DOCSLIB.ORG

Alterations and Mutations in Bruton's Tyrosine Kinase Affect The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alterations and Mutations in Bruton's Tyrosine Kinase Affect The Alterations and mutations in Bruton’s tyrosine kinase affect the transcriptional profile and phenotype of chronic lymphocytic leukemia cells DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Daphne Allyn Guinn Graduate Program in Integrated Biomedical Science Program The Ohio State University 2016 Dissertation Committee: John Byrd, MD, Co-Advisor Amy Johnson, PhD, Co-Advisor Flavia Pichiorri, PhD Albert de la Chapelle, MD, PhD Copyright by Daphne Allyn Guinn 2016 Abstract Chronic Lymphocytic Leukemia (CLL) is currently an incurable disease. The current front-line therapy is chemoimmunotherapy, which is associated with significant toxicity and immunosuppression. Targeted therapeutics have the potential to provide well-tolerated therapies, however the lack of a unifying genetic alteration in CLL has made target identification difficult. Activation of B cell receptor signaling (BCR) is aberrant leading to enhanced pro-survival signaling. An integral kinase in the BCR pathway, Bruton agammaglobulinemia Tyrosine Kinase (BTK) was identified as a viable target in CLL. Targeting BTK with ibrutinib, an irreversible inhibitor, can decrease pro- survival signaling, has significant clinical activity and is now FDA approved. Some patients on long-term ibrutinib therapy acquire a point mutation in ibrutinib’s binding site (BTKC481S). This mutation renders ibrutinib a reversible inhibitor reducing the efficacy of the drug. Determining the transcriptional and phenotypic differences after alteration of BTK is integral for understanding the role of BTK in CLL progression and development of targeted agents to subvert resistance. It is known that ibrutinib targets CLL survival signaling, but it is not known how targeting BTK alters the microRNA (miR) profile. Lymphocytes from ibrutinib treated patients were collected pre- and post-therapy and were analyzed by miR Nanostring. A unique profile of differentially expressed miRs was identified. OncomiR, miR-155 was confirmed to be down-modulated with ibrutinib therapy. Analysis of miR-155 expression ii was done on responding versus relapse patients on long-term ibrutinib therapy. miR-155 expression remained down-modulated in responding patients, but was elevated in relapsed patients. We conclude that miR-155 can be favorably down-modulated by ibrutinib treatment and may play a role in resistance. Another novel miR identified was tumor suppressive, miR-126. In our studies, we show that miR-126 is reduced with CLL disease progression. miR-126 expression is negatively correlated with levels of p85β, a regulatory subunit of PI3K complex, in CLL patients and in miR-126 overexpression cells lines. This study identified a novel miR and its role in targeting PI3K complex in CLL. The development of the BTKC481S ibrutinib resistant mutation is associated with shorter patient survival after relapse. To study the growth advantage the resistant clone provides, B lymphocyte cell lines that are lacking BTK were obtained and BTKWT and BTKC481S were expressed. Infection with BTKC481S rendered the cells ibrutinib resistant. The BTKC481S shows enhanced kinase activity, migration, pro-survival signaling and increased levels of immune modulatory molecules. After engraftment of BTKWT and BTKC481S cell lines into NSG mice, the mice who received mutant cells had a shorter median survival. Overall we see BTKC481S significantly alters the phenotype of the cells leading to survival of the resistant clone. In conclusion, this work demonstrates that targeting BTK with ibrutinib can alter the miR profile of the CLL cells, identifying miR-155 and miR-126 as having a role in CLL disease biology. We have also shown that cells that acquire the BTKC481S mutation have enhanced activity and can accelerate disease progression. Overall we can conclude iii that alterations to BTK through pharmacological inhibition or mutation can affect the CLL disease phenotype. iv Dedication To my wonderfully supportive family and friends v Acknowledgments First I would like to thank my mentor Dr. John Byrd. You are an inspiration every day. The passion you have for you patients, science and life is an inspiration. Thank you for asking the hard questions and constantly striving to achieve your best. I greatly appreciated the way you can look at negative data and find the silver lining. Thank you for you high standard of ethical conduct in the laboratory and in clinic. The constant reminder that our research is impactful and could lead to clinical breakthroughs is a driving force for me every day. Finally thank you for seeing something in me and investing your time to mold me into the scientist I am today. To my co-mentor, Dr. Amy Johnson, you are an amazing woman and you lead by example. Thank you for you direct, but constructive mentorship style. I initially wanted you as a mentor because of your honesty and the fantastic projects you had to offer. The science was not always easy and you made sure to make time to help me through the difficult experiments. Thank you for all the weekly meetings of talking science and sharing your wisdom. I hope to be as successful as you at solving new scientific problems and enjoying life. I also want to thank my committee members, Drs. Flavia Pichiorri and Albert de la Chapelle for your time, thoughtful questions and guidance through my graduate school experience. Thank you to Drs. Jennifer Woyach, Erin Hertlein, David Lucas and Yuh-Ying Yeh, for your advice and mentorship over the years, having so many brilliant scientists around really vi made the laboratory a fun and innovatively environment. I would also like to thank all the Byrd lab members, each one of you has played an important role in my growth as a scientist. First to Derek West, thank you for all that you do, I cannot begin to list the number of things you have done for me over the years, but I greatly appreciate it all. To the Byrd lab technicians, especially Lisa Smith, Frank Frissora, Katie Williams, Arletta Lozanski, Carolyn Cheney, and Shelley Orwick, who gave such great advice and help. To the undergraduate students that I had the pleasure to mentor, Ben Whitfield and Catherine Fabian, thanks for your optimism and hard work, being your mentor was so rewarding and fun. To all the Byrd lab graduate students thanks for support and sharing in the gratifying experience that is getting a PhD, journal club, lab meeting, and the occasional happy hour. Especially to Priscilla Do, Cecelia Miller, and Tim Chen, thank you for your friendship, the lunchtime talks, experiment advice and all the adventures. To my IBGP friends and their significant others, Brynn Hollingsworth, Chris Buettner, Jacque Corry and JC Regan, I am so happy that I had the opportunity to meet and get to know you. You have been amazing friends and I wish you all the best of luck, as you move on as well. Thank you to my family in-law, Joe, Karla, and Sam. I couldn’t have married into a more loving and supportive family. To my siblings and niece and nephew, you helped mold me into the woman I am today with all your humor and love. To my parents, Chuck and Beth Guinn, you are the two best parents a girl could have. Thank you for teaching me the value of hard work and perseverance. You have made me the women I am today with your love, faith and support. I love you so much and you make me proud every day to call you my parents. To my amazing and super supportive husband, I couldn’t have done vii this without you. Thank you for your patience and love. You have been with me every step of the way, keeping me company during long nights of studying, driving me to work on late nights and weekends, and providing me words of support when I needed them the most. I cannot wait to see where our next step in life takes us. Finally I would like to thank all the CLL patients that consented to provide samples as part of clinical trials at OSU. Without your help, this work would not have been possible. viii Vita December 7, 1988 ....................................Born, Columbus, OH May 2011 .................................................B.S. Toxicology/Biology, Ashland University July 2011 to present ................................Graduate Research Associate, Biomedical Science Graduate Program, The Ohio State University Publications Guinn D, Lehman A, Yu L, Maddocks K, Jaglowski S, Woyach J, Byrd JC, and Johnson AJ. The regulation of tumor suppressive microRNA, miR-126, in chronic lymphocytic leukemia. In preparation Woyach JA*, Guinn D*, Ruppert AS, Lehman A, Blachly JS, Lozanski A, et al. Resistance to ibrutinib in Chronic Lymphocytic Leukemia is due to mutations in BTK and PLCG2 that are associated with an aggressive disease phenotype and poor outcomes. In preparation. Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith LL, Williams K, Johnson AJ, Lehman AM, Byrd JC, Woyach JA, Lapalombella R. (2015) Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood 125: 3128-3132. Guinn D, Ruppert AS, Maddocks K, Jaglowski S, Gordon A, Lin TS, Larson R, Marcucci G, Hertlein E, Woyach J, Johnson AJ, and Byrd JC. (2015). miR-155 expression is associated with chemoimmunotherapy outcome and is modulated by Bruton’s tyrosine kinase inhibition with Ibrutinib. Leukemia 29:1210-1213. Dong S, Guinn D, Dubovsky JA, Zhong Y, Lehman A, Kutok J, Woyach JA, Byrd JC, Johnson AJ. (2014). IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 124: 3583-3586. ix Fields of Study Major Field: Integrated Biomedical Science Program Area of Research Emphasis: Experimental Therapeutics, Chronic Lymphocytic Leukemia, microRNAs, Kinase inhibitors, B cell receptor signaling x Table of Contents Abstract ............................................................................................................................... ii Dedication ..........................................................................................................................
Load more

Recommended publications
  • Non-Coding Rnas As Cancer Hallmarks in Chronic Lymphocytic Leukemia
    International Journal of Molecular Sciences Review Non-Coding RNAs as Cancer Hallmarks in Chronic Lymphocytic Leukemia Linda Fabris 1, Jaroslav Juracek 2 and George Calin 1,* 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] 2 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] * Correspondence: [email protected] Received: 24 July 2020; Accepted: 10 September 2020; Published: 14 September 2020 Abstract: The discovery of non-coding RNAs (ncRNAs) and their role in tumor onset and progression has revolutionized the way scientists and clinicians study cancers. This discovery opened new layers of complexity in understanding the fine-tuned regulation of cellular processes leading to cancer. NcRNAs represent a heterogeneous group of transcripts, ranging from a few base pairs to several kilobases, that are able to regulate gene networks and intracellular pathways by interacting with DNA, transcripts or proteins. Deregulation of ncRNAs impinge on several cellular responses and can play a major role in each single hallmark of cancer. This review will focus on the most important short and long non-coding RNAs in chronic lymphocytic leukemia (CLL), highlighting their implications as potential biomarkers and therapeutic targets as they relate to the well-established hallmarks of cancer. The key molecular events in the onset of CLL will be contextualized, taking into account the role of the “dark matter” of the genome. Keywords: chronic lymphocytic leukemia; lncRNA; miRNA; hallmarks 1. Introduction: Current Status of Chronic Lymphocytic Leukemia Research Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world, representing more than 30% of all leukemia cases [1].
    [Show full text]
  • Micrornas Mediated Regulation of the Ribosomal Proteins and Its Consequences on the Global Translation of Proteins
    cells Review microRNAs Mediated Regulation of the Ribosomal Proteins and Its Consequences on the Global Translation of Proteins Abu Musa Md Talimur Reza 1,2 and Yu-Guo Yuan 1,3,* 1 Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; [email protected] 2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawi´nskiego5a, 02-106 Warsaw, Poland 3 Jiangsu Key Laboratory of Zoonosis/Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China * Correspondence: [email protected]; Tel.: +86-514-8797-9228 Abstract: Ribosomal proteins (RPs) are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases, and are important structural components of the ribosome, which is a supramolecular ribonucleoprotein complex, composed of Ribosomal RNA (rRNA) and RPs, coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors. Not all RPs are indispensable; in other words, the ribosome could be functional and could continue the translation of proteins instead of lacking in some of the RPs. However, the lack of many RPs could result in severe defects in the biogenesis of ribosomes, which could directly influence the overall translation processes and global expression of the proteins leading to the emergence of different diseases including cancer. While microRNAs (miRNAs) are small non-coding RNAs and one of the potent regulators of the post-transcriptional 0 gene expression, miRNAs regulate gene expression by targeting the 3 untranslated region and/or coding region of the messenger RNAs (mRNAs), and by interacting with the 50 untranslated region, Citation: Reza, A.M.M.T.; Yuan, Y.-G.
    [Show full text]
  • Oncomir Mir-125B Regulates Hematopoiesis by Targeting the Gene Lin28a
    Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A Aadel A. Chaudhuria,1, Alex Yick-Lun Soa,1, Arnav Mehtaa, Aarathi Minisandrama, Nikita Sinhaa, Vanessa D. Jonssonb, Dinesh S. Raoc, Ryan M. O’Connelld, and David Baltimorea,2 Departments of aBiology and bComputing and Mathematical Sciences, California Institute of Technology, Pasadena, CA 91125; cDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and dDepartment of Pathology, University of Utah, Salt Lake City, UT 84112 Contributed by David Baltimore, January 23, 2012 (sent for review October 29, 2011) MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. regulation of miR-125b has profound effects on normal hema- Overexpression of miR-125b alone in mice causes a very aggressive, topoiesis, and Lin28A overexpression mimics those effects. transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; Results rather, the hematopoietic compartment shows lineage-skewing, with miR-125b Ectopic Expression Favors Myeloid Differentiation and myeloid cell numbers dramatically increased and B-cell numbers Causes a Highly Invasive Myeloid Leukemia. Previously, we showed severely diminished. miR-125b exerts this effect by up-regulating the that overexpression of miR-125b in bone marrow-transplanted number of common myeloid progenitors while inhibiting develop- recipient mice causes a myeloid leukemia 4–6 mo after bone ment of pre-B cells. We applied a miR-125b sponge loss of function marrow reconstitution (5). Here, we found that the neoplastic system in vivo to show that miR-125b physiologically regulates myeloid cells infiltrate nonhematopoietic organs, including the hematopoietic development.
    [Show full text]
  • The Oncogenic Role of Mir-155 in Breast Cancer
    Published OnlineFirst June 26, 2012; DOI: 10.1158/1055-9965.EPI-12-0173 Cancer Epidemiology, MiniReview Biomarkers & Prevention The Oncogenic Role of miR-155 in Breast Cancer Sam Mattiske, Rachel J. Suetani, Paul M. Neilsen, and David F. Callen Abstract miR-155isanoncogenicmiRNAwithwelldescribedrolesinleukemia.However,additionalrolesof miR-155 in breast cancer progression have recently been described. A thorough literature search was conducted to review all published data to date, examining the role of miR-155 in breast cancer. Data on all validated miR-155 target genes was collated to identify biologic pathways relevant to miR-155 and breast cancer progression. Publications describing the clinical relevance, functional characterization, and regu- lation of expression of miR-155 in the context of breast cancer are reviewed. A total of 147 validated miR- 155 target genes were identified from the literature. Pathway analysis of these genes identified likely roles in apoptosis, differentiation, angiogenesis, proliferation, and epithelial–mesenchymal transition. The large number of validated miR-155 targets presented here provide many avenues of interest as to the clinical potential of miR-155. Further investigation of these target genes will be required to elucidate the specific mechanisms and functions of miR-155 in breast cancer. This is the first review examining the role of miR- 155 in breast cancer progression. The collated data of target genes and biologic pathways of miR-155 identified in this review suggest new avenues of research for this oncogenic miRNA. Cancer Epidemiol Biomarkers Prev; 21(8); 1236–43. Ó2012 AACR. Introduction found to regulate levels of LIN-14 protein (7, 8). Since this miRNAs are small noncoding RNAs that control discovery, there have been over 500 miRNAs described, expression of target genes by either inhibiting protein regulating a wide range of genes and cellular processes, translation or directly targeting mRNA transcripts of although the total predicted number of unique miRNAs target genes for degradation (1).
    [Show full text]
  • Development of Novel Therapeutic Agents by Inhibition of Oncogenic Micrornas
    International Journal of Molecular Sciences Review Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs Dinh-Duc Nguyen and Suhwan Chang * ID Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea; [email protected] * Correspondence: [email protected] Received: 21 November 2017; Accepted: 22 December 2017; Published: 27 December 2017 Abstract: MicroRNAs (miRs, miRNAs) are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge. In contrast, an indirect approach is to block the biogenesis of miRNA by genome editing using the CRISPR/Cas9 system or a small molecule inhibitor. The development of these inhibitors is straightforward but involves significant scientific and therapeutic challenges that need to be resolved. In this review, we summarize recent relevant studies on the development of miRNA inhibitors against cancer. Keywords: antimiR; antagomiR; miRNA-sponge; oncomiR; CRISPR/Cas9; cancer therapeutics 1. Introduction Cancer has been the leading cause of death and a major health problem worldwide for many years; basically, it results from out-of-control cell proliferation. Traditionally, several key proteins have been identified and found to affect signaling pathways regulating cell cycle progression, apoptosis, and gene transcription in various types of cancers [1,2].
    [Show full text]
  • Microrna-155-3P Promotes Hepatocellular Carcinoma Formation
    Tang et al. Journal of Experimental & Clinical Cancer Research (2016) 35:93 DOI 10.1186/s13046-016-0371-6 RESEARCH Open Access MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression Bo Tang1,2†, Biao Lei1,2†, Guangying Qi3†, Xingsi Liang1,2, Fang Tang1,2, Shengguang Yuan1,2, Zhenran Wang1,2, Shuiping Yu1,2 and Songqing He1,2* Abstract Background: MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignant tumors. In the present study, we analyzed the role miR-155-3p plays in Hepatocellular carcinoma (HCC), which has been reported participation in some other types of cancer. Methods: qRT-PCR was used to measure the levels of miR-155-3p in HCC specimens and HCC cell lines. Overexpression of miR-155-3p and miR-155-3p inhibitor were transfected into HCC cell lines to investigate its role in HCC. Colony formation assay and 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays were used to analyses cell proliferation in vitro. In vivo tumor formation assays were performed in BALB/c nude mice. Luciferase reporter assay was carried out to measure the translation of F-Box and WD repeat romain containing 7 (FBXW7). Results: We found that miR-155-3p was remarkably upregulated both in HCC tissue and cell lines. Overexpression of miR-155-3p enhanced HCC cell proliferation in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155-3p is correlated with decreased levels FBXW7 mainly through inhibiting the expression of FBXW7. Conclusions: Our studies suggest that miR-155-3p plays an important role in the pathogenesis of HCC and implicates its potential applications in the treatment of HCC cancer.
    [Show full text]
  • Integrative Genome Analysis Reveals an Oncomir/ Oncogene Cluster Regulating Glioblastoma Survivorship
    Integrative genome analysis reveals an oncomir/ oncogene cluster regulating glioblastoma survivorship Hyunsoo Kima,1, Wei Huangb,1, Xiuli Jiangb, Brenton Pennicookeb, Peter J. Parka,2, and Mark D. Johnsonb,3 aHarvard Partners Center for Genetics and Genomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and bDepartment of Neurological Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 Edited by Jonathan G. Seidman, Harvard Medical School, Boston, MA, and approved December 4, 2009 (received for review September 1, 2009) Using a multidimensional genomic data set on glioblastoma from cooperates with CDK4 and CENTG1 to increase GBM growth. The Cancer Genome Atlas, we identified hsa-miR-26a as a cooper- Amplification of this oncomir/oncogene cluster correlates with ating component of a frequently occurring amplicon that also shortened survival in GBM patients. contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA Results copy number, mRNA, microRNA, and DNA methylation data, we miR-26a Is a Frequent Target of the 12q13.3–14.1 Amplicon. Analysis identified functionally relevant targets of miR-26a in glioblastoma, of TCGA data from GBM revealed numerous genomic alter- including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that ations (3). To identify microRNAs that are likely to play a key miR-26a alone can transform cells and it promotes glioblastoma role in GBM, we searched for microRNAs whose expression is cell growth in vitro and in the mouse brain by decreasing PTEN, driven by copy number.
    [Show full text]
  • Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies
    International Journal of Molecular Sciences Review Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies 1, 2, 2 2, Kinga B. Stopa y , Agnieszka A. Kusiak y, Mateusz D. Szopa , Pawel E. Ferdek * and Monika A. Jakubowska 1,* 1 Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7A, 30-387 Krakow, Poland; [email protected] 2 Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland; [email protected] (A.A.K.); [email protected] (M.D.S.) * Correspondence: [email protected] (P.E.F.); [email protected] (M.A.J.) These authors contributed equally to this work. y Received: 9 April 2020; Accepted: 29 April 2020; Published: 1 May 2020 Abstract: Pancreatic ductal adenocarcinoma (PDAC) causes annually well over 400,000 deaths world-wide and remains one of the major unresolved health problems. This exocrine pancreatic cancer originates from the mutated epithelial cells: acinar and ductal cells. However, the epithelia-derived cancer component forms only a relatively small fraction of the tumor mass. The majority of the tumor consists of acellular fibrous stroma and diverse populations of the non-neoplastic cancer-associated cells. Importantly, the tumor microenvironment is maintained by dynamic cell-cell and cell-matrix interactions. In this article, we aim to review the most common drivers of PDAC. Then we summarize the current knowledge on PDAC microenvironment, particularly in relation to pancreatic cancer therapy. The focus is placed on the acellular stroma as well as cell populations that inhabit the matrix.
    [Show full text]
  • Research Article Mir-31 Functions As an Oncomir Which Promotes Epithelial-Mesenchymal Transition Via Regulating BAP1 in Cervical Cancer
    Hindawi BioMed Research International Volume 2017, Article ID 6361420, 12 pages https://doi.org/10.1155/2017/6361420 Research Article miR-31 Functions as an Oncomir Which Promotes Epithelial-Mesenchymal Transition via Regulating BAP1 in Cervical Cancer Nan Wang,1 Yong Li,2 andJianhongZhou1 1 Laboratory of Molecular Biology, College of Life Science, Jiaying University, Meizhou 514015, China 2Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, China Correspondence should be addressed to Nan Wang; [email protected] Received 16 May 2017; Accepted 29 August 2017; Published 11 October 2017 Academic Editor: Stephen H. Safe Copyright © 2017 Nan Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MicroRNA-31 (miR-31) functions as tumor suppressors or oncogenes that are involved in tumor behavior. However, the function of miR-31 in cervical carcinogenesis remains unclear. The aim of this study was to validate the potential role of miR-31 and BRCA1- associated protein-1 (BAP1) on regulating epithelial-mesenchymal transition (EMT) in cervical cancer. In the present study, qRT- PCR assay revealed that the expression of miR-31 was upregulated in human cervical cancer cells and clinical tissues. Results of wound healing and cell migration assay revealed that knockdown of miR-31 inhibited cell metastasis and migration. Bioinformatic and dual-luciferase reporter gene assay showed that BAP1 was the direct target of miR-31.
    [Show full text]
  • Tumor Penetrating Nanomedicine Targeting Both an Oncomir and an Oncogene in Pancreatic Cancer
    www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 51), pp: 5349-5358 Research Paper Tumor penetrating nanomedicine targeting both an oncomiR and an oncogene in pancreatic cancer Maud-Emmanuelle Gilles1, Liangliang Hao2,3, Kaelyn Brown1, Jihoon Lim1, Sangeeta N. Bhatia2,3,4,5,6,7 and Frank J. Slack1 1HMS Initiative for RNA Medicine, Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 2Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA 3Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA 4Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 5Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA 6Howard Hughes Medical Institute, Cambridge, Massachusetts, USA 7Marble Center for Cancer Nanomedicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Correspondence to: Frank J. Slack, email: [email protected] Keywords: miRNAs; KRAS; RNA-based-therapy; PDAC; tumor-penetrating nanocomplexes Received: March 28, 2019 Accepted: July 28, 2019 Published: September 03, 2019 Copyright: Gilles et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Developing new targeted therapy for pancreatic cancer is one of the major current challenges in cancer research. KRAS mutations and miRNA dysregulation (e.g. miR-21-5p oncomiR) play key roles in Pancreatic Ductal Adenocarcinoma (PDAC), leading to rapid progression of the disease.
    [Show full text]
  • A Feedback Loop Between Mirna-155, Programmed Cell Death 4 and Activation Protein-1 Modulates the Expression of Mir-155 and Tumorigenesis in Tongue Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/394130; this version posted August 17, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A feedback loop between miRNA-155, Programmed cell death 4 and Activation Protein-1 modulates the expression of miR-155 and tumorigenesis in tongue cancer Shabir Zargar1, Vivek Tomar2, Vidyarani Shyamsundar 3, Ramshankar Vijayalakshmi4, Kumaravel Somasundaram2 and Devarajan Karunagaran1 1 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India 2 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 3 Center for Oral Cancer Prevention Awareness and Research, Sree Balaji Dental College and Hospital, Bharath University, Chennai, India 4 Department of Preventive Oncology, Cancer Institute, Adyar, Chennai, India Correspondence: Dr D Karunagaran, E-mail: [email protected], +91-44-2257-4126 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Adyar, Chennai 600036, India Running title: miR-155/Pdcd4/AP-1 feedback loop in tongue cancer. Keywords: miR-155, Pdcd4, AP-1, NF-κB, BIC, miR-155 sponge, apoptosis, tumor xenografts. 1 bioRxiv preprint doi: https://doi.org/10.1101/394130; this version posted August 17, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT miR-155 is an oncomir, generated as a non-coding RNA from BIC gene whose promoter activity is mainly controlled via AP-1 and NF-κB transcription factors.
    [Show full text]
  • The E2F3-Oncomir-1 Axis Is Activated in Wilms' Tumor
    Priority Report The E2F3-Oncomir-1 Axis Is Activated in Wilms’ Tumor Eric J. Kort,1,2 Leslie Farber,2 Maria Tretiakova,5 David Petillo,2 Kyle A. Furge,3 Ximing J. Yang,6 Albert Cornelius,4 and Bin T. Teh2,7 Laboratories of 1Molecular Epidemiology, 2Cancer Genetics, and 3Computational Biology, Van Andel ResearchInstitute; 4Division of Pediatric Hematology/Oncology, De Vos Children’s Hospital, Grand Rapids, Michigan; 5Department of Pathology, University of Chicago; 6Department of Pathology, Northwestern University, Chicago, Illinois; and 7NCCS-VARI Translational ResearchLaboratory, National Cancer Centre, Singapore Abstract Our results indicated that the E2F3 signature is strongly Oncomir-1 is an oncogenic cluster of microRNAs (miRNA) activated in WT samples—a phenomenon not consistently located on chromosome 13. Previous in vitro studies showed observed in other renal tumors. E2F3 is an activator of that it is transcriptionally regulated by the transcription transcription that is amplified or overexpressed in several tumors, factor E2F3. In this report, we combine expression profiling of including those of the bladder (4), prostate (5), and lung (6). Interestingly, E2F3 has been shown to drive the expression of both mRNA and miRNAs in Wilms’ tumor (WT) samples to Oncomir-1 in vitro Oncomir-1 provide the first evidence that the E2F3-Oncomir-1 axis, (7). is an oncogenic cluster of previously identified in cell culture, is deregulated in primary miRNAs located on chromosome 13 that has been shown to play an important role in promoting tumor cell proliferation (8). Here, we human tumors. Analysis of RNA expression signatures showed Oncomir-1 in vivo that an E2F3 gene signature was activated in all WT samples show that both E2F3 and are overexpressed in analyzed, in contrast to other kidney tumors.
    [Show full text]