Publications by authors named "Young-Jun Jeon"

34 Publications

miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury.

Basic Res Cardiol 2021 Mar 19;116(1):19. Epub 2021 Mar 19.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.
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http://dx.doi.org/10.1007/s00395-021-00858-8DOI Listing
March 2021

Targeting Non-Oncogene Addiction for Cancer Therapy.

Biomolecules 2021 Jan 20;11(2). Epub 2021 Jan 20.

Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul 04310, Korea.

While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.
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http://dx.doi.org/10.3390/biom11020129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909239PMC
January 2021

Fhit induces the reciprocal suppressions between Lin28/Let-7 and miR-17/92miR.

Int J Med Sci 2021 1;18(3):706-714. Epub 2021 Jan 1.

Department of Biosciences, Mokpo National University, Joennam 58554, South Korea.

Fhit gene is known as a genome "caretaker" and frequently inactivated by deletion or hypermethylation on the promoter in several cancers. In spite of several lines of evidence, the exact mechanism underlying Fhit-induced biology is relatively less studied. This study will focus the role of Fhit in regulating Lin28 and microRNAs (miRNAs) loop. : To this end, we employed Fhit overexpressing isogenic cell lines to conduct miRNA nanostring array, and differentially expressed miRNAs were identified. Using real-time PCR and Western blot analysis, expression levels of Lin28b or miRNAs were investigated in response to the overexpression of Fhit gene in H1299 lung cancer cells. A series of including gene nanostring analyses revealed that Lin28B protein was induced by Fhit gene overexpression, which consequently suppressed Let-7 miRNAs. Also, we found that miRNAs in miR-17/92 clusters are redundantly increased and there is an inverse correlation between Let-7 and miR-17/92 clusters in Fhit-expressing cells. Also, a series of in vitro experiments suggests that ELF-1- and/or STAT1-dependent Lin28b regulation is responsible for Let-7 induction in Fhit-expressing cancer cells. Based on the same experimental system proving that Fhit gene has a robust role in suppressing tumor progression and epithelial-mesenchymal transition, our data show that Fhit mediates the negative feedback between Lin28/Let-7 axis and miR-17/-92 miRNA although the physiological relevance of current interesting observation should be further investigated.
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http://dx.doi.org/10.7150/ijms.51429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797533PMC
January 2021

Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.

Cancer Discov 2020 Dec 18;10(12):1826-1841. Epub 2020 Oct 18.

Department of Radiation Oncology, Stanford University, Stanford, California.

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that and mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes -mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in and predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of -mutant tumors..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710558PMC
December 2020

Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.

Cell 2020 Oct 1;183(2):363-376.e13. Epub 2020 Oct 1.

Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address:

Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
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http://dx.doi.org/10.1016/j.cell.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572899PMC
October 2020

Extracellular RNA: Emerging roles in cancer cell communication and biomarkers.

Cancer Lett 2020 12 8;495:33-40. Epub 2020 Sep 8.

Department of Integrative Biotechnology, Sungkyunkwan University, Republic of Korea. Electronic address:

Extracellular RNAs (exRNAs) are a type of RNA molecules that present in various biological fluids. exRNAs are heterogenous populations including small (e.g., miRNA) and long non-coding RNAs and coding RNAs (e.g., mRNA). They can exist in a free form or associate with carriers range from lipo- and ribo-proteins to extracellular vesicles such as exosomes in the extracellular fluids. exRNAs participate in cell-to-cell communication to regulate a broad array of physiological and pathological processes. exRNAs have been widely studied as a biomarker for cancer and other diseases. In this review, we will discuss the sorts of exRNAs with potential carriers as well as their roles in cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.09.002DOI Listing
December 2020

Ablation of the Brca1-Palb2 Interaction Phenocopies Fanconi Anemia in Mice.

Cancer Res 2020 10 30;80(19):4172-4184. Epub 2020 Jul 30.

Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Heterozygous mutations in the gene predispose women to breast and ovarian cancer, while biallelic BRCA1 mutations are a cause of Fanconi anemia (FA), a rare genetic disorder characterized by developmental abnormalities, early-onset bone marrow failure, increased risk of cancers, and hypersensitivity to DNA-crosslinking agents. BRCA1 is critical for homologous recombination of DNA double-strand breaks (DSB). Through its coiled-coil domain, BRCA1 interacts with an essential partner, PALB2, recruiting BRCA2 and RAD51 to sites of DNA damage. Missense mutations within the coiled-coil domain of BRCA1 (e.g., L1407P) that affect the interaction with PALB2 have been reported in familial breast cancer. We hypothesized that if PALB2 regulates or mediates BRCA1 tumor suppressor function, ablation of the BRCA1-PALB2 interaction may also elicit genomic instability and tumor susceptibility. We generated mice defective for the Brca1-Palb2 interaction (Brca1 L1363P in mice) and established MEF cells from these mice. MEF exhibited hypersensitivity to DNA-damaging agents and failed to recruit Rad51 to DSB. mice were viable but exhibited various FA symptoms including growth retardation, hyperpigmentation, skeletal abnormalities, and male/female infertility. Furthermore, all mice exhibited macrocytosis and died due to bone marrow failure or lymphoblastic lymphoma/leukemia with activating Notch1 mutations. These phenotypes closely recapitulate clinical features observed in patients with FA. Collectively, this model effectively demonstrates the significance of the BRCA1-PALB2 interaction in genome integrity and provides an FA model to investigate hematopoietic stem cells for mechanisms underlying progressive failure of hematopoiesis and associated development of leukemia/lymphoma, and other FA phenotypes. SIGNIFICANCE: A new Brca1 mouse model for Fanconi anemia (FA) complementation group S provides a system in which to study phenotypes observed in human FA patients including bone marrow failure..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0486DOI Listing
October 2020

Integrating genomic features for non-invasive early lung cancer detection.

Nature 2020 04 25;580(7802):245-251. Epub 2020 Mar 25.

Stanford Cancer Institute, Stanford University, Stanford, CA, USA.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality; however, a small minority of eligible individuals undergo such screening in the United States. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
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http://dx.doi.org/10.1038/s41586-020-2140-0DOI Listing
April 2020

Functional significance of U2AF1 S34F mutations in lung adenocarcinomas.

Nat Commun 2019 12 13;10(1):5712. Epub 2019 Dec 13.

Stanford Cancer Institute, Stanford University, Stanford, USA.

The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions. The presence of S34F caused a shift in cross-linking at 3' splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.
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http://dx.doi.org/10.1038/s41467-019-13392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911043PMC
December 2019

Osteogenic Cell Behavior on Titanium Surfaces in Hard Tissue.

J Clin Med 2019 May 2;8(5). Epub 2019 May 2.

Department of Prosthodontics, School of Dentistry and Dental Research Institute, Seoul National University, 101 Daehak-ro, Jongro-gu, Seoul 03080, Korea.

It is challenging to remove dental implants once they have been inserted into the bone because it is hard to visualize the actual process of bone formation after implant installation, not to mention the cellular events that occur therein. During bone formation, contact osteogenesis occurs on roughened implant surfaces, while distance osteogenesis occurs on smooth implant surfaces. In the literature, there have been many in vitro model studies of bone formation on simulated dental implants using flattened titanium (Ti) discs; however, the purpose of this study was to identify the in vivo cell responses to the implant surfaces on actual, three-dimensional (3D) dental Ti implants and the surrounding bone in contact with such implants at the electron microscopic level using two different types of implant surfaces. In particular, the different parts of the implant structures were scrutinized. In this study, dental implants were installed in rabbit tibiae. The implants and bone were removed on day 10 and, subsequently, assessed using scanning electron microscopy (SEM), immunofluorescence microscopy (IF), transmission electron microscopy (TEM), focused ion-beam (FIB) system with Cs-corrected TEM (Cs-STEM), and confocal laser scanning microscopy (CLSM)-which were used to determine the implant surface characteristics and to identify the cells according to the different structural parts of the turned and roughened implants. The cell attachment pattern was revealed according to the different structural components of each implant surface and bone. Different cell responses to the implant surfaces and the surrounding bone were attained at an electron microscopic level in an in vivo model. These results shed light on cell behavioral patterns that occur during bone regeneration and could be a guide in the use of electron microscopy for 3D dental implants in an in vivo model.
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http://dx.doi.org/10.3390/jcm8050604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571803PMC
May 2019

DR4-Ser424 -GlcNAcylation Promotes Sensitization of TRAIL-Tolerant Persisters and TRAIL-Resistant Cancer Cells to Death.

Cancer Res 2019 06 15;79(11):2839-2852. Epub 2019 Apr 15.

School of Biological Science, Seoul National University, Gwanak-gu, Seoul, Republic of Korea.

TNF-related apoptosis-inducing ligand (TRAIL) resistance, including nongenetically acquired tolerance in cancer persister cells, is a major obstacle to translating TRAIL therapy into patients with cancer. However, the underlying mechanisms remain to be elucidated. Here, we show that DR4/TRAIL-R1 is -GlcNAcylated at Ser424 in its death domain to mediate both apoptosis and necrosis upon TRAIL ligation. We found that DR4-Ser424 mutations, identified from our cell-based functional screen using a cancer patient-derived cDNA expression library and from The Cancer Genome Atlas, caused TRAIL resistance in various human cancer cell lines. Using -GlcNAc transferase knockdown cells, DR4-preferred versus DR5-preferred cancer cells, and a DR5-neutralizing antibody, we evaluated the essential role of DR4-specific -GlcNAc modification in TRAIL cytotoxicity. In contrast to DR4, DR5 was not -GlcNAcylated by TRAIL treatment, discriminating DR4 from DR5-mediated signaling. Apart from genetic changes in DR4-Ser424, we further classified various cancer cell lines originated from stomach, colon, lung, and glioblastoma according to their sensitivity to and receptor preference upon TRAIL death signaling and generated TRAIL-tolerant persister-derived DLD-1 cells. Among these, we discovered that DR4 was not modified by -GlcNAc in most of the TRAIL-resistant cancer cells and DLD-1 cells. Interestingly, promoting DR4 -GlcNAcylation intentionally using 2-deoxy-d-glucose or a high concentration of glucose sensitized those resistant cancer cells to TRAIL. The -GlcNAcylation-defective DR4 failed to form DISC/necrosome and could not translocate to aggregated platforms for receptor clustering. Our findings demonstrate that DR4 -GlcNAcylation is crucial for TRAIL death signaling, providing new opportunities for TRAIL therapy overcoming TRAIL resistance in cancers. SIGNIFICANCE: This study reports that a novel posttranslational modification by -GlcNAcylation of one of the two human TRAIL receptors with a death domain, TRAIL-R1 (DR4), plays a crucial role in enabling both apoptotic and necroptotic cell death induction by TRAIL.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1991DOI Listing
June 2019

The Comprehensive Roles of ATRANORIN, A Secondary Metabolite from the Antarctic Lichen , in HCC Tumorigenesis.

Molecules 2019 Apr 10;24(7). Epub 2019 Apr 10.

Department of Bioscience, Mokpo National University, Muan 58554, Korea.

Hepatocellular carcinoma (HCC) is one of the most deadly genetic diseases, but surprisingly chemotherapeutic approaches against HCC are only limited to a few targets. In particular, considering the difficulty of a chemotherapeutic drug development in terms of cost and time enforces searching for surrogates to minimize effort and maximize efficiency in anti-cancer therapy. In spite of the report that approximately one thousand lichen-derived metabolites have been isolated, the knowledge about their functions and consequences in cancer development is relatively limited. Moreover, one of the major second metabolites from lichens, Atranorin has never been studied in HCC. Regarding this, we comprehensively analyze the effect of Atranorin by employing representative HCC cell lines and experimental approaches. Cell proliferation and cell cycle analysis using the compound consistently show the inhibitory effects of Atranorin. Moreover, cell death determination using Annexin-V and (Propidium Iodide) PI staining suggests that it induces cell death through necrosis. Lastly, the metastatic potential of HCC cell lines is significantly inhibited by the drug. Taken these together, we claim a novel functional finding that Atranorin comprehensively suppresses HCC tumorigenesis and metastatic potential, which could provide an important basis for anti-cancer therapeutics.
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http://dx.doi.org/10.3390/molecules24071414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480312PMC
April 2019

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.

Nat Commun 2018 11 30;9(1):5110. Epub 2018 Nov 30.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.
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http://dx.doi.org/10.1038/s41467-018-07561-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269493PMC
November 2018

KRAS induces lung tumorigenesis through microRNAs modulation.

Cell Death Dis 2018 02 13;9(2):219. Epub 2018 Feb 13.

Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.

Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRAS) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.
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http://dx.doi.org/10.1038/s41419-017-0243-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833396PMC
February 2018

Comparative expression profiling of testis-enriched genes regulated during the development of spermatogonial cells.

PLoS One 2017 17;12(4):e0175787. Epub 2017 Apr 17.

Department of Animal Sciences, The Ohio State University, Columbus, Ohio, United States of America.

The testis has been identified as the organ in which a large number of tissue-enriched genes are present. However, a large portion of transcripts related to each stage or cell type in the testis still remains unknown. In this study, databases combined with confirmatory measurements were used to investigate testis-enriched genes, localization in the testis, developmental regulation, gene expression profiles of testicular disease, and signaling pathways. Our comparative analysis of GEO DataSets showed that 24 genes are predominantly expressed in testis. Cellular locations of 15 testis-enriched proteins in human testis have been identified and most of them were located in spermatocytes and round spermatids. Real-time PCR revealed that expressions of these 15 genes are significantly increased during testis development. Also, an analysis of GEO DataSets indicated that expressions of these 15 genes were significantly decreased in teratozoospermic patients and polyubiquitin knockout mice, suggesting their involvement in normal testis development. Pathway analysis revealed that most of those 15 genes are implicated in various sperm-related cell processes and disease conditions. This approach provides effective strategies for discovering novel testis-enriched genes and their expression patterns, paving the way for future characterization of their functions regarding infertility and providing new biomarkers for specific stages of spematogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175787PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393594PMC
May 2017

ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.

Cancer Cell 2016 Nov;30(5):723-736

Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA. Electronic address:

MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.
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http://dx.doi.org/10.1016/j.ccell.2016.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127275PMC
November 2016

APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis.

Oncotarget 2016 Apr;7(16):21601-17

School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.

Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-β1 (HRG-β1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-β1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG-β1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip-/- MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer.
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http://dx.doi.org/10.18632/oncotarget.7802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008309PMC
April 2016

MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7.

Oncotarget 2015 Sep;6(26):21802-15

Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-α induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-κB signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-κB/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.
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http://dx.doi.org/10.18632/oncotarget.5224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673127PMC
September 2015

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer.

Proc Natl Acad Sci U S A 2015 Aug 17;112(31):E4288-97. Epub 2015 Jul 17.

Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.
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http://dx.doi.org/10.1073/pnas.1502068112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534291PMC
August 2015

MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC.

Proc Natl Acad Sci U S A 2015 Jul 29;112(28):8650-5. Epub 2015 Jun 29.

Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;

Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.
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http://dx.doi.org/10.1073/pnas.1500886112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507199PMC
July 2015

A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Proc Natl Acad Sci U S A 2015 Jun 15;112(26):E3355-64. Epub 2015 Jun 15.

Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;

TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
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http://dx.doi.org/10.1073/pnas.1504630112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491797PMC
June 2015

MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression.

Oncotarget 2015 Aug;6(22):18780-9

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC-repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo-4 and MYCLo-6.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662455PMC
http://dx.doi.org/10.18632/oncotarget.3909DOI Listing
August 2015

Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis.

J Natl Cancer Inst 2015 Apr 6;107(4). Epub 2015 Feb 6.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).

Background: The functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis.

Methods: CRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, ChIP, RNA pull-down assay, deletion mapping assay, LC-MS/MS and RNA immunoprecipitation to determine the mechanisms of MYC regulation of lncRNAs. Moreover, soft agar assay and in vivo xenograft experiments (four athymic nude mice per group) provided evidence of MYC-regulated lncRNAs in cancer cell transformation and tumorigenesis. The Kaplan-Meier method was used for survival analyses. All statistical tests were two-sided.

Results: We identified lncRNAs differentially expressed in CRC (P < .05, greater than two-fold) and verified four lncRNAs upregulated and two downregulated in CRC cells and tissues. We further identified MYC-regulated lncRNAs, named MYCLos. The MYC-regulated MYCLos may function in cell proliferation and cell cycle by regulating MYC target genes such as CDKN1A (p21) and CDKN2B (p15), suggesting new regulatory mechanisms of MYC-repressed target genes through lncRNAs. RNA binding proteins including HuR and hnRNPK are involved in the function of MYCLos by interacting with MYCLo-1 and MYCLo-2, respectively. Knockdown experiments also showed that MYCLo-2, differentially expressed not only in CRC but also in prostate cancer, has a role in cancer transformation and tumorigenesis.

Conclusions: Our results provide novel regulatory mechanisms in MYC function through lncRNAs and new potential lncRNA targets of CRC.
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http://dx.doi.org/10.1093/jnci/dju505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402359PMC
April 2015

MicroRNAs in lung cancer.

World J Methodol 2014 Jun 26;4(2):59-72. Epub 2014 Jun 26.

Pooja Joshi, Justin Middleton, Young-Jun Jeon, Michela Garofalo, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, United States.

MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.
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http://dx.doi.org/10.5662/wjm.v4.i2.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202482PMC
June 2014

Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5.

Proc Natl Acad Sci U S A 2014 Mar 4;111(11):4173-8. Epub 2014 Mar 4.

Department of Molecular Virology, Immunology and Medical Genetics and Department of Anesthesiology, Wexner Medical Center, and Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210.

The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.
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http://dx.doi.org/10.1073/pnas.1400350111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964128PMC
March 2014

Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer.

Proc Natl Acad Sci U S A 2013 Sep 26;110(37):15043-8. Epub 2013 Aug 26.

Department of Molecular Virology, Immunology, and Medical Genetics and Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.

MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.
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http://dx.doi.org/10.1073/pnas.1307107110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773758PMC
September 2013

MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.

PLoS One 2013 21;8(6):e67581. Epub 2013 Jun 21.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, United States of America.

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067581PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689725PMC
October 2017

MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme.

Proc Natl Acad Sci U S A 2012 Apr 19;109(14):5316-21. Epub 2012 Mar 19.

Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma.
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http://dx.doi.org/10.1073/pnas.1202465109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325690PMC
April 2012

EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.

Nat Med 2011 Dec 11;18(1):74-82. Epub 2011 Dec 11.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.

The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.
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http://dx.doi.org/10.1038/nm.2577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467100PMC
December 2011