New Class Of Therapeutic Targets Research Articles

Functionalized siRNA-chitosan nanoformulations promote triple-negative breast cancer cell death via blocking the miRNA-21/AKT/ERK signaling axis: in-silico and in vitro studies.

Oncogenic microRNA (miRNA), especially miRNA-21 upregulation in triple-negative breast cancer (TNBC), suggests a new class of therapeutic targets. In this study, we aimed to create GE11 peptide-conjugated small interfering RNA-loaded chitosan nanoparticles (GE11-siRNA-CSNPs) for the targeting of EGFR overexpressed TNBC and selectively inhibit miRNA-21 expression. A variety of in-silico and in vitro cellular and molecular studies were conducted to investigate the binding affinities of specific targets used as well as the anticancer efficacies and mechanisms of GE11-siRNA-CSNPs in TNBC cells. An in-silico assessment reveals a distinct binding affinity of miRNA-21 with siRNA as well as between the extracellular domain of EGFR and synthesized peptides. Notably, the in vitro results showed that GE11-siRNA-CSNPs were revealed to have better cytotoxicity against TNBC cells. It significantly inhibits miRNA-21 expression, cell migration, and colony formation. The results also indicated that GE11-siRNA-CSNPs impeded cell cycle progression. It induces cell death by reducing the expression of the antiapoptotic gene Bcl-2 and increasing the expression of the proapoptotic genes Bax, Caspase 3, and Caspase 9. Additionally, the docking analysis and immunoblot investigations verified that GE1-siRNA-CSNPs, which specifically target TNBC cells and suppress miRNA-21, can prevent the effects of miRNA-21 on the proliferation of TNBC cells via controlling EGFR and subsequently inhibiting the PI3K/AKT and ERK1/2 signaling axis. The GE11-siRNA-CSNPs design, which specifically targets TNBC cells, offers a novel approach for the treatment of breast cancer with improved effectiveness. This study suggests that GE11-siRNA-CSNPs could be a promising candidate for further assessment as an additional strategy in the treatment of TNBC.

Deletion of microRNA‐21 exacerbates multiple phenotypes associated with Alzheimer’s disease through the RECK and ADAM10 pathway in a mouse model of Aβ amyloidosis

AbstractBackgroundmicroRNAs have emerged as a new class of therapeutic targets that regulate the expression of target genes by binding their 3’‐untranslated regions. Growing evidence suggests that dysregulation of microRNAs may contribute to the onset and/or progression of various diseases. However, the functional and therapeutic implications of microRNA dysregulation in Alzheimer’s disease (AD) remain largely unclear. To gain insight into the roles of microRNAs in AD pathogenesis, we recently performed unbiased microRNA profiling with entorhinal cortices of AD and age‐matched non‐demented subjects. We found that miRNA‐21 (miR‐21) expression was markedly increased in AD patients. In addition, miR‐21 levels were increased in oligomeric amyloid‐beta (Aβ)‐treated neurons, suggesting that miR‐21 induction is directly associated with Aβ pathology. Therefore, we investigated the pathogenic/therapeutic potential of miR‐21 in AD.MethodTo investigate the role of miR‐21 in amyloid pathology in vivo, we crossed APP/PS1 mice with mir‐21−/− mice to generate APP/PS1;mir‐21+/+, APP/PS1;mir‐21+/− and, APP/PS1;mir‐21−/− mice. We evaluated the changes in the pathological features of AD, such as Aβ levels, amyloid plaques, and gliosis in these mice. Moreover, to investigate the effects of miR‐21 deletion on spatial learning and memory functions, we performed the Morris Water Maze (MWM) and Contextual fear conditioning (CFC) tests.ResultDeletion of miR‐21 increased the levels of insoluble and soluble Aβ40 and Aβ42 levels, as well as increased Aβ‐positive and X‐34‐positive plaque deposition in the cortex and hippocampus. CD45‐positive, IBA1‐positive microgliosis, and GFAP‐positive astrogliosis were also increased in the brain of APP/PS1;mir‐21+/− and APP/PS1;mir‐21−/− mice compared to APP/PS1;mir‐21+/+ mice. Mechanistic studies identified RECK as a potential target gene of miR‐21. miR‐21 deficiency upregulated the RECK protein level, leading to the inhibition of ADAM10 activity. This finding was also corroborated by the decrease in the soluble APPα level. Furthermore, we demonstrated that miR‐21 deficiency decreased spatial learning and contextual memory in MWM and CFC tests, respectively in APP/PS1 mice.ConclusionTaken together, our results demonstrated that miR‐21 may regulate multiple AD‐associated pathologies. Therefore, modulation of miR‐21 may represent a novel potential therapeutic strategy for AD.

The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

LGG-59. Identifying hidden drivers of low-grade glioma tumor growth

Genomic drivers of pediatric low-grade gliomas (pLGGs) converge on alterations that activate the MAPK pathway. However, expression of individual driver oncogenes fails to induce tumor formation with high penetrance and, paradoxically, expression of these oncogenes suppresses growth in vitro. This, combined with the non-monotonic tumor growth rate in patients, suggests that there are “hidden drivers” beyond a single driver oncogene that are necessary to support tumor growth. The goal of this project is to leverage high-throughput functional genomics strategies to identify these hidden drivers of pLGG. Our preliminary data indicates that genes which modulate differentiation are required for the survival of LGG cells, suggesting that these genes may be hidden drivers of LGG tumor growth. Additionally, we hypothesize that secreted factors in the tumor microenvironment regulate pLGG tumor growth, potentially by modulating differentiation. In total, genes which cooperate with pLGG driver oncogenes to promote tumor growth may represent a new class of therapeutic targets and may explain the complex patterns of tumor growth that are observed in patients.

Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation

ObjectiveDysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution,...

Abstract PO022: Somatic mutations in tumor infiltrating lymphocytes can affect the expression of immune system genes in the tumor microenvironment

Abstract Avoiding immune destruction is an emerging hallmark of cancer. It includes tumor cell mutations and epigenetic modifications that allow tumor cells to either evade detection by the immune system, or render the immune response ineffective. However, mutations in tumor infiltrating lymphocytes that inhibit immune response to tumor growth, have not been specifically identified as a hallmark of cancer. We have identified four distinct somatic mutations in tumor infiltrating lymphocytes that affect the expression of immune system genes in tumor samples, suggesting that these lymphocytic mutation may cause a deficient immune response, contributing to cancer progression. These rare mutations occurred frequently in specific cancer types. The T292Nfs*18 mutation in the FETUB gene, R216Gfs*20 in CCDC43, N377D in CLEC4M and V78Gfs*46 in RAB11FIP4 occurred in 13% of breast invasive carcinoma, 41% of colon adenocarcinoma, 12% of ovarian cystadenocarcinoma (OV) and 16% of OV samples respectively, compared to 0.002%, 0.003%, 0.014% and 0.001% in aggregated variant databases. These variants were found in 7-20% of DNA sequences in both tumor and matched normal blood samples, indicating that they originated in tumor infiltrating lymphocytes, rather than in the tumor cells. We argue that these mutations are unlikely to be passenger mutations since each of them occur in only 0-2% of normal tissue samples and in less than 2% of tumor samples from 24-32 of 32 cancer types other than the one noted above for each of the four mutations. The set of differentially expressed genes (FDR<0.05) in samples with each of the four variants, compared to samples without the variant, included 22-445 genes associated with the immune system pathway, suggesting a possible mechanism by which these mutations may affect tumor growth. Given the myriad of diverse mechanisms and genes implicated in cancer, it is not unexpected that mutations in tumor infiltrating lymphocytes could contribute to cancer progression. With further validation, genetic lesions in tumor infiltrating lymphocytes may represent a previously unstudied mechanism affecting tumor growth, and a new class of therapeutic targets. These mutations may also represent potential “somatic” risk markers that may present with age, supplementing traditional germline risk markers. Citation Format: Ramu Anandakrishnan, Robin T. Varghese, Nicholas A. Kinney, Harold R. Garner. Somatic mutations in tumor infiltrating lymphocytes can affect the expression of immune system genes in the tumor microenvironment [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO022.

Estrogen-induced circRNA, circPGR, functions as a ceRNA to promote estrogen receptor-positive breast cancer cell growth by regulating cell cycle-related genes

Estrogen and estrogen receptor (ER)-regulated gene transcriptional events have been well known to be involved in ER-positive breast carcinogenesis. Meanwhile, circular RNAs (circRNAs) are emerging as a new family of functional non-coding RNAs (ncRNAs) with implications in a variety of pathological processes, such as cancer. However, the estrogen-regulated circRNA program and the function of such program remain uncharacterized.Methods: CircRNA sequencing (circRNA-seq) was performed to identify circRNAs induced by estrogen, and cell proliferation, colony formation, wound healing, transwell and tumor xenograft experiments were applied to examine the function of estrogen-induced circRNA, circPGR. RNA sequencing (RNA-seq) and ceRNA network analysis wereperformed to identify circPGR's target genes and the microRNA (miRNA) bound to circPGR. Anti-sense oligonucleotide (ASO) was used to assess circPGR's effects on ER-positive breast cancer cell growth.Results: Genome-wide circRNA profiling by circRNA sequencing (circRNA-seq) revealed that a large number of circRNAs were induced by estrogen, and further functional screening for the several circRNAs originated from PGR revealed that one of them, which we named as circPGR, was required for ER-positive breast cancer cell growth and tumorigenesis. CircPGR was found to be localized in the cytosol of cells and functioned as a competing endogenous RNA (ceRNA) to sponge miR-301a-5p to regulate the expression of multiple cell cycle genes. The clinical relevance of circPGR was underscored by its high and specific expression in ER-positive breast cancer cell lines and clinical breast cancer tissue samples. Accordingly, anti-sense oligonucleotide (ASO) targeting circPGR was proven to be effective in suppressing ER-positive breast cancer cell growth.Conclusions: These findings reveled that, besides the well-known messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and enhancer RNA (eRNA) programs, estrogen also induced a circRNA program, and exemplified by circPGR, these estrogen-induced circRNAs were required for ER-positive breast cancer cell growth, providing a new class of therapeutic targets for ER-positive breast cancer.

Proliferation‐associated long noncoding RNA, TMPO‐AS1, is a potential therapeutic target for triple‐negative breast cancer

Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer compared with luminal or epidermal growth factor receptor 2 subtypes, thus effective therapeutic options for TNBC are yet to be developed. Nowadays, oncogenic long noncoding RNAs (lncRNAs) are applied to cancer management as a new class of therapeutic targets. We previously showed that thymopoietin antisense transcript 1 (TMPO‐AS1) is a proliferation‐associated lncRNA that contributes to hormone‐dependent breast cancer progression by stabilizing estrogen receptor‐α mRNA. We here showed that TMPO‐AS1 is abundantly expressed in basal‐like breast cancer subtype based on the transcriptomic data in The Cancer Genome Atlas as well as in TNBC cell lines and patient‐derived cells. Small interfering RNA‐based loss‐of‐function analyses showed that TMPO‐AS1 knockdown substantially represses the proliferation and migration of TNBC cells. Expression microarray analysis showed that TMPO‐AS1 alters gene signatures related to transforming growth factor‐β signaling in addition to proliferative E2F signaling pathways. TMPO‐AS1‐targeted siRNA treatment through engineered drug delivery systems using cancer‐targeted polyion complex micelle or nanoball technology significantly impaired the in vivo growth of primary and metastatic TNBC xenograft tumors. Our findings suggest that TMPO‐AS1 plays a key role in TNBC pathophysiology and could be a potential therapeutic target for TNBC.

Abstract IA21: Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies

Abstract We have developed network-based methodologies for the systematic identification, validation, and pharmacologic targeting of a new class of therapeutic targets. These targets comprise Master Regulator proteins, whose concerted aberrant activity within tightly regulated modules (tumor checkpoints) is responsible for the mechanistic implementation and maintenance of specific tumor cell states. By leveraging these methodologies, we have developed OncoTreat, a NY CLIA-certified test that leverages large-scale drug-perturbation assays to systematically identify drugs and drug combinations whose mechanism of action is specifically effective in abrogating tumor checkpoint activity, on an individual patient basis. These tests have shown 60% validation rate across 39 predicted drugs that were validated in PDX models from patients who had failed multiple standard-of-care therapies. In this talk, we will introduce these concepts and then demonstrate their application to elucidating drugs capable of targeting transcriptionally distinct tumor niches by single-cell analysis (N-of-1-of-1 studies). In particular, we will show identification and validation, in vivo, of drugs targeting the stemlike progenitor niche of breast adenocarcinomas and the four transcriptionally distinct single-cell subtypes identified in glioblastoma patients. Citation Format: Andrea Califano. Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA21.

NcRNAs in Type-2 Immunity.

Immunological diseases, including asthma, autoimmunity and immunodeficiencies, affect a growing percentage of the population with significant unmet medical needs. As we slowly untangle and better appreciate these complex genetic and environment-influenced diseases, new therapeutically targetable pathways are emerging. Non-coding RNA species, which regulate epigenetic, transcriptional and translational responses are critical regulators of immune cell development, differentiation and effector function, and may represent one such new class of therapeutic targets. In this review we focus on type-2 immune responses, orchestrated by TH2 cell-derived cytokines, IL-4, IL-5 and IL-13, which stimulate a variety of immune and tissue responses- commonly referred to as type-2 immunity. Evolved to protect us from parasitic helminths, type-2 immune responses are observed in individuals with allergic diseases, including Asthma, atopic dermatitis and food allergy. A growing number of studies have identified the involvement of various RNA species, including microRNAs (miRNA) and long non-coding (lncRNA), in type-2 immune responses and in both clinical and pre-clinical disease settings. We highlight these recent findings, identify gaps in our understanding and provide a perspective on how our current understanding can be harnessed for novel treat opportunities to treat type-2 immune-mediated diseases.

Splicing dysregulation in cancer: from mechanistic understanding to a new class of therapeutic targets.

RNA splicing dysregulation is widespread in cancer. Accumulating evidence demonstrates that splicing defects resulting from splicing dysregulation play critical roles in cancer pathogenesis and can serve as new biomarkers and therapeutic targets for cancer intervention. These findings have greatly deepened the mechanistic understandings of the regulation of alternative splicing in cancer cells, leading to rapidly growing interests in targeting cancer-related splicing defects as new therapies. Here we summarize the current research progress on splicing dysregulation in cancer and highlight the strategies available or under development for targeting RNA splicing defects in cancer.

Breaking the chains: deubiquitylating enzyme specificity begets function.

The deubiquitylating enzymes (DUBs, also known as deubiquitylases or deubiquitinases) maintain the dynamic state of the cellular ubiquitome by releasing conjugated ubiquitin from proteins. In light of the many cellular functions of ubiquitin, DUBs occupy key roles in almost all aspects of cell behaviour. Many DUBs show selectivity for particular ubiquitin linkage types or positions within ubiquitin chains. Others show chain-type promiscuity but can select a distinct palette of protein substrates via specific protein-protein interactions established through bindingmodules outside of the catalytic domain. The ubiquitin chain cleavage mode or chain linkage specificity has been related directly to biological functions. Examples include regulation of protein degradation and ubiquitin recycling by the proteasome, DNA repair pathways and innate immune signalling. DUB cleavage specificity is also being harnessed for analysis of ubiquitin chain architecture that is assembled on specific proteins. The recent development of highly specific DUB inhibitors heralds their emergence as a new class of therapeutic targets for numerous diseases.

In silico insights on tankyrase protein: A potential target for colorectal cancer

The Wnt/β-catenin pathway plays an important regulatory role in cancer signaling and cell regenerative mechanisms. Its suppression has long been considered as an important challenge of anticancer treatment and management. The poly(ADP-ribose) polymerase (PARP) family represented as a new class of therapeutic targets with diverse potential disease indications. Tankyrase (TNKS) is considered to be a potential target for the intervention of various cancers. The main objective of the work is to explore the molecular and quantum mechanics of the drug-like compounds and to identify the potential inhibitors for TNKS protein using the structure and ligand-based virtual screening from several databases and to explore the binding pocket and interactions of active residues. The screened compounds were further filtered using binding-free energy calculation and molecular dynamics simulation studies. The results have provided a strong molecular knowledge of TNKS and offered top hit potent inhibitors. The identified lead compounds LC_40781, LC_40777, LC_39767, LC_8346, NCI_682438, and NCI_721141 were observed to have potent activity against TNKS protein. The hydrogen bonding of compounds with Asp1198, His1201, Tyr1203 in TNKS1 and Gly1032, Ser1068 in TNKS2 are the key interactions plays a major role in binding energy. Therefore, the outcome of the study would help for further validation and provides valuable information to guide the future TNKS-specific inhibitor designing.Communicated by Ramaswamy H. Sarma

Adhesion GPCRs in Kidney Development and Disease.

Chronic kidney disease (CKD) represents the fastest growing pathology worldwide with a prevalence of >10% in many countries. In addition, kidney cancer represents 5% of all new diagnosed cancers. As currently no effective therapies exist to restore kidney function after CKD- as well as cancer-induced renal damage, it is important to elucidate new regulators of kidney development and disease as new therapeutic targets. G protein-coupled receptors (GPCRs) represent the most successful class of pharmaceutical targets. In recent years adhesion GPCRs (aGPCRs), the second largest GPCR family, gained significant attention as they are present on almost all mammalian cells, are associated to a plethora of diseases and regulate important cellular processes. aGPCRs regulate for example cell polarity, mitotic spindle orientation, cell migration, and cell aggregation; all processes that play important roles in kidney development and/or disease. Moreover, polycystin-1, a major regulator of kidney development and disease, contains a GAIN domain, which is otherwise only found in aGPCRs. In this review, we assess the potential of aGPCRs as therapeutic targets for kidney disease. For this purpose we have summarized the available literature and analyzed data from the databases The Human Protein Atlas, EURExpress, Nephroseq, FireBrowse, cBioPortal for Cancer Genomics and the National Cancer Institute Genomic Data Commons data portal (NCIGDC). Our data indicate that most aGPCRs are expressed in different spatio-temporal patterns during kidney development and that altered aGPCR expression is associated with a variety of kidney diseases including CKD, diabetic nephropathy, lupus nephritis as well as renal cell carcinoma. We conclude that aGPCRs present a promising new class of therapeutic targets and/or might be useful as diagnostic markers in kidney disease.

The long non-coding RNA SNHG14 inhibits cell proliferation and invasion and promotes apoptosis by sponging miR-92a-3p in glioma.

Malignant glioma is one of the most common types of primary brain tumours. Long non-coding RNAs (lncRNAs) have recently emerged as a new class of therapeutic targets for many cancers. In this study, we aimed to explore the functional involvement of small nucleolar RNA host gene 14 (SNHG14) and its potential regulatory mechanism in glioma progression. SNHG14 was found to be downregulated in human glioma tissues and cell lines. SNHG14 significantly inhibited cell viability, reduced cell invasion, and induced apoptosis in glioma cell lines. Furthermore, a correlation analysis demonstrated that there was a negative correlation between SNHG14 expression and miR-92a-3p expression. Bioinformatics prediction and luciferase reporter assays demonstrated that miR-92a-3p could directly bind to SNHG14. miR-92a-3p was significantly upregulated in glioma and acted as an oncogene in glioma cells by inhibiting Bim. Moreover, mechanistic investigations showed that miR-92a-3p could reverse the tumour suppressive effects induced by SNHG14 in glioma, indicating that SNHG14 may act as an endogenous sponge that competes for binding to miR-92a-3p. Our results suggest that SNHG14 and miR-92a-3p may be promising molecular targets for glioma therapy.

Marching towards Making Evolution-Proof Antibiotics

Antibiotic resistance in bacterial pathogens has increased to alarming levels and warrants immediate attention Traditional antibiotics kill the bacteria by targeting the bacterial structures and mechanisms that are essential for their survival putting great selection pressure to develop resistance Anti virulence drugs are new class of therapeutic targets being investigated to tackle this crisis As anti virulence drugs disarm the pathogen rather than killing it may pose less selection pressure on bacteria to develop resistance

Targeted deletion of GD3 synthase protects against MPTP-induced neurodegeneration.

Parkinson's disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside-such as inhibition of GD3 synthase (GD3S) or administration of sialidase-are neuroprotective in vitro and in a number of preclinical models. In this study, we investigated the effects of GD3S deletion on parkinsonism induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S-/- mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day × 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures-such as the force-plate actimeter and treadmill gait parameters-detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice, MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S-/- mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results show that inhibition of GD3S has neuroprotective properties in the MPTP model and may warrant further investigation as a therapeutic target.

Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling.

Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin-collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets.

GENO-04REGULATION OF GLIOBLASTOMA BY NOVEL LONG NONCODING RNA (lncRNA)

The human genome produces many thousands of long noncoding RNAs (lncRNAs) – transcripts >200 nucleotides long with little evidence of protein coding potential. It is now clear that lncRNAs can have critical biological functions and roles in human disease including cancer. Because lncRNAs are particularly cell and disease specific, they are attractive as therapeutic targets. However, very few specific lncRNAs have been identified as potential targets for cancer therapy. We have recently identifiedPinky (Pnky) as a novel lncRNA that regulates the production of neurons from neural stem cells (NSCs) in the embryonic and adult brain (Ramos et al., Cell Stem Cell 2013; Ramos et al., Cell Stem Cell 2015). Pnky-deficiency in NSCs increased neuronal differentiation, depleting the NSC population. Moreover, human GBM tumors expressed the human PNKY transcript, and single cell RNA-seq data analysis indicated that PNKYis present in a specific subset of individual GBM tumor cells. In the Ink/Arf-null, EGFRvIII mouse glioma model, Pnky was also found to be highly expressed, and ongoing studies indicate a function for Pnky in this brain tumor model. Upcoming results may reveal the critical importance of Pnky and other specific lncRNAs in the proliferation of GBM. Overall, our work lays important groundwork for the development of lncRNAs as a large new class of therapeutic targets for the treatment of gliomas.

Les microARNs : en quoi intéressent-ils les cardiologues ?

MiRNAs are small 21-22 nucleotides long RNAs transcribed from non coding genes or introns of coding genes that are involved the repression of cellular messenger RNAs by the RISC complex. Close to 2000 miRNAs have been identified in the human genome and the expression of hundreds of them is increased or decreased in pathological condition, modifying on a global scale the expression of cardiac and vascular proteins. MiRNAs regulate most cellular processes involved in the cardiovascular pathophysiology including apoptosis, proliferation and migration, left ventricle hypertrophy, cardiac fibrosis and conduction. MiRNAs form a new class of therapeutic targets that can be introduced in the cells in various forms (synthetic molecules, expression vectors) or inhibited by antisens oligonucleotides called anti-miRs. MiRNAs are actively secreted by specific cells including cardiac fibroblasts and endothelial cells during certain pathophysiological processes, or passively following cell death and can be quantified in all kind of body fluids. They emerge as a new category of cardiovascular disease biomarkers, notably in the context of myocardial infarction.