7,878 research outputs found
MicroRNA-129-1 acts as tumour suppressor and induces cell cycle arrest of GBM cancer cells through targeting IGF2BP3 and MAPK1
Background MicroRNA-129-1 (miR-129-1) seems to behave as a tumour suppressor since its decreased expression is associated with different tumours such as glioblastoma multiforme (GBM). GBM is the most common form of brain tumours originating from glial cells. The impact of miR-129-1 downregulation on GBM pathogenesis has yet to be elucidated. Methods MiR-129-1 was overexpressed in GBM cells, and its effect on proliferation was investigated by cell cycle assay. MiR-129-1 predicted targets (CDK6, IGF1, HDAC2, IGF2BP3 and MAPK1) were also evaluated by western blot and luciferase assay. Results Restoration of miR-129-1 reduced cell proliferation and induced G1 accumulation, significantly. Several functional assays confirmed IGF2BP3, MAPK1 and CDK6 as targets of miR-129-1. Despite the fact that IGF1 expression can be suppressed by miR-129-1, through 30-untranslated region complementary sequence, we could not find any association between IGF1 expression and GBM. MiR-129-1 expression inversely correlates with CDK6, IGF2BP3 and MAPK1 in primary clinical samples. Conclusion This is the first study to propose miR129-1 as a negative regulator of IGF2BP3 and MAPK1 and also a cell cycle arrest inducer in GBM cells. Our data suggests miR-129-1 as a potential tumour suppressor and presents a rationale for the use of miR-129-1 as a novel strategy to improve treatment response in GBM
MicroRNA regulation of bovine monocyte inflammatory and metabolic networks in an in vivo infection model.
peer-reviewedBovine mastitis is an inflammation-driven disease of the bovine mammary gland that costs the global dairy industry several billion dollars per annum. Because disease susceptibility is a multi-factorial complex phenotype, an integrative biology approach is required to dissect the molecular networks involved. Here, we report such an approach, using next generation sequencing combined with advanced network and pathway biology methods to simultaneously profile mRNA and miRNA expression at multiple time-points (0, 12, 24, 36 and 48h) in both milk and blood FACS-isolated CD14+ monocytes from animals infected in vivo with Streptococcus uberis. More than 3,700 differentially expressed (DE) genes were identified in milk-isolated monocytes (MIMs), a key immune cell recruited to the site of infection during mastitis. Up-regulated genes were significantly enriched for inflammatory pathways, while down-regulated genes were enriched for non-glycolytic metabolic pathways. Monocyte transcriptional changes in the blood, however, were more subtle but highlighted the impact of this infection systemically. Genes up-regulated in blood-isolated-monocytes (BIMs) showed a significant association with interferon and chemokine signalling. Furthermore, twenty-six miRNAs were differentially expressed in MIMs and three in BIMs. Pathway analysis revealed that predicted targets of down-regulated miRNAs were highly enriched for roles in innate immunity (FDR < 3.4E-8) in particular TLR signalling, while up-regulated miRNAs preferentially targeted genes involved in metabolism. We conclude that during S. uberis infection miRNAs are key amplifiers of monocyte inflammatory response networks and repressors of several metabolic pathways.This study was funded in part by Teagasc RMIS 6018 and United States Department of Agriculture ARS funding 3625-32000-102-00. NL is supported by a Teagasc Walsh Fellowship
Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients
The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients
Epigenetic reprogramming of muscle progenitors: inspiration for clinical therapies
In the context of regenerative medicine, based on the potential of stem cells to restore diseased tissues, epigenetics is becoming a pivotal area of interest. Therapeutic interventions that promote tissue and organ regeneration have as primary objective the selective control of gene expression in adult stem cells. This requires a deep understanding of the epigenetic mechanisms controlling transcriptional programs in tissue progenitors. This review attempts to elucidate the principle epigenetic regulations responsible of stem cells differentiation. In particular we focus on the current understanding of the epigenetic networks that regulate differentiation of muscle progenitors by the concerted action of chromatin-modifying enzymes and noncoding RNAs. The novel exciting role of exosome-bound microRNA in mediating epigenetic information transfer is also discussed. Finally we show an overview of the epigenetic strategies and therapies that aim to potentiate muscle regeneration and counteract the progression of Duchenne Muscular Dystrophy (DMD)
MiRNAs as novel adipokines : obesity-related circulating MiRNAs influence chemosensitivity in cancer patients
Adipose tissue is an endocrine organ, capable of regulating distant physiological processes in other tissues via the release of adipokines into the bloodstream. Recently, circulating adipose-derived microRNAs (miRNAs) have been proposed as a novel class of adipokine, due to their capacity to regulate gene expression in tissues other than fat. Circulating levels of adipokines are known to be altered in obese individuals compared with typical weight individuals and are linked to poorer health outcomes. For example, obese individuals are known to be more prone to the development of some cancers, and less likely to achieve event-free survival following chemotherapy. The purpose of this review was twofold; first to identify circulating miRNAs which are reproducibly altered in obesity, and secondly to identify mechanisms by which these obesity-linked miRNAs might influence the sensitivity of tumors to treatment. We identified 8 candidate circulating miRNAs with altered levels in obese individuals (6 increased, 2 decreased). A second literature review was then performed to investigate if these candidates might have a role in mediating resistance to cancer treatment. All of the circulating miRNAs identified were capable of mediating responses to cancer treatment at the cellular level, and so this review provides novel insights which can be used by future studies which aim to improve obese patient outcomes
Coupled Reversible and Irreversible Bistable Switches Underlying TGF-\beta-induced Epithelial to Mesenchymal Transition
Epithelial to mesenchymal transition (EMT) plays important roles in embryonic
development, tissue regeneration and cancer metastasis. While several feedback
loops have been shown to regulate EMT, it remains elusive how they coordinately
modulate EMT response to TGF-\beta treatment. We construct a mathematical model
for the core regulatory network controlling TGF-\beta-induced EMT. Through
deterministic analyses and stochastic simulations, we show that EMT is a
sequential two-step program that an epithelial cell first transits to partial
EMT then to the mesenchymal state, depending on the strength and duration of
TGF-\beta stimulation. Mechanistically the system is governed by coupled
reversible and irreversible bistable switches. The SNAIL1/miR-34 double
negative feedback loop is responsible for the reversible switch and regulates
the initiation of EMT, while the ZEB/miR-200 feedback loop is accountable for
the irreversible switch and controls the establishment of the mesenchymal
state. Furthermore, an autocrine TGF-\beta/miR-200 feedback loop makes the
second switch irreversible, modulating the maintenance of EMT. Such coupled
bistable switches are robust to parameter variation and molecular noise. We
provide a mechanistic explanation on multiple experimental observations. The
model makes several explicit predictions on hysteretic dynamic behaviors,
system response to pulsed stimulation and various perturbations, which can be
straightforwardly tested.Comment: 32 pages, 8 figures, accepted by Biophysical Journa
Modulação da expressão de microrna’s para reprogramar o fenótipo dos macrófagos como imunoterapia anti-cancro
Macrophages play an important role in tumour progression and metastasis
due to the plasticity expressed during activation, especially noticeable in vivo.
Depending on the signals present in the tumour microenvironment (TME),
macrophages can have a pro-inflammatory phenotype, known as M1
macrophages, or an anti-inflammatory phenotype, known as M2
macrophages. M1 macrophages are associated with the cancer-related
inflammation common in the early stages of tumorigenesis. Later, signals from
the TME can polarize macrophages towards an M2-like phenotype, referred
as tumour-associated macrophages (TAMs), a pro-tumour response, which
leads to tumour progression, angiogenesis, and metastasis. The presence of
TAMs in the TME is normally linked to a poor prognosis for cancer patients.
The activation state and, consequently, the functions of macrophages are
tightly regulated by microRNAs (miRNAs). miRNAs regulate geneexpression
after transcription and modulate many aspectsof the immune responses such
as differentiation, proliferation, cells’ function, but also, cytokine responses.
miRNAs can act either as oncogenes or as tumour suppressors, by affecting
the polarization of macrophages. There are miRNAs involved both in the
promotion or inhibition of macrophage activated phenotypes, besides miRNAs
involved in differentiation. Alterations in miRNA expression can drive
oncogenesis, tumour progression and metastasis, by contributing to the
generation of TAMs.
TAMs in conjunction with miRNAs are great therapeutic candidates.
Therapeutically regulating miRNA levels may be linked to cancer treatment
and to the regulation of the immune response. Reactivating pro-inflammatory
genes in TAMs might help to promote tumour rejection.
This project aims to compile a review of the literature concerning miRNA’s
modulation towards cancer immunotherapy, but also to assess the effect of
anticancer drugs in the expression of selected miRNAs, focusing on
reprogramming TAMs phenotype.Os macrófagos desempenham um papel importante na progressão tumoral e
metástase devido à plasticidade demonstrada durante a sua ativação, sendo
especialmente percetível in vivo. Dependendo dos sinais presentes no
microambiente tumoral (TME), os macrófagos podem ter um fenótipo próinflamatório, conhecidos como macrófagos M1, ou um fenótipo antiinflamatório, conhecidos como macrófagos M2. Os macrófagos M1 estão
associados à inflamação comum nos estágios iniciais da tumorigénese.
Posteriormente, os sinais do TME podem polarizar macrófagos em direção a
um fenótipo semelhante ao dos macrófagos M2, denominados como
macrófagos associados ao tumor (TAMs), uma resposta pró-tumor, que leva
à progressão tumoral, angiogénese e metástase. A presença de TAMs no
TME está normalmente associada a um prognóstico negativo para pacientes
oncológicos.
O estado de ativação e, consequentemente, as funções dos macrófagos são
estritamente reguladas por microRNAs (miRNAs). Os miRNAs regulam a
expressão génica após a transcrição e modulam muitos aspetos das
respostas imunes, como a diferenciação, proliferação, função das células, e
também, libertação de citocinas. Os miRNAs podem atuar como oncogenes
ou como supressores de tumor, afetando a polarização dos macrófagos.
Existem miRNAs envolvidos tanto na promoção quanto na inibição de
fenótipos dos macrófagos, além de existirem miRNAs envolvidos na
diferenciação celular. Alterações na expressão de miRNAs podem conduzir a
oncogénese, progressão tumoral e metástase, contribuindo para a geração
de TAMs.
Os TAMs em conjunto com miRNAs são ótimos candidatos terapêuticos. A
regulação terapêutica dos níveis de miRNA pode estar ligada ao tratamento
do cancro e à regulação da resposta imune. A reativação de genes próinflamatórios nos TAMs pode ajudar a promover a rejeição do tumor.
Este projeto tem como objetivo compilar uma revisão da literatura sobre a
modulação de miRNAs de encontro à imunoterapia contra o cancro, mas
também avaliar o efeito de compostos na expressão de miRNAs
selecionados, com foco na reprogramação do fenótipo dos TAMs.Mestrado em Biologia Aplicad
Transcriptional landscape of neuronal and cancer stem cells
Tumor mass is composed by heterogeneous cell population including a subset of “cancer stem cells” (CSC).
Oncogenic signals foster CSC by transforming tissue stem cells or by reprogramming progenitor/differentiated
cells towards stemness. Thus, CSC share features with cancer and stem cells (e.g. self-renewal, hierarchical
developmental program leading to differentiated cells, epithelial/mesenchimal transition) and these latter are
maintained by the constitutive activation of stemness-promoting signals. CSC could trigger tumor formation,
drive to resistance to conventional therapeutics and underlie patients’ relapse. Indeed, stem cell signatures
have been associated with poor prognosis in various.
This background makes the identification of CSC molecular features mandatory to highlight the survival inner
working and to design novel CSC specific therapeutic strategies.
Medulloblastoma (MB) is the most common childhood malignant brain tumor and a leading cause of cancerrelated
morbidity and mortality. Current multimodal therapies are effective in about 50% of patients but often
cause long-term side effects, i.e. developmental, neurological, neuroendocrine and psychosocial deficits
(Northcott PA Nature Rev cancer 2012). For many years, MB treated as a single tumor entity despite the
divergent tumor histology, patients’ outcome and drug sensitivity, and also by the diversity of the stem cell of
origin. Very recently the scenario of human MB has dramatically changed since its heterogeneous biology has
been addressed by high-throughput gene expression analysis (oligonucleotide microarrays) or by the powerful
genomic next-generation sequencing. These led to the identification of four tumor subgroups (WNT, SHH,
Group 3 and Group 4) uncovering the existence of a highly diverse mutational spectra and gene expression.
However a quantitative approach has not yet been applied to the transcriptional landscape of Medulloblastoma
stem cells (MbSC) through RNA Next Generation Sequencing (RNA-Seq) technology. This is a relevant issue,
since RNA-Seq is able to interrogate the genome wide global transcriptome including new transcripts,
alternative spliced isoforms and non-coding RNAs.
Lower rhombic lip progenitors of the dorsal brainstem are considered the trigger cells in WNT tumors; in SHH
subgroup initiation cells are Prominin1+ CD15+ stem cells from the subventricular zone requiring the
commitment to Math1+ granule cell progenitors [GCP] of the external granule cell layer [EGL]; while Math1+ or
Math1- EGL-GCP or Prominin1+/lineage-negative stem cells sustain the MYC driven Group 3.
MbSC derived from SHH tumors and postnatal normal cerebellar stem cells (NcSC) have been reported to
share several features. A key signal for both of them is Hedgehog. Furthermore, both NcSC and MbSC display
up-regulation of stemness genes (e.g Sox2, Nestin, Nanog, Prom1). Finally, constitutive activation of the Shh
pathway by conditional deletion of Ptch1 inhibitory receptor in NcSC, promote medulloblastoma in vivo,
producing a mouse model of the human SHH tumor. Acquisition of stemness features may therefore represent
the first step of oncogenic conversion. Cooperation with additional oncogenic signals is however needed to
enhance MbSC tumorigenicity.
In order to understand the MbSCs transcriptional programs, we analyze by RNA-Seq, MbSC derived from
Ptch1+/- tumors (Ptch1+/- MbSC). This choice, of a genetically determined model of MB, has allowed us to
work with Ptch1+/- MbSC together with appropriate NcSC counterpart, and to analyze biological replicates
doing statistical analysis.
We identify a number of transcripts, annotated ones, novel isoforms, and long non-coding RNAs,
characterizing MbSC and/or NcSC. Some of these genes control stemness or are cancer related and
conserved in human medulloblastomas. Interestingly a subset of them, belonging to cell stress response, are
of prognostic relevance being significantly related to clinical outcome. Correlation of genes expression
characterizing MbSC with survival information from our human medulloblastomas database further
demonstrates the significance of these findings. Our data suggest that the modulation of normal and cancer
stem cell functions observed in vitro is effective in dissecting the transcriptional programs underlying the in
vivo behavior of human medulloblastomas
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