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Interleukin-1β Promotes Ovarian Tumorigenesis through a p53/NF-κB-Mediated Inflammatory Response in Stromal Fibroblasts

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NEOPLASIA 2013年第4期15卷 409-+页

作者： Schauer, Isaiah Gregory Zhang, Jing Xing, Zhen Guo, Xiaoqing Mercado-Uribe, Imelda Sood, Anil K. Huang, Peng Liu, Jinsong Univ Texas MD Anderson Canc Ctr Dept Pathol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNA Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Mol Pathol Houston TX 77030 USA

Cancer has long been considered a disease that mimics an "unhealed wound," with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1 beta (IL-1 beta) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1 beta and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-alpha), IL-6, IL-1 beta, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-kappa B) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1 beta as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.

关键词： OVARIAN cancer RESEARCH INTERLEUKIN-1 CANCER invasiveness CANCER cells VASCULAR endothelial growth factors TUMORS -- Growth

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Nanotechnology in cancer therapy

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JOUrnaL OF DRUG TARGETING 2013年第10期21卷 904-913页

作者： Aslan, Burcu Ozpolat, Bulent Sood, Anil K. Lopez-Berestein, Gabriel Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNA Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas Hlth Sci Ctr Houston UTHealth Dept Nanomed & Bioengn Houston TX USA

Cancer is one of the major causes of mortality worldwide and advanced techniques for therapy are urgently needed. The development of novel nanomaterials and nanocarriers has allowed a major drive to improve drug delivery in cancer. The major aim of most nanocarrier applications has been to protect the drug from rapid degradation after systemic delivery and allowing it to reach tumor site at therapeutic concentrations, meanwhile avoiding drug delivery to normal sites as much as possible to reduce adverse effects. These nanocarriers are formulated to deliver drugs either by passive targeting, taking advantage of leaky tumor vasculature or by active targeting using ligands that increase tumoral uptake potentially resulting in enhanced antitumor efficacy, thus achieving a net improvement in therapeutic index. The rational design of nanoparticles plays a critical role since structural and physical characteristics, such as size, charge, shape, and surface characteristics determine the biodistribution, pharmacokinetics, internalization and safety of the drugs. In this review, we focus on several novel and improved strategies in nanocarrier design for cancer therapy.

关键词： Cancer therapy drug delivery nanoparticles nanomedicine

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Profiling of Ribose Methylations in rna by High‐Throughput Sequencing†

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Angewandte Chemie 2014年第2期127卷

作者： Ulf Birkedal Mikkel Christensen‐Dalsgaard Nicolai Krogh Radhakrishnan Sabarinathan Jan Gorodkin Henrik Nielsen Department of Cellular and Molecular Medicine University of Copenhagen Blegdamsvej 3B 2200 Copenhagen N (Denmark) Center for Non‐coding RNA in Technology and Health Department of Veterinary Clinical and Animal Science University of Copenhagen Grønnegårdsvej 3 1870 Frederiksberg C (Denmark)

Ribose methylations are the most abundant chemical modifications of ribosomal rna and are critical for ribosome assembly and fidelity of translation. Many aspects of ribose methylations have been difficult to study due to lack of efficient mapping methods. Here, we present a sequencing‐based method (RiboMeth‐seq) and its application to yeast ribosomes, presently the best‐studied eukaryotic model system. We demonstrate detection of the known as well as new modifications, reveal partial modifications and unexpected communication between modification events, and determine the order of modification at several sites during ribosome biogenesis. Surprisingly, the method also provides information on a subset of other modifications. Hence, RiboMeth‐seq enables a detailed evaluation of the importance of rna modifications in the cells most sophisticated molecular machine. RiboMeth‐seq can be adapted to other rna classes, for example, mrna, to reveal new biology involving rna modifications.

关键词： Ribosome Ribozyme rna‐Erkennung rna‐Strukturen Transferasen

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Corrigendum to “A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group study” [Gynecol Oncol 127 (2012) 538–543 ]

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Gynecologic Oncology 2013年第1期130卷 252-253页

作者： Coleman, Robert L. Sill, Michael W. Lankes, Heather A. Fader, Amanda Nickles Finkler, Neil J. Hoffman, James S. Rose, Peter G. Sutton, Gregory P. Drescher, Charles W. McMeekin, D. Scott Hu, Wei Deavers, Michael Godwin, Andrew K. Alpaugh, R. Katherine Sood, Anil K. Dept. of Gynecologic Oncology & Reproductive Medicine University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA Gynecologic Oncology Group Statistical & Data Center Roswell Park Cancer Institute Buffalo NY 14263 USA Gynecologic Oncology/Clinical Trials Dept. Walter Reed National Military Medical Center — Bethesda Bethesda MD 20889 USA Dept. of Obstetrics & Gynecology Division of Gynecologic Oncology Florida Hospital Cancer Institute Orlando FL 32804 USA Dept. of Obstetrics & Gynecology Division of Gynecologic Oncology The Hospital of Central Connecticut New Britain CT 06050 USA Dept. of Obstetrics & Gynecology Division of Gynecologic Oncology Cleveland Clinic Foundation Cleveland OH 44195 USA Dept. of Obstetrics & Gynecology Division of Gynecologic Oncology Saint Vincent's Hospital Indianapolis IN 46260 USA Pacific Gynecologic Specialists PD Seattle WA 98104 USA Dept. of Obstetrics & Gynecology Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK 73190 USA Dept. of Pathology University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA Dept. of Pathology The University of Kansas Medical Center Kansas City KS 66160 USA Protocol Support Laboratory Fox Chase Cancer Center Philadelphia PA 19111 USA Department of Gynecologic Oncology Center for RNA Interference and Non-Coding RNA University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA Department of Reproductive Medicine Center for RNA Interference and Non-Coding RNA University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA Department of Cancer Biology Center for RNA Interference and Non-Coding RNA University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA

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Highlights from the 11th ISCB Student Council Symposium 2015. Dublin, Ireland. 10 July 2015

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BMC bioinformatics 2016年第3期17 Suppl 3卷 95页

作者： Katie Wilkins Mehedi Hassan Margherita Francescatto Jakob Jespersen R. Gonzalo Parra Bart Cuypers Dan DeBlasio Alexander Junge Anupama Jigisha Farzana Rahman Griet Laenen Sander Willems Lieven Thorrez Yves Moreau Nagarajan Raju Sonia Pankaj Chothani C. Ramakrishnan Masakazu Sekijima M. Michael Gromiha Paddy J Slator Nigel J Burroughs Przemysław Szałaj Zhonghui Tang Paul Michalski Oskar Luo Xingwang Li Yijun Ruan Dariusz Plewczynski Giulia Fiscon Emanuel Weitschek Massimo Ciccozzi Paola Bertolazzi Giovanni Felici Pieter Meysman Manu Vanaerschot Maya Berg Hideo Imamura Jean-Claude Dujardin Kris Laukens Westa Domanova James R. Krycer Rima Chaudhuri Pengyi Yang Fatemeh Vafaee Daniel J. Fazakerley Sean J. Humphrey David E. James Zdenka Kuncic Plant Pathology and Plant-Microbe Biology Section School of Integrative Plant Science Cornell University Ithaca USA Graduate Field of Computational Biology Cornell University Ithaca USA School of Computing & Mathematics University of South Wales Cardiff UK Department of Genome Biology for Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association ᅟ Germany Department of Surgery Massachusetts General Hospital The Broad Institute of MIT and Harvard Boston USA Department of Systems Biology Technical University of Denmark Kemitorvet Denmark Protein Physiology Lab Facultad de Ciencias Exactas y Naturales Universidad de Buenos Aires Buenos Aires Argentina Molecular Parasitology Unit (MPU) Institute of Tropical Medicine Antwerp Belgium Advanced Database Research and Modeling (ADReM) research group University of Antwerp Antwerpen Belgium Department of Computer Science University of Arizona Tucson USA Department of Veterinary Clinical and Animal Sciences Center for non-coding RNA in Technology and Health University of Copenhagen Copenhagen Denmark University College Dublin Dublin Ireland Department of Electrical Engineering (ESAT) STADIUS Center for Dynamical Systems Signal Processing and Data Analytics KU Leuven Leuven Belgium Minds Medical IT Department Leuven Belgium Scientific Institute of Public Health (WIV-ISP) Platform of Biotechnology and Molecular Biology (PBB) Brussels Belgium Department of Development and Regeneration @ Kulak KU Leuven Kortrijk Belgium Department of Biotechnology Bhupat and Jyoti Metha School of Biosciences Indian Institute of Technology Madras Chennai India Philips Research North America Briarcliff Manor USA Global Scientific Information and Computing Center (GSIC) Tokyo Institute of Technology Tokyo Japan Systems Biology Centre University of Warwick Senate House Coventry UK Systems Biology Doctoral Training Centre University of Warwick Senate House Coventry UK Center for B

A1 Highlights from the eleventh ISCB Student Council Symposium 2015 Katie Wilkins, Mehedi Hassan, Margherita Francescatto, Jakob Jespersen, R. Gonzalo Parra, Bart Cuypers, Dan DeBlasio, Alexander Junge, Anupama Jigisha, Farzana Rahman O1 Prioritizing a drug’s targets using both gene expression and structural similarity Griet Laenen, Sander Willems, Lieven Thorrez, Yves Moreau O2 Organism specific protein-rna recognition: A computational analysis of protein-rna complex structures from different organisms Nagarajan Raju, Sonia Pankaj Chothani, C. Ramakrishnan, Masakazu Sekijima; M. Michael Gromiha O3 Detection of Heterogeneity in Single Particle Tracking Trajectories Paddy J Slator, Nigel J Burroughs O4 3D-NOME: 3D NucleOme Multiscale Engine for data-driven modeling of three-dimensional genome architecture Przemysław Szałaj, Zhonghui Tang, Paul Michalski, Oskar Luo, Xingwang Li, Yijun Ruan, Dariusz Plewczynski O5 A novel feature selection method to extract multiple adjacent solutions for viral genomic sequences classification Giulia Fiscon, Emanuel Weitschek, Massimo Ciccozzi, Paola Bertolazzi, Giovanni Felici O6 A Systems Biology Compendium for Leishmania donovani Bart Cuypers, Pieter Meysman, Manu Vanaerschot, Maya Berg, Hideo Imamura, Jean-Claude Dujardin, Kris Laukens O7 Unravelling signal coordination from large scale phosphorylation kinetic data Westa Domanova, James R. Krycer, Rima Chaudhuri, Pengyi Yang, Fatemeh Vafaee, Daniel J. Fazakerley, Sean J. Humphrey, David E. James, Zdenka Kuncic

关键词： Visceral Leishmaniasis Feature Selection Method Frequent Itemset Mining Leishmania Donovani Student Council

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Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response

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细胞研究（英文版） 2013年第10期23卷 1215-1228页

作者： Yucai Wang Xiao Han Fangming Wu Justin W Leung Megan G Lowery Huong Do Junjie Chen Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Laboratory of Non-coding RNA Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China High Magnetic Field Laboratory Chinese Academy of Sciences Hefei Anhui 230031 China Department of Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center Smithville TX 78957 USA

The FANCM/FAAP24 heterodimer has distinct functions in protecting cells from complex DNA lesions such as interstrand crosslinks. These functions rely on the biochemical activity of FANCM/FAAP24 to recognize and bind to damaged DNA or stalled replication forks. However, the DNA-binding activity of this complex was not clearly defined. We investigated how FAAP24 contributes to the DNA-interacting functions of the FANCM/FAAP24 complex by acquiring the N-terminal and C-terminal solution structures of human FAAP24. Modeling of the FAAP24 structure indicates that FAAP24 may possess a high affinity toward single-stranded DNA (ssDNA). Testing of various FAAP24 mutations in vitro and in vivo validated this prediction derived from structural analyses. We found that the DNA-binding and FANCM-interacting functions of FAAP24, although both require the C-terminal (HhH)₂ domain, can be distinguished by segregation-of-function mutations. These results demonstrate dual roles of FAAP24 in DNA damage response against crosslinking lesions, one through the formation of FANCM/FAAP24 heterodimer and the other via its ssDNA-binding activity required in optimized checkpoint activation.

关键词： FAAP24 FANCM DNA binding DNA damage response

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miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2

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Nature 2014年第7515期512卷 431-5页

作者： Jing Y Krzeszinski Wei Wei HoangDinh Huynh Zixue Jin Xunde Wang Tsung-Cheng Chang Xian-Jin Xie Lin He Lingegowda S Mangala Gabriel Lopez-Berestein Anil K Sood Joshua T Mendell Yihong Wan Department of Pharmacology The University of Texas Southwestern Medical Center Dallas Texas 75390 USA. Department of Molecular Biology The University of Texas Southwestern Medical Center Dallas Texas 75390 USA. Department of Clinical Sciences The University of Texas Southwestern Medical Center Dallas Texas 75390 USA. Division of Cellular and Developmental Biology Molecular and Cell Biology Department University of California at Berkeley Berkeley California 94705 USA. Center for RNA Interference and Non-coding RNA The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA. Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA. Department of Cancer Biology The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA. Simmons Cancer Center The University of Texas Southwestern Medical Center Dallas Texas 75390 USA. Simmons Cancer Center The University of Texas Southwestern Medical Center Dallas Texas 75390 USA.

Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. Micrornas play important roles in physiology and disease, and present tremendous therapeutic potential. nonetheless, how micrornas regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

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Structural and Functional Research of ALS Associated Protein FUS(fused in sarcoma)

Structural and Functional Research of ALS Associated Protein...

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第一届国际暨第十三次中国生物物理学术大会

作者： Chunyan Niu Xuehui Liu Jintao Ren Minze Jia Feng Gao Wei Feng Haining Zhu Weimin Gong Laboratory of Non-coding RNA Institute of BiophysicsChinese Academy of Sciences National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of Sciences Department of Molecular and Cellular Biochemistry & Center for Structural Biology College of MedicineUniversity of Kentucky741 South LimestoneLexingtonKY 40536USA

Fused in sarcoma/translocated in liposarcoma(FUS/TLS)is a DNA/rna binding protein that is involved in many processes of rna metabolism including gene transcription regulation,rna splicing and transport,translation,process of micro rnas,and maintenance of genomic *** have been recently reported to cause a familial form of amyotrophic lateral sclerosis(ALS).This study solved the crystal structure of FUS-NLS/Transportin 1 *** binding

关键词： ALS rna fused in sarcoma Structural and Functional Research of ALS Associated Protein FUS

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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER

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NATURE COMMUNICATIONS 2014年第Oct.期5卷 5203-5215页

作者： van den Beucken, Twan Koch, Elizabeth Chu, Kenneth Rupaimoole, Rajesha Prickaerts, Peggy Adriaens, Michiel Voncken, Jan Willem Harris, Adrian L. Buffa, Francesca M. Haider, Syed Starmans, Maud H. W. Yao, Cindy Q. Ivan, Mircea Ivan, Cristina Pecot, Chad V. Boutros, Paul C. Sood, Anil K. Koritzinsky, Marianne Wouters, Bradly G. Princess Margaret Canc Ctr Toronto ON M5G IL7 Canada Campbell Family Inst Canc Res Univ Hlth Network Toronto ON M5G IL7 Canada Maastricht Univ Med Ctr GROW Sch Oncol & Dev Biol Dept Radiat Oncol NL-6200 MD Maastricht Netherlands Maastricht Univ Med Ctr GROW Sch Oncol & Dev Biol Dept Toxicogen NL-6200 MD Maastricht Netherlands Univ Toronto Dept Med Biophys Toronto ON M5G 1L7 Canada Ontario Inst Canc Res Informat & Biocomp Program Toronto ON M5G 1L7 Canada Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Amsterdam Acad Med Ctr Heart Failure Res Ctr Dept Expt Cardiol NL-1105 AZ Amsterdam Netherlands Maastricht Univ BiGCaT Dept Bioinformat NL-6200 MD Maastricht Netherlands Maastricht Univ BiGCaT Dept Bioinformat NL-6200 MD Maastricht Netherlands John Radcliffe Hosp Weatherall Inst Mol Med Canc Res UK Dept Oncol Oxford OX3 9DS England Indiana Univ Melvin & Bren Simon Canc Ctr Dept Med Indianapolis IN 46202 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Thorac Head & Neck Oncol Houston TX 77030 USA Univ Toronto Dept Pharmacol & Toxicol Toronto ON M5S 1A8 Canada Univ Toronto Inst Med Sci Toronto ON M5S 1A8 Canada Univ Toronto Dept Radiat Oncol Toronto ON M5T 1P5 Canada Ontario Inst Canc Res Select Therapies Program Toronto ON M5G 1L7 Canada

Micrornas are small regulatory rnas that post transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microrna processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet, the underlying mechanisms are not well understood. Here we identify tumour hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced mirna processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, mirna biogenesis and tumour stem cell phenotypes that may underlie poor outcome in breast cancer.

关键词： EPITHELIAL-MESENCHYMAL TRANSITION DEMETHYLASE JMJD3 CONTRIBUTES BREAST-CANCER EXPRESSION PROFILES SOMATIC MUTATIONS INDUCIBLE FACTORS DOWN-REGULATION OVARIAN-CANCER METASTASIS EZH2 Stem Cells Ovary Cancer Somatic Mutation Epithelial-Mesenchymal Transition Derepression Hypoxia Epigenetic Processes Regulators poor prognosis Phenotype Breast Cancer Down-Regulation metastasis Micrornas Epigenetics

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IT-22TARGETING THE IMMUNE CHECKPOINT NETWORK WITH miR-138 EXERTS THERAPEUTIC EFFICACY IN MURINE MODELS OF GLIOMA

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Neuro-Oncology 2014年第SUPPL_5期16卷 v114-v114页

作者： Nduom, Edjah K. Wei, Jun Kong, Ling-Yuan Xu, Shuo Gabrusiewicz, Konrad Ling, Xiaoyang Huang, Neal Qiao, Wei Zhou, Shouhao Ivan, Cristina Chen, Jie Qing Ji, Yongjie Radvanyi, Laszlo Fuller, Greg N. Gilbert, Mark Conrad, Charles A. Overwijk, Willem Calin, George A. Heimberger, Amy B. Department of Neurosurgery The University of Texas M.D. Anderson Cancer Center Houston TX USA Department of Neurosurgery Qilu Hospital of Shandong University Jinan China Department of Biostatistics The University of Texas M.D. Anderson Cancer Center Houston TX USA Center for RNA Interference and Non-Coding RNAs The University of Texas M.D. Anderson Cancer Center Houston TX USA Department of Melanoma Medical Oncology The University of Texas M.D. Anderson Cancer Center Houston TX USA Department of Neuro-Oncology The University of Texas M.D. Anderson Cancer Center Houston TX USA Department of Neuropathology The University of Texas M.D. Anderson Cancer Center Houston TX USA Depatment of Experimental Therapeutics The University of Texas M.D. Anderson Cancer Center Houston TX USA

Antibody therapeutic targeting of the immune checkpoints CTLA-4 and PD-1 has demonstrated marked tumor regression in clinical trials; however, this requires multimodality treatment and has known toxicity. Micrornas (mirnas) can modulate gene transcripts, including those of tumor-mediated immune suppressive pathways. Mirnas can be delivered to the systemic immune compartment, which can initiate anti-tumor immune response, overcoming the issue of mirna delivery to the tumor. To identify potential mirna therapeutics, we exploited human glioblastoma mirna expression assays followed by a screening process of predicted binding sites in the 3' UTR of immune suppressive pathways and immune checkpoints. MiR-138 emerged as a leading candidate with binding sites in the 3' UTR of CTLA-4 and PD-1, which were functionally confirmed with luciferase expression assays. The miR-138 targeting of CTLA-4 and PD-1 was further validated by expression analysis of transfected human CD4+ T cells. Using human glioma tumor microarrays and in situ hybridization, heterogeneous expression of miR-138 was found amongst all glioma grades and pathological subtypes. The PD-1 ligand, PD-L1, was frequently expressed in glioblastomas based on immunohistochemistry and ex vivo flow cytometry from human glioblastoma. Analysis of TCGA database revealed that co-expression of PD-1 and PD-L1 impacts glioblastoma survival. The role of CTLA-4 in glioblastoma-mediated immune suppression is well documented, suggesting that targeting of CTLA-4 and PD-1 with miR-138 in glioblastoma patients may have anti-tumor activity. In vivo treatment with miR-138 in immune-competent mice with GL261 gliomas demonstrated marked tumor regression, a 43% increase in median survival (P = 0.011), and an associated decrease in intratumoral FoxP3+ Tregs, CTLA-4, and PD-1 expression. Conversely, in an immune-incompetent animal background, miR-138 failed to exert any therapeutic effect, indicating that miR-138 mediates in vivo activity via

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