression. Their discovery and functional understanding have only been uncovered in the past ten years. Long pri-miRNAs are transcribed from the genome and processed into pre-miRNAs by Dicer; and then into short single stranded mature miRNAs complexed with Argonaute proteins to inhibit protein translation. The first link of miRNAs to cancer was made only relatively recently, but the field has expanded exponentially since. TGF-beta induced Epithelial to Mesenchymal Transition model in Normal Mouse Mammary Gland Epithelia Cells (NMuMG) is a commonly used model to dissect the molecular processes of breast cancer metastasis. Using miRNA microarray, we demonstrated miR-155 was upregulated along with alterations of other miRNAs. This observation was validated with Northern and qRT-PCR analysis. Promoter and ChIP analysis revealed TGF-beta activated the Smad4 transcriptional complex to induce the expression of miR-155. The reduction of RhoA protein levels by ubiquitination has been described to be a critical step during EMT, and we showed miR-155 down regulates RhoA proteins without degrading its mRNA levels; therefore, preventing de novo synthesis of RhoA proteins in the course of EMT. The interaction between miR-155 and RhoA's 3'UTR was confirmed by reporter assays. In summary, we reported the importance of miR-155 during TGF-beta induced EMT in NMuMG cells. FOXO3a is a well studied tumor suppressor transcriptional factor and resides in the nucleus to transcribe pro-apoptotic genes such as Bim, or p27 in the active state. During conditions when cells are signaled to grow and divide, it is phosphorylated by oncogenes such as AKT or IKK-beta, becomes inactivated and translocates into the cytoplasm. We have shown for the first time that FOXO3a activity is also regulated by miRNAs, specifically miR-155. Western and Northern analysis revealed a correlation between FOXO3a protein and mature miR-155 RNA levels in breast cancer cell lines along with breast tumor and normal tissues. Specifically, miR-155 expression is low in BT474 and high in HS578T, and inversely correlates with endogenous FOXO3a protein levels. Overexpression of miR-155 decreased endogenous FOXO3a protein and knockdown of miR-155 HS578T rescued its expression. Reporter assay experiments validated the interaction between miR-155 and FOXO3a 3'UTR. More importantly, overexpression of miR-155 in BT474 protected the cells from apoptosis induced by drugs while knockdown of miR-155 in HS578T initiated cell death even in the absence of drugs. In summary, we have shown the importance of miR-155 in chemosensitivity by targeting FOXO3a in breast cancer. MiR-155 has been previously shown up-regulated in multiple types of malignancies, including breast cancer. In addition, miR-155 expression was reported to correlate very strongly to survival in lung and pancreatic cancer. We validated by qRT-PCR and Northern analysis that miR-155 expression is detected only in breast tumors and not normal breast tissue. In situ hybridization of breast cancer tissue microarrays revealed similar results. In light of previous studies that showed a correlation between miR-155 and survival in lung and pancreatic cancers, we performed an X-tile analysis to determine an optimal cut point for miR-155 level in our breast cancer sample population that would correlate to ten years overall survival. Verification using Kaplan-Meier validated a cut point at 90.14 to significantly correlate to overall survival (P=0.007). In addition, Chi-square analysis revealed miR-155 expression to correlate with high tumor stage, grade and lymph node metastasis. However, miR-155 expression did not correspond to ER, PR, or HER2/neu status, but this is hardly surprising since computational analysis does not predict miR-155 to target these genes. In summary, we have shown deviant expression of miR-155 in breast cancer. Due to its correlation with overall survival; higher grade and stage; lymph node metastasis, and triple negative subtype, miR-155 may prove to be a valuable prognostic marker and therapeutic target for breast cancer intervention.
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: Shree Ram Singh
Publisher: Springer Science & Business
ISBN: 1489980652
Category : Medical
Languages : en
Pages : 410
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Book Description
miRNAs are a class of endogenous, small non-protein coding RNA molecules (~ 22 nucleotides) which are novel post-transcriptional regulators of gene expression. Since we have hundreds of miRNAs, the major challenge is now to understand their specific biological function. In fact the experimental evidence suggests that signaling pathways could be ideal candidates for miRNA-mediated regulation. Several studies suggest that miRNAs affect the responsiveness of cells to signaling molecules such as WNT, Notch, TGF-β and EGFR. Altered expression of particular miRNAs has been implicated in the onset and development of cancer and could be used as potential biomarkers for the disease. Recently, many studies have found miRNAs have crucial regulatory roles in Cancer stem cells (CSCs) a kind of tumor initiating cells (TICs) and dormancy. Findings also suggest that DNA methylation may be important in regulating the expression of many miRNAs in several cancer initiating cells. Several miRNAs are known to either upregulated or downregulated in CSCs when compared to non-cancerous cells from the same tissues. CSCs are a small subpopulation of cells identified in a variety of tumors and involve in self-renewal, differentiation, chemoresistance and tumorigenesis. The volume will give a comprehensive account of important advancements in the area of miRNAs and cancer.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 41
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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: William C.S. Cho
Publisher: Springer Science & Business Media
ISBN: 9400702981
Category : Medical
Languages : en
Pages : 553
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Book Description
MicroRNA (miRNA) is a cutting-edge topic in the scientific and medical fields. This is a timely and specialized book focusing on the current understanding of miRNAs and the potential for their application in cancer diagnosis, prognosis, and therapeutic targets. It also provides discussion of the lessons learned from translational miRNA studies and exploration of the next steps required to advance this field. The unique book comprises 22 in-depth chapters by gathering unparalleled topics of interest in miRNAs by international team of world-renowned experts in the field. The first fifteen chapters provide comprehensive and expert perspectives on the most common cancers from bench to bedside applications, there is no current book structured in this cancer-oriented way. The next seven chapters providing thorough overviews of miRNAs and cancer stem cells; miRNAs in cancer invasion and metastasis; miRNAs in predicting radiotherapy and chemotherapy response; as well as expounding the role of miRNA in anti-cancer drug resistance and as blood-based cancer biomarkers. Furthermore, this book explicates the interplay of miRNAs in cancer metabolism and an update on the pioneering RNAi-based treatment approaches is also presented. This specialized book will contribute great to the scientific and medical community by providing the up-to-date discoveries of miRNAs and their important roles in cancer translational research.
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: Seema Sethi
Publisher: Springer
ISBN: 3319081624
Category : Medical
Languages : en
Pages : 83
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Book Description
This SpringerBrief gives the latest research on the role of miRNAs in breast cancer metastasis. MicroRNAs (miRNAs) are recently described small endogenous noncoding RNAs implicated in the posttranscriptional control of gene expression. These tiny molecules are involved in developmental, physiologic phenomenon as well as pathologic processes including cancers. In fact, miRNAs have emerged as critical regulators of cancer progression, invasion and metastasis. This is mainly because a single miRNA can affect several downstream genes and signaling pathways with oncogenic or tumor suppressor actions depending on the target genes affected. Due to this multimodal downstream signaling effects, these small endogenous molecules hold great promise in metastasis prevention and treatment. Modulating the activity of miRNAs can provide opportunities for novel cancer interventions. Targeting miRNAs could become a novel prognostic and therapeutic strategy to prevent the future development of metastasis. Thus, miRNAs could also serve as a potential targets for anti-metastatic therapy. The book explores how the expression of miRNAs in the primary tumor could be silenced using antagomirs (chemically modified anti-miRNA oligonucleotides), which could prevent the development of metastasis; whereas once metastasis develops then it could be treated with miRNA mimics for inducing its expression for the treatment. Therefore, development of miRNA-based prophylactic therapies could serve as precision and personalized medicine against future development of metastasis of breast and other cancers.
Author: DKV Prasad
Publisher: Springer Nature
ISBN: 981169186X
Category : Medical
Languages : en
Pages : 183
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Book Description
This book discusses the potential roles of miRNA as a crucial regulator in cancer biology. It examines the regulation of drug resistance by miRNAs in cancers and the mechanism of their deregulated expression. The book discusses the role and molecular mechanism of miRNA in regulating cellular proliferation and cell cycle. It analyses circulating miRNAs as biomarkers for cancer diagnosis and prognosis. It also analyzes the role of miRNA as a modulator of the development and function of tumor-associated immune cells. It explores the cross-talk between miRNA and reactive oxygen species (ROS) in pathogenesis, cancer therapeutic tolerance, and resistance. It provides insights into the role of miRNA in cancer angiogenesis, metastasis and describes strategies and associated challenges of miRNA-based therapies.
