Activating PTEN Tumor Suppressor Expression with the CRISPR/dCas9 System.

Abstract:

:PTEN expression is lost in many cancers, and even small changes in PTEN activity affect susceptibility and prognosis in a range of highly aggressive malignancies, such as melanoma and triple-negative breast cancer (TNBC). Loss of PTEN expression occurs via multiple mechanisms, including mutation, transcriptional repression and epigenetic silencing. Transcriptional repression of PTEN contributes to resistance to inhibitors used in the clinic, such as B-Raf inhibitors in BRAF mutant melanoma. We aimed to activate PTEN expression using the CRISPR system, specifically dead (d) Cas9 fused to the transactivator VP64-p65-Rta (VPR). dCas9-VPR was directed to the PTEN proximal promoter by single-guide RNAs (sgRNAs), in cancer cells that exhibited low levels of PTEN expression. The dCas9-VPR system increased PTEN expression in melanoma and TNBC cell lines, without transcriptional regulation at predicted off-target sgRNA binding sites. PTEN activation significantly repressed downstream oncogenic pathways, including AKT, mTOR, and MAPK signaling. BRAF V600E mutant melanoma cells transduced with dCas9-VPR displayed reduced migration, as well as diminished colony formation in the presence of B-Raf inhibitors, PI3K/mTOR inhibitors, and with combined PI3K/mTOR and B-Raf inhibition. CRISPR-mediated targeted activation of PTEN may provide an alternative therapeutic approach for highly aggressive cancers that are refractory to current treatments.

journal_name

Mol Ther Nucleic Acids

authors

Moses C,Nugent F,Waryah CB,Garcia-Bloj B,Harvey AR,Blancafort P

doi

10.1016/j.omtn.2018.12.003

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

287-300

issn

2162-2531

pii

S2162-2531(18)30318-4

journal_volume

14

pub_type

杂志文章
  • Triple bioluminescence imaging for in vivo monitoring of cellular processes.

    abstract::Bioluminescence imaging (BLI) has shown to be crucial for monitoring in vivo biological processes. So far, only dual bioluminescence imaging using firefly (Fluc) and Renilla or Gaussia (Gluc) luciferase has been achieved due to the lack of availability of other efficiently expressed luciferases using different substra...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2013.25

    authors: Maguire CA,Bovenberg MS,Crommentuijn MH,Niers JM,Kerami M,Teng J,Sena-Esteves M,Badr CE,Tannous BA

    更新日期:2013-06-18 00:00:00

  • Binding and Structural Properties of DNA Aptamers with VEGF-A-Mimic Activity.

    abstract::Vascular endothelial growth factors (VEGFs) are hypoxia-inducible secreted proteins to promote angiogenesis, in which VEGF-A is an important molecule that binds and activates VEGF receptor-1 (VEGFR-1) and VEGFR-2. In this study, two DNA aptamers, Apt01 and Apt02, were successfully isolated by alternating consecutive s...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.12.034

    authors: Yoshitomi T,Hayashi M,Oguro T,Kimura K,Wayama F,Furusho H,Yoshimoto K

    更新日期:2020-03-06 00:00:00

  • lnc-3215 Suppression Leads to Calcium Overload in Selenium Deficiency-Induced Chicken Heart Lesion via the lnc-3215-miR-1594-TNN2 Pathway.

    abstract::Selenium deficiency has been proven to induce calcium disorders in the chicken heart. However, detailed regulatory mechanisms, e.g., the long noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA regulatory axis, have not yet been described. Here, we point out lnc-2315, miR-1594, and Troponin T (TNNT2) based on the results of ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.08.003

    authors: Yang J,Gong Y,Cai J,Liu Q,Zhang Z

    更新日期:2019-12-06 00:00:00

  • Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS.

    abstract::Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited sprea...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.06.011

    authors: Kanaan NM,Sellnow RC,Boye SL,Coberly B,Bennett A,Agbandje-McKenna M,Sortwell CE,Hauswirth WW,Boye SE,Manfredsson FP

    更新日期:2017-09-15 00:00:00

  • MicroRNA-129 Inhibits Glioma Cell Growth by Targeting CDK4, CDK6, and MDM2.

    abstract::Glioblastoma is the most common malignant primary brain tumor among adults and one of the most lethal cancers. It is characterized by the deregulation of signaling pathways involving proliferation, growth, survival, and other factors. MicroRNAs (miRNAs) play a role in the regulation of genes by affecting the 3' untran...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.11.033

    authors: Moradimotlagh A,Arefian E,Rezazadeh Valojerdi R,Ghaemi S,Jamshidi Adegani F,Soleimani M

    更新日期:2020-03-06 00:00:00

  • Overexpression of microRNA-203 Suppresses Proliferation, Invasion, and Migration while Accelerating Apoptosis of CSCC Cell Line SCL-1.

    abstract::Cutaneous squamous cell carcinoma (CSCC) is a malignant proliferation of cutaneous epithelium that has been observed to have an alarming rise in incidence. Numerous studies have demonstrated microRNAs (miRNAs or miRs) as important biomarkers in the diagnosis, prognosis, and treatment of CSCC. This study aims to invest...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.04.014

    authors: Ting W,Feng C,Zhang M,Long F,Bai M

    更新日期:2020-09-04 00:00:00

  • An innovative data analysis strategy for accurate next-generation sequencing detection of tumor mitochondrial DNA mutations.

    abstract::Next-generation sequencing technology has been commonly applied to detect mitochondrial DNA (mtDNA) mutations, which are reported to be strongly associated with cancers. However, several key challenges still exist regarding bioinformatics analysis of mtDNA sequencing data that greatly affect the detection accuracy of ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.11.002

    authors: Guo S,Zhou K,Yuan Q,Su L,Liu Y,Ji X,Gu X,Guo X,Xing J

    更新日期:2020-11-11 00:00:00

  • Acacetin and chrysin, two polyphenolic compounds, alleviate telomeric position effect in human cells.

    abstract::We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in huma...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2013.42

    authors: Boussouar A,Barette C,Nadon R,Saint-Léger A,Broucqsault N,Ottaviani A,Firozhoussen A,Lu Y,Lafanechère L,Gilson E,Magdinier F,Ye J

    更新日期:2013-08-20 00:00:00

  • E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases.

    abstract::E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2016.103

    authors: Morita Y,Kamal M,Kang SA,Zhang R,Lokesh GL,Thiviyanathan V,Hasan N,Woo S,Zhao D,Leslie M,Suh S,Razaq W,Rui H,Gorenstein DG,Volk DE,Tanaka T

    更新日期:2016-12-13 00:00:00

  • Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

    abstract::Numerous studies have suggested that dysregulated long noncoding RNAs (lncRNAs) contributed to the development and progression of many cancers. lncRNA OIP5 antisense RNA 1 (OIP5-AS1) has been reported to be increased in several cancers. However, the roles of OIP5-AS1 in liver hepatocellular carcinoma (LIHC) remain to ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.05.032

    authors: Ma YS,Chu KJ,Ling CC,Wu TM,Zhu XC,Liu JB,Yu F,Li ZZ,Wang JH,Gao QX,Yi B,Wang HM,Gu LP,Li L,Tian LL,Shi Y,Jiang XQ,Fu D,Zhang XW

    更新日期:2020-09-04 00:00:00

  • Activation of Fetal γ-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains.

    abstract::Reactivation of γ-globin expression has been shown to ameliorate disease phenotypes associated with mutations in the adult β-globin gene, including sickle cell disease. Specific mutations in the promoter of the γ-globin genes are known to prevent repression of the genes in the adult and thus lead to hereditary persist...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2016.85

    authors: Hossain MA,Shen Y,Knudson I,Thakur S,Stees JR,Qiu Y,Pace BS,Peterson KR,Bungert J

    更新日期:2016-10-18 00:00:00

  • Erratum: Fructose Promotes Uptake and Activity of Oligonucleotides with Different Chemistries in a Context-Dependent Manner in mdx Mice.

    abstract::[This corrects the article DOI: 10.1038/mtna.2016.46.]. ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 已发布勘误

    doi:10.1016/j.omtn.2020.08.028

    authors: Cao L,Han G,Lin C,Gu B,Gao X,Moulton HM,Seow Y,Yin H

    更新日期:2020-11-19 00:00:00

  • miR-137: A Novel Therapeutic Target for Human Glioma.

    abstract::MicroRNA (miR)-137 is highly expressed in the brain and plays a crucial role in the development and prognosis of glioma. In this review, we aim to summarize the latest findings regarding miR-137 in glioma cell apoptosis, proliferation, migration, invasion, angiogenesis, drug resistance, and cancer treatment. In additi...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章,评审

    doi:10.1016/j.omtn.2020.06.028

    authors: Wang Y,Chen R,Zhou X,Guo R,Yin J,Li Y,Ma G

    更新日期:2020-09-04 00:00:00

  • Overexpressed lncRNA GATA6-AS1 Inhibits LNM and EMT via FZD4 through the Wnt/β-Catenin Signaling Pathway in GC.

    abstract::Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Accumulating evidence reveals the significance of long non-coding RNAs (lncRNAs) in various cancers. The current study aimed to evaluate the role of GATA6 antisense RNA 1 (GATA6-AS1) in the epithelial-mesenchymal transition (EMT) and ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.09.034

    authors: Li ZT,Zhang X,Wang DW,Xu J,Kou KJ,Wang ZW,Yong G,Liang DS,Sun XY

    更新日期:2020-03-06 00:00:00

  • The Bipartite Network Projection-Recommended Algorithm for Predicting Long Non-coding RNA-Protein Interactions.

    abstract::With the development of science and biotechnology, many evidences show that ncRNAs play an important role in the development of important biological processes, especially in chromatin modification, cell differentiation and proliferation, RNA progressing, human diseases, etc. Moreover, lncRNAs account for the majority ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.09.020

    authors: Zhao Q,Yu H,Ming Z,Hu H,Ren G,Liu H

    更新日期:2018-12-07 00:00:00

  • The miR-93-3p/ZFP36L1/ZFX axis regulates keratinocyte proliferation and migration during skin wound healing.

    abstract::Keratinocyte proliferation and migration are crucial steps during skin wound healing. The functional role of microRNAs (miRs) remains relatively unknown during this process. miR-93 levels have been reported to increase within 24 h of skin wound healing; however, whether miR-93-3p or miR-93-5p plays a specific role in ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.11.017

    authors: Feng X,Zhou S,Cai W,Guo J

    更新日期:2020-11-26 00:00:00

  • Schizandrin A Protects Human Retinal Pigment Epithelial Cell Line ARPE-19 against HG-Induced Cell Injury by Regulation of miR-145.

    abstract::Diabetic retinopathy (DR) is a serious complication of diabetes, which is the main cause of blindness among adults. Traditional Chinese medicines (TCMs) have been proven to delay the development of DR. Nonetheless, the effect of Schizandrin A (SchA) on DR remains uninvestigated. The present study aimed to probe the pr...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.10.026

    authors: Dong Y,Qian C,Wan G,Yan P,Liang S,Wang J

    更新日期:2020-03-06 00:00:00

  • Circular RNA Expression Profiling and the Potential Role of hsa_circ_0089172 in Hashimoto's Thyroiditis via Sponging miR125a-3p.

    abstract::Circular RNA (circRNA) is a novel subclass of noncoding-RNA molecules that participate in development and progression of a variety of human diseases via sponging microRNAs (miRNAs), but the role of circRNAs in Hashimoto's thyroiditis (HT) has not been defined. In this study, peripheral blood samples from five patients...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.05.004

    authors: Xiong S,Peng H,Ding X,Wang X,Wang L,Wu C,Wang S,Xu H,Liu Y

    更新日期:2019-09-06 00:00:00

  • Tat-haFGF14-154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP/PS1 Mice through the PI3K-CREB-IRE1α/XBP1 Pathway.

    abstract::Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer's disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF14-154 is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.05.004

    authors: Meng T,Cao Q,Lei P,Bush AI,Xiang Q,Su Z,He X,Rogers JT,Chiu IM,Zhang Q,Huang Y

    更新日期:2017-06-16 00:00:00

  • Compatibility and Fidelity of Mirror-Image Thymidine in Transcription Events by T7 RNA Polymerase.

    abstract::Due to highly enzymatic d-stereoselectivity, l-nucleotides (l-2'-deoxynucleoside 5'-triphosphates [l-dNTPs]) are not natural targets of polymerases. In this study, we synthesized series of l-thymidine (l-T)-modified DNA strands and evaluated the processivity of nucleotide incorporation for transcription by T7 RNA poly...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.06.023

    authors: Liu Q,Ke Y,Kan Y,Tang X,Li X,He Y,Wu L

    更新日期:2020-09-04 00:00:00

  • miR-185 Inhibits Fibrogenic Activation of Hepatic Stellate Cells and Prevents Liver Fibrosis.

    abstract::Recent studies have shown the effect of microRNAs on HSC activation and transformation, which is essential for the pathogenesis of liver fibrosis. In our study, we explored the role of miR-185 in liver fibrosis. Plasma miR-185 was detected in hepatitis B virus-related liver fibrosis patients (S2/3, n = 10) by Illumina...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.11.010

    authors: Zhou L,Liu S,Han M,Ma Y,Feng S,Zhao J,Lu H,Yuan X,Cheng J

    更新日期:2018-03-02 00:00:00

  • Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells.

    abstract::Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV) cell suicide system into ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.03.004

    authors: Ingemarsdotter CK,Poddar S,Mercier S,Patzel V,Lever AML

    更新日期:2017-06-16 00:00:00

  • Identifying Involvement of H19-miR-675-3p-IGF1R and H19-miR-200a-PDCD4 in Treating Pulmonary Hypertension with Melatonin.

    abstract::Non-coding RNAs play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). The aim of this study was to characterize the therapeutic role of melatonin as well as the underlying molecular mechanism (its effects on the expression of H19 and its downstream signaling pathways) in the treatment of...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.08.015

    authors: Wang R,Zhou S,Wu P,Li M,Ding X,Sun L,Xu X,Zhou X,Zhou L,Cao C,Fei G

    更新日期:2018-12-07 00:00:00

  • MiR-663a Stimulates Proliferation and Suppresses Early Apoptosis of Human Spermatogonial Stem Cells by Targeting NFIX and Regulating Cell Cycle.

    abstract::Human spermatogonial stem cells (SSCs) could have significant applications in reproductive medicine and regenerative medicine because of their great plasticity. The fate determinations of human SSCs are mediated by epigenetic factors. However, nothing is known about the regulation of non-coding RNA on human SSCs. Here...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.05.015

    authors: Zhou F,Yuan Q,Zhang W,Niu M,Fu H,Qiu Q,Mao G,Wang H,Wen L,Wang H,Lu M,Li Z,He Z

    更新日期:2018-09-07 00:00:00

  • Exosomes from Microglia Attenuate Photoreceptor Injury and Neovascularization in an Animal Model of Retinopathy of Prematurity.

    abstract::The role of microglia in the pathophysiology of ischemic retinal diseases has been studied extensively. Exosomes from microglial cells exert protective effects during several nervous system diseases, but their roles in hypoxia-induced retinopathy remain unclear. In our study, exosomes derived from microglial cells wer...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.04.029

    authors: Xu W,Wu Y,Hu Z,Sun L,Dou G,Zhang Z,Wang H,Guo C,Wang Y

    更新日期:2019-06-07 00:00:00

  • sTAM: An Online Tool for the Discovery of miRNA-Set Level Disease Biomarkers.

    abstract::MicroRNAs (miRNAs) are an important class of small noncoding RNA molecules that serve as excellent biomarkers of various diseases. However, current miRNA biomarkers, including those comprised of multiple miRNAs, work at a single-miRNA level but not at a miRNA-set level, which is defined as a group of miRNAs sharing co...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.07.004

    authors: Shi J,Cui Q

    更新日期:2020-09-04 00:00:00

  • miR-149-3p Regulates the Switch between Adipogenic and Osteogenic Differentiation of BMSCs by Targeting FTO.

    abstract::Bone marrow-derived mesenchymal stem cells (BMSCs) have been suggested to possess the capacity to differentiate into different cell lineages. Maintaining a balanced stem cell differentiation program is crucial to the bone microenvironment and bone development. MicroRNAs (miRNAs) have played a critical role in regulati...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.06.023

    authors: Li Y,Yang F,Gao M,Gong R,Jin M,Liu T,Sun Y,Fu Y,Huang Q,Zhang W,Liu S,Yu M,Yan G,Feng C,He M,Zhang L,Ding F,Ma W,Bi Z,Xu C,Yuan Y,Cai B,Yang L

    更新日期:2019-09-06 00:00:00

  • circHMCU Promotes Proliferation and Metastasis of Breast Cancer by Sponging the let-7 Family.

    abstract::Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMC...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.03.014

    authors: Song X,Liang Y,Sang Y,Li Y,Zhang H,Chen B,Du L,Liu Y,Wang L,Zhao W,Ma T,Wang C,Yang Q

    更新日期:2020-06-05 00:00:00

  • One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection.

    abstract::Monogenic disorders (MGDs), which are caused by single gene mutations, have a serious effect on human health. Among these, β-thalassemia (β-thal) represents one of the most common hereditary hematological diseases caused by mutations in the human hemoglobin β (HBB) gene. The technologies of induced pluripotent stem ce...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2016.11.010

    authors: Liu Y,Yang Y,Kang X,Lin B,Yu Q,Song B,Gao G,Chen Y,Sun X,Li X,Bu L,Fan Y

    更新日期:2017-03-17 00:00:00

  • Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers.

    abstract::Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a num...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2015.11

    authors: Prodeus A,Abdul-Wahid A,Fischer NW,Huang EH,Cydzik M,Gariépy J

    更新日期:2015-04-28 00:00:00