Publications by authors named "Isabella Screpanti"

125 Publications

miR-125b/NRF2/HO-1 axis is involved in protection against oxidative stress of cystic fibrosis: A pilot study.

Exp Ther Med 2021 Jun 2;21(6):585. Epub 2021 Apr 2.

Department of Molecular Medicine, Sapienza University of Rome, I-00161 Rome, Italy.

In the physiopathology of cystic fibrosis (CF), oxidative stress implications are recognized and widely accepted. The cystic fibrosis transmembrane conductance regulator (CFTR) defects disrupt the intracellular redox balance causing CF pathological hallmarks. Therefore, oxidative stress together with aberrant expression levels of detoxification genes and microRNAs (miRNAs/miRs) may be associated with clinical outcome. Using total RNA extracted from epithelial nasal cells, the present study analyzed the expression levels of oxidative stress genes and one miRNA using quantitative PCR in a representative number of patients with CF compared with in healthy individuals. The present pilot study revealed the existence of an association among CFTR, genes involved in the oxidative stress response and miR-125b. The observed downregulation of CFTR gene expression was accompanied by increased expression levels of Nuclear factor erythroid derived-2 like2 and its targets NAD(P)H:Quinone Oxidoreductase and glutathione S-transferase 1. Moreover, the expression levels of heme oxygenase-1 (HO-1) and miR-125b were positively correlated with a forced expiratory volume in 1 sec (FEV1) >60% in patients with CF with chronic lung infection (r=0.74; P<0.001 and r=0.57; P<0.001, respectively). The present study revealed the activation of an inducible, but not fully functional, oxidative stress response to protect airway cells against reactive oxygen species-dependent injury in CF disease. Additionally, the correlations of HO-1 and miR-125b expression with an improved FEV1 value suggested that these factors may synergistically protect the airway cells from oxidative stress damage, inflammation and apoptosis. Furthermore, HO-1 and miR-125b may be used as prognostic markers explaining the wide CF phenotypic variability as an additional control level over the CFTR gene mutations.
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http://dx.doi.org/10.3892/etm.2021.10017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027740PMC
June 2021

Functional cooperation between ASK1 and p21 in the balance of cell-cycle arrest, cell death and tumorigenesis of stressed keratinocytes.

Cell Death Discov 2021 Apr 12;7(1):75. Epub 2021 Apr 12.

Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, Rome, 00161, Italy.

Both CDKN1A (p21 ) and Apoptosis signal-regulating kinase 1 (ASK1) play important roles in tumorigenesis. The role of p21 in attenuating ASK1-induced apoptosis by various stress conditions is well established. However, how ASK1 and p21 functionally interact during tumorigenesis is still unclear. To address this aspect, we crossed ASK1 knockout (ASK1KO) mice with p21 knockout (p21KO) mice to compare single and double-mutant mice. We observed that deletion of p21 leads to increased keratinocyte proliferation but also increased cell death. This is mechanistically linked to the ASK1 axis-induced apoptosis, including p38 and PARP. Indeed, deletion of ASK1 does not alter the proliferation but decreases the apoptosis of p21KO keratinocytes. To analyze as this interaction might affect skin carcinogenesis, we investigated the response of ASK1KO and p21KO mice to DMBA/TPA-induced tumorigenesis. Here we show that while endogenous ASK1 is dispensable for skin homeostasis, ASK1KO mice are resistant to DMBA/TPA-induced tumorigenesis. However, we found that epidermis lacking both p21 and ASK1 reacquires increased sensitivity to DMBA/TPA-induced tumorigenesis. We demonstrate that apoptosis and cell-cycle progression in p21KO keratinocytes are uncoupled in the absence of ASK1. These data support the model that a critical event ensuring the balance between cell death, cell-cycle arrest, and successful divisions in keratinocytes during stress conditions is the p21-dependent ASK1 inactivation.
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http://dx.doi.org/10.1038/s41420-021-00459-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042117PMC
April 2021

A Dynamic Role of Mastermind-Like 1: A Journey Through the Main (Path)ways Between Development and Cancer.

Front Cell Dev Biol 2020 21;8:613557. Epub 2020 Dec 21.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

Major signaling pathways, such as Notch, Hedgehog (Hh), Wnt/β-catenin and Hippo, are targeted by a plethora of physiological and pathological stimuli, ultimately resulting in the modulation of genes that act coordinately to establish specific biological processes. Many biological programs are strictly controlled by the assembly of multiprotein complexes into the nucleus, where a regulated recruitment of specific transcription factors and coactivators on gene promoter region leads to different transcriptional outcomes. MAML1 results to be a versatile coactivator, able to set up synergistic interlinking with pivotal signaling cascades and able to coordinate the network of cross-talking pathways. Accordingly, despite its original identification as a component of the Notch signaling pathway, several recent reports suggest a more articulated role for MAML1 protein, showing that it is able to sustain/empower Wnt/β-catenin, Hh and Hippo pathways, in a Notch-independent manner. For this reason, MAML1 may be associated to a molecular "switch", with the function to control the activation of major signaling pathways, triggering in this way critical biological processes during embryonic and post-natal life. In this review, we summarize the current knowledge about the pleiotropic role played by MAML proteins, in particular MAML1, and we recapitulate how it takes part actively in physiological and pathological signaling networks. On this point, we also discuss the contribution of MAML proteins to malignant transformation. Accordingly, genetic alterations or impaired expression of MAML proteins may lead to a deregulated crosstalk among the pathways, culminating in a series of pathological disorders, including cancer development. Given their central role, a better knowledge of the molecular mechanisms that regulate the interplay of MAML proteins with several signaling pathways involved in tumorigenesis may open up novel opportunities for an attractive molecular targeted anticancer therapy.
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http://dx.doi.org/10.3389/fcell.2020.613557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787167PMC
December 2020

Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response.

Oncogenesis 2020 Oct 18;9(10):93. Epub 2020 Oct 18.

Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy.

Unfolded protein response (UPR) is a conserved adaptive response that tries to restore protein homeostasis after endoplasmic reticulum (ER) stress. Recent studies highlighted the role of UPR in acute leukemias and UPR targeting has been suggested as a therapeutic approach. Aberrant Notch signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), as downregulation of Notch activity negatively affects T-ALL cell survival, leading to the employment of Notch inhibitors in T-ALL therapy. Here we demonstrate that Notch3 is able to sustain UPR in T-ALL cells, as Notch3 silencing favored a Bip-dependent IRE1α inactivation under ER stress conditions, leading to increased apoptosis via upregulation of the ER stress cell death mediator CHOP. By using Juglone, a naturally occurring naphthoquinone acting as an anticancer agent, to decrease Notch3 expression and induce ER stress, we observed an increased ER stress-associated apoptosis. Altogether our results suggest that Notch3 inhibition may prevent leukemia cells from engaging a functional UPR needed to compensate the Juglone-mediated ER proteotoxic stress. Notably, in vivo administration of Juglone to human T-ALL xenotransplant models significantly reduced tumor growth, finally fostering the exploitation of Juglone-dependent Notch3 inhibition to perturb the ER stress/UPR signaling in Notch3-dependent T-ALL subsets.
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http://dx.doi.org/10.1038/s41389-020-00279-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569087PMC
October 2020

NOTCH3 signaling is essential for NF-κB activation in TLR-activated macrophages.

Sci Rep 2020 09 9;10(1):14839. Epub 2020 Sep 9.

Universidad de Castilla-La Mancha, Medical School/CRIB, Laboratory of Biochemistry and Molecular Biology, Department of Inorganic and Organic Chemistry and Biochemistry, UCLM, C/Almansa 14, 02008, Albacete, Spain.

Macrophage activation by Toll receptors is an essential event in the development of the response against pathogens. NOTCH signaling pathway is involved in the control of macrophage activation and the inflammatory processes. In this work, we have characterized NOTCH signaling in macrophages activated by Toll-like receptor (TLR) triggering and determined that DLL1 and DLL4 are the main ligands responsible for NOTCH signaling. We have identified ADAM10 as the main protease implicated in NOTCH processing and activation. We have also observed that furin, which processes NOTCH receptors, is induced by TLR signaling in a NOTCH-dependent manner. NOTCH3 is the only NOTCH receptor expressed in resting macrophages. Its expression increased rapidly in the first hours after TLR4 activation, followed by a gradual decrease, which was coincident with an elevation of the expression of the other NOTCH receptors. All NOTCH1, 2 and 3 contribute to the increased NOTCH signaling detected in activated macrophages. We also observed a crosstalk between NOTCH3 and NOTCH1 during macrophage activation. Finally, our results highlight the relevance of NOTCH3 in the activation of NF-κB, increasing p65 phosphorylation by p38 MAP kinase. Our data identify, for the first time, NOTCH3 as a relevant player in the control of inflammation.
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http://dx.doi.org/10.1038/s41598-020-71810-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481794PMC
September 2020

Current Trends in ATRA Delivery for Cancer Therapy.

Pharmaceutics 2020 Jul 28;12(8). Epub 2020 Jul 28.

Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy.

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer.
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http://dx.doi.org/10.3390/pharmaceutics12080707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465813PMC
July 2020

NF-κB1 Regulates Immune Environment and Outcome of Notch-Dependent T-Cell Acute Lymphoblastic Leukemia.

Front Immunol 2020 3;11:541. Epub 2020 Apr 3.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric malignancy that arises from the transformation of immature T-cell progenitors and has no definitive cure. Notch signaling governs many steps of T cell development and its dysregulation represents the most common causative event in the pathogenesis of T-ALL. The activation of canonical NF-κB pathway has been described as a critical downstream mediator of Notch oncogenic functions, through the sustaining of tumor cell survival and growth. The potential role of Notch/NF-κB partnership is also emerging in the generation and function of regulatory T cells (Tregs) in the context of cancer. However, little is known about the effects of combined mutations of Notch and NF-κB in regulating immune-environment and progression of T-ALL. To shed light on the topics above we generated double-mutant mice, harboring conventional mutation of NF-κB1/p50 on the genetic background of a transgenic model of Notch-dependent T-ALL. The immunophenotyping of double-mutant mice demonstrates that NF-κB1 deletion inhibits the progression of T-ALL and strongly modifies immune-environment of the disease. Double-mutant mice display indeed a dramatic reduction of pre-leukemic CD4CD8 (DP) T cells and regulatory T cells (Tregs) and, concurrently, the rising of an aggressive myeloproliferative trait with a massive expansion of CD11bGr-1 cells in the periphery, and an accumulation of the granulocyte/monocyte progenitors in the bone-marrow. Interestingly, double-mutant T cells are able to improve the growth of CD11bGr-1 cells , and, more importantly, the depletion of T cells in double-mutant mice significantly reduces the expansion of myeloid compartment. Our results strongly suggest that the myeloproliferative trait observed in double-mutant mice may depend on non-cell-autonomous mechanism/s driven by T cells. Moreover, we demonstrate that the reduction of CD4CD8 (DP) T cells and Tregs in double-mutant mice relies on a significant enhancement of their apoptotic rate. In conclusion, double-mutant mice may represent a useful model to deepen the knowledge of the consequences on T-ALL immune-environment of modulating Notch/NF-κB relationships in tumor cells. More importantly, information derived from these studies may help in the refinement of multitarget therapies for the disease.
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http://dx.doi.org/10.3389/fimmu.2020.00541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169422PMC
March 2021

Author Correction: Interplay of protein corona and immune cells controls blood residency of liposomes.

Nat Commun 2020 Mar 31;11(1):1697. Epub 2020 Mar 31.

Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-15500-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109038PMC
March 2020

Hypotonic, Acidic Oxidizing Solution Containing Hypochlorous Acid (HClO) as a Potential Treatment of Hailey-Hailey Disease.

Molecules 2019 Dec 4;24(24). Epub 2019 Dec 4.

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. Mutation of the Golgi Ca-ATPase has been identified as having a causative role in Hailey-Hailey disease. HHD-derived keratinocytes have increased oxidative-stress that is associated with impaired proliferation and differentiation. Additionally, HHD is characterized by skin lesions that do not heal and by recurrent skin infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. Hypochlorous acid has been demonstrated in vitro and in vivo to possess properties that rescue both oxidative stress and altered wound repair process. Thus, we investigated the potential effects of a stabilized form of hypochlorous acid (APR-TD012) in an in vitro model of HHD. We found that treatment of ATP2C1-defective keratinocytes with APR-TD012 contributed to upregulation of Nrf2 (nuclear factor (erythroid-derived 2)-like 2). Additionally, APR TD012-treatment restored the defective proliferative capability of siATP2C1-treated keratinocytes. We also found that the APR-TD012 treatment might support wound healing process, due to its ability to modulate the expression of wound healing associated cytokines. These observations suggested that the APR-TD012 might be a potential therapeutic agent for HHD-lesions.
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http://dx.doi.org/10.3390/molecules24244427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943548PMC
December 2019

PLK1 targets NOTCH1 during DNA damage and mitotic progression.

J Biol Chem 2019 11 9;294(47):17941-17950. Epub 2019 Oct 9.

Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy

Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor suppressor and oncogenic components. To identify regulators that might control this dual activity of NOTCH1, we screened a chemical library targeting kinases and identified Polo-like kinase 1 (PLK1) as one of the kinases involved in arsenite-induced NOTCH1 down-modulation. As PLK1 activity drives mitotic entry but also is inhibited after DNA damage, we investigated the PLK1-NOTCH1 interplay in the G phase of the cell cycle and in response to DNA damage. Here, we found that PLK1 regulates NOTCH1 expression at G/M transition. However, when cells in G phase are challenged with DNA damage, PLK1 is inhibited to prevent entry into mitosis. Interestingly, we found that the interaction between NOTCH1 and PLK1 is functionally important during the DNA damage response, as we found that whereas PLK1 activity is inhibited, NOTCH1 expression is maintained during DNA damage response. During genotoxic stress, cellular transformation requires that promitotic activity must override DNA damage checkpoint signaling to drive proliferation. Interestingly, we found that arsenite-induced genotoxic stress causes a PLK1-dependent signaling response that antagonizes the involvement of NOTCH1 in the DNA damage checkpoint. Taken together, our data provide evidence that Notch signaling is altered but not abolished in SCC cells. Thus, it is also important to recognize that Notch plasticity might be modulated and could represent a key determinant to switch on/off either the oncogenic or tumor suppressor function of Notch signaling in a single type of tumor.
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http://dx.doi.org/10.1074/jbc.RA119.009881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879332PMC
November 2019

Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer.

Front Genet 2019 21;10:711. Epub 2019 Aug 21.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

Constitutive activation of the Hedgehog (Hh) signaling pathway is associated with increased risk of developing several malignancies. The biological and pathogenic importance of Hh signaling emphasizes the need to control its action tightly, both physiologically and therapeutically. Evidence of crosstalk between Hh and other signaling pathways is reported in many tumor types. Here, we provide an overview of the current knowledge about the communication between Hh and major signaling pathways, such as Notch, Wnt, and transforming growth factor β (TGF-β), which play critical roles in both embryonic and adult life. When these pathways are unbalanced, impaired crosstalk contributes to disease development. It is reported that more than one of these pathways are active in different type of tumors, at the same time. Therefore, starting from a plethora of stimuli that activate multiple signaling pathways, we describe the signals that preferentially converge on the Hh signaling cascade that influence its activity. Moreover, we highlight several connection points between Hh and Notch, Wnt, or TGF-β pathways, showing a reciprocal synergism that contributes to tumorigenesis, supporting a more malignant behavior by tumor cells, such as in leukemia and brain tumors. Understanding the importance of these molecular interlinking networks will provide a rational basis for combined anticancer drug development.
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http://dx.doi.org/10.3389/fgene.2019.00711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736567PMC
August 2019

Kras/ADAM17-Dependent Jag1-ICD Reverse Signaling Sustains Colorectal Cancer Progression and Chemoresistance.

Cancer Res 2019 Nov 10;79(21):5575-5586. Epub 2019 Sep 10.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial-mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both and . These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. SIGNIFICANCE: These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0145DOI Listing
November 2019

Broadening phenotype of adenylosuccinate lyase deficiency: A novel clinical pattern resembling neuronal ceroid lipofuscinosis.

Mol Genet Metab Rep 2019 Dec 21;21:100502. Epub 2019 Aug 21.

Division of Child Neurology and Infantile Psychiatry, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

We describe a 7-year-old boy presenting with a developmental encephalopathy, severe epilepsy, retinopathy with salt and pepper fundus, and ultrastructural skin alterations resembling a neuronal ceroid lipofuscinosis. Whole exome-sequencing detected biallelic variants in the gene (c.65C > T [p.(Ala22Val)] and c.340 T > C [p.(Tyr114His)]). The increase of SAICAR and S-Ado in blood and urine was consistent with the pattern of adenylosuccinate lyase deficiency (OMIM 103050). An unusual increase of AICAR, that was due to a residual ADSL enzyme activity of about 28%, was also detected. Neither salt and pepper retinopathy nor ultrastructural skin alterations had been reported in ADSL deficiency before. Impaired purinergic signaling inside the retina is probably involved in visual failure. Ultrastructural alterations in fibroblasts suggest a possible damage of autophagic processes, whose role in the pathogenesis of neurological dysfunction deserves further study.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713842PMC
December 2019

Interplay of protein corona and immune cells controls blood residency of liposomes.

Nat Commun 2019 08 15;10(1):3686. Epub 2019 Aug 15.

Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy.

In vivo liposomes, like other types of nanoparticles, acquire a totally new 'biological identity' due to the formation of a biomolecular coating known as the protein corona that depends on and modifies the liposomes' synthetic identity. The liposome-protein corona is a dynamic interface that regulates the interaction of liposomes with the physiological environment. Here we show that the biological identity of liposomes is clearly linked to their sequestration from peripheral blood mononuclear cells (PBMCs) of healthy donors that ultimately leads to removal from the bloodstream. Pre-coating liposomes with an artificial corona made of human plasma proteins drastically reduces capture by circulating leukocytes in whole blood and may be an effective strategy to enable prolonged circulation in vivo. We conclude with a critical assessment of the key concepts of liposome technology that need to be reviewed for its definitive clinical translation.
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http://dx.doi.org/10.1038/s41467-019-11642-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695391PMC
August 2019

Histone Modifications Drive Aberrant Notch3 Expression/Activity and Growth in T-ALL.

Front Oncol 2019 3;9:198. Epub 2019 Apr 3.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer caused by the deregulation of key T-cell developmental pathways, including Notch signaling. Aberrant Notch signaling in T-ALL occurs by gain-of-function mutations and by overexpression. Although is assumed as a Notch1 target, machinery driving its transcription in T-ALL is undefined in leukemia subsets lacking Notch1 activation. Here, we found that the binding of the intracellular Notch3 domain, as well as of the activated Notch1 fragment, to the gene locus led to the recruitment of the H3K27 modifiers JMJD3 and p300, and it was required to preserve transcriptional permissive/active H3K27 marks and to sustain gene expression levels. Consistently, pharmacological inhibition of JMJD3 by GSKJ4 treatment or of p300 by A-485 decreased the levels of expression of and of the Notch target genes and c-Myc and abrogated cell viability in both Notch1- and Notch3-dependent T-cell contexts. Notably, re-introduction of exogenous Notch1, Notch3 as well as c-Myc partially rescued cells from anti-growth effects induced by either treatment. Overall our findings indicate JMJD3 and p300 as general Notch1 and Notch3 signaling co-activators in T-ALL and suggest further investigation on the potential therapeutic anti-leukemic efficacy of their enzymatic inhibition in Notch/c-Myc axis-related cancers and diseases.
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http://dx.doi.org/10.3389/fonc.2019.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456714PMC
April 2019

Chalcones and Chalcone-mimetic Derivatives as Notch Inhibitors in a Model of T-cell Acute Lymphoblastic Leukemia.

ACS Med Chem Lett 2019 Apr 26;10(4):639-643. Epub 2019 Feb 26.

Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.

Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound , featuring a tetrahydronaphthalene-based scaffold, as a new promising Notch-blocking agent.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466818PMC
April 2019

Notch3 Targeting: A Novel Weapon against Ovarian Cancer Stem Cells.

Stem Cells Int 2019 6;2019:6264931. Epub 2019 Jan 6.

Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy.

Notch signaling is frequently activated in ovarian cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor survival of OC-bearing patients. This suggests that Notch3 can represent both a biomarker and a target for therapeutic interventions in OC patients. Although it is still unclear how chemoresistance arises, different lines of evidence support a critical role of cancer stem cells (CSCs), suggesting that CSC targeting by innovative therapeutic approaches might represent a promising tool to efficiently reduce OC recurrence. To date, CSC-directed therapies in OC tumors are mainly targeted to the inhibition of CSC-related signaling pathways, including Notch. As it is increasingly evident the involvement of Notch signaling, and in particular of Notch3, in regulating stem-like cell maintenance and expansion in several tumors, here we provide an overview of the current knowledge of Notch3 role in CSC-mediated OC chemoresistance, finally exploring the potential design of innovative Notch3 inhibition-based therapies for OC treatment, aimed at eradicating tumor through the suppression of CSCs.
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http://dx.doi.org/10.1155/2019/6264931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339748PMC
January 2019

IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation.

Cell Death Dis 2018 11 26;9(12):1160. Epub 2018 Nov 26.

Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy.

As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL-4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL.
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http://dx.doi.org/10.1038/s41419-018-1185-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255763PMC
November 2018

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer.

Front Immunol 2018 11;9:2165. Epub 2018 Oct 11.

Department of Experimental Medicine, La Sapienza University, Rome, Italy.

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4 regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.
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http://dx.doi.org/10.3389/fimmu.2018.02165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193072PMC
September 2019

Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation.

Oncogene 2018 12 23;37(49):6285-6298. Epub 2018 Jul 23.

Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Roma, Italy.

Notch hyperactivation dominates T-cell acute lymphoblastic leukemia development, but the mechanisms underlying "pre-leukemic" cell dissemination are still unclear. Here we describe how deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4CD8 thymocytes, possibly contributing to "pre-leukemic" cell propagation, early in disease progression. In transgenic mice overexpressing the constitutively active Notch3 intracellular domain, we detect the progressive increase in circulating blood and bone marrow of CD4CD8 cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4CD8 cells reveals their competence in infiltrating spleen and bone marrow of immunocompromised recipient mice. We also show that CXCR4 surface expression is central to the migratory ability of CD4CD8 cells and such an expression is regulated by Notch3 through β-arrestin in human leukemia cells. De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4CD8 cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4CD8 cells in young Notch3 transgenic mice. Therefore, our data suggest that combined therapies precociously counteracting intrathymic Notch3/CXCR4 crosstalk may prevent dissemination of "pre-leukemic" CD4CD8 cells, by a "thymus-autonomous" mechanism.
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http://dx.doi.org/10.1038/s41388-018-0401-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284016PMC
December 2018

The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms.

Adv Exp Med Biol 2018 ;1066:205-222

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

During evolution, gene duplication of the Notch receptor suggests a progressive functional diversification. The Notch3 receptor displays a number of structural differences with respect to Notch1 and Notch2, most of which have been reported in the transmembrane and in the intracellular regions, mainly localized in the negative regulatory region (NRR) and trans-activation domain (TAD). Targeted deletion of Notch3 does not result in embryonic lethality, which is in line with its highly restricted tissue expression pattern. Importantly, deregulated Notch3 expression and/or activation, often results in disrupted cell differentiation and/or pathological development, most notably in oncogenesis in different cell contexts. Mechanistically this is due to Notch3-related genetic alterations or epigenetic or posttranslational control mechanisms. In this chapter we discuss the possible relationships between the structural differences and the pathological role of Notch3 in the control of mouse and human cancers. In future, targeting the unique features of Notch3-oncogenic mechanisms could be exploited to develop anticancer therapeutics.
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http://dx.doi.org/10.1007/978-3-319-89512-3_10DOI Listing
February 2019

Brain Targeting by Liposome-Biomolecular Corona Boosts Anticancer Efficacy of Temozolomide in Glioblastoma Cells.

ACS Chem Neurosci 2018 12 31;9(12):3166-3174. Epub 2018 Jul 31.

Department of Molecular Medicine , Sapienza University of Rome , Viale Regina Elena 291 , 00161 Rome , Italy.

Temozolomide (TMZ) is the current first-line chemotherapy for treatment of glioblastoma multiforme (GBM). However, similar to other brain therapeutic compounds, access of TMZ to brain tumors is impaired by the blood-brain barrier (BBB) leading to poor response for GBM patients. To overcome this major hurdle, we have synthesized a set of TMZ-encapsulating nanomedicines made of four cationic liposome (CL) formulations with systematic changes in lipid composition and physical-chemical properties. The targeting nature of this nanomedicine is provided by the recruitment of proteins, with natural targeting capacity, in the biomolecular corona (BC) layer that forms around CLs after exposure to human plasma (HP). TMZ-loaded CL-BC complexes were thoroughly characterized by dynamic light scattering (DLS), electrophoretic light scattering (ELS), and nanoliquid chromatography tandem mass spectrometry (nano-LC MS/MS). BCs were found to be enriched of typical BC fingerprints (BCFs) (e.g., Apolipoproteins, Vitronectin, and vitamin K-dependent protein), which have a substantial capacity in binding to receptors that are overexpressed at the BBB (e.g., scavenger receptor class B, type I and low-density lipoprotein receptor). We found that the CL formulation exhibiting the highest levels of targeting BCFs had larger uptake in human umbilical vein endothelial cells (HUVECs) that are commonly used as an in vitro model of the BBB. This formulation could also deliver TMZ to the human glioblastoma U-87 MG cell line and thus substantially enhance their antitumor efficacy compared to corona free CLs. Thus, we propose that the BC-based nanomedicines may pave a more effective way for efficient treatment of GBM.
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http://dx.doi.org/10.1021/acschemneuro.8b00339DOI Listing
December 2018

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

Front Oncol 2018 20;8:105. Epub 2018 Apr 20.

Institute of Hematology-Centro di Ricerche Emato-Oncologiche (CREO), University of Perugia, Perugia, Italy.

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed mutation/expression in hematopoietic stem cells (HSCs). In mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.
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http://dx.doi.org/10.3389/fonc.2018.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919960PMC
April 2018

A non-conserved amino acid variant regulates differential signalling between human and mouse CD28.

Nat Commun 2018 03 14;9(1):1080. Epub 2018 Mar 14.

Department of Biology and Biotechnology Charles Darwin, Laboratory Affiliated at Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185, Rome, Italy.

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P in human vs. A in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this YAPP sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside.
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http://dx.doi.org/10.1038/s41467-018-03385-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852078PMC
March 2018

Notch signaling as a therapeutic target for acute lymphoblastic leukemia.

Expert Opin Ther Targets 2018 04 21;22(4):331-342. Epub 2018 Mar 21.

e Department of Medico-Surgical Sciences and Biotechnology , Sapienza University , Latina , Italy.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease. Therapeutic alternatives with effective anti-leukemic potential and low toxicity are needed. Areas covered: This review provides an overview of the currently available drugs directly or indirectly targeting Notch signaling in ALL. Besides considering the known Notch targeting approaches, such as γ-secretase inhibitors (GSIs) and Notch inhibiting antibodies (mAbs), currently in clinical trials, we focus on the recent insights into the molecular mechanisms underlying the Notch signaling regulation in ALL. Expert opinion: Novel drugs targeting specific steps of Notch signaling or intersecting pathways could improve the efficiency of the conventional hematological cancers therapies. Further studies are required to translate the new findings into future clinical applications.
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http://dx.doi.org/10.1080/14728222.2018.1451840DOI Listing
April 2018

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis.

Nat Commun 2018 03 7;9(1):976. Epub 2018 Mar 7.

Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy.

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis.
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http://dx.doi.org/10.1038/s41467-018-03339-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841288PMC
March 2018

Optimizing the identification of risk-relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families.

Cancer Med 2018 01 22;7(1):46-55. Epub 2017 Dec 22.

Department of Molecular Medicine, University La Sapienza, V.le R. Elena 291, Rome, 00161, Italy.

The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence-based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger-sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2-negative families to be subjected to the BROCA-Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss-of-heterozygosity and further molecular studies. We identified loss-of-function mutations in 6 out 20 high-risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk-relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre-organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk-relevant alleles impacting on the clinical management of their carriers.
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http://dx.doi.org/10.1002/cam4.1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773970PMC
January 2018

Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs).

Int J Mol Sci 2017 Dec 17;18(12). Epub 2017 Dec 17.

Department of Experimental Medicine, Sapienza University, Viale Regina Elena, 291, 00161 Rome, Italy.

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality.
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http://dx.doi.org/10.3390/ijms18122742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751342PMC
December 2017

Maml1 acts cooperatively with Gli proteins to regulate sonic hedgehog signaling pathway.

Cell Death Dis 2017 07 20;8(7):e2942. Epub 2017 Jul 20.

Department of Molecular Medicine, Sapienza University, Rome 00161, Italy.

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (GCPs) and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma. The effects of Shh pathway are mediated by the Gli family of transcription factors, which controls the expression of a number of target genes, including Gli1. Here, we identify Mastermind-like 1 (Maml1) as a novel regulator of the Shh signaling since it interacts with Gli proteins, working as a potent transcriptional coactivator. Notably, Maml1 silencing results in a significant reduction of Gli target genes expression, with a negative impact on cell growth of NIH3T3 and Patched1 mouse embryonic fibroblasts (MEFs), bearing a constitutively active Shh signaling. Remarkably, Shh pathway activity results severely compromised both in MEFs and GCPs deriving from Maml1 mice with an impairment of GCPs proliferation and cerebellum development. Therefore Maml1 phenotype mimics aspects of Shh pathway deficiency, suggesting an intrinsic requirement for Maml1 in cerebellum development. The present study shows a new role for Maml1 as a component of Shh signaling, which plays a crucial role in both development and tumorigenesis.
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http://dx.doi.org/10.1038/cddis.2017.326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550871PMC
July 2017

β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells.

BMC Cancer 2017 Jul 17;17(1):488. Epub 2017 Jul 17.

Department of Experimental Medicine Sapienza University, Viale Regina Elena, 291 - 00161, 00161, Rome, Italy.

Background: Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326.

Methods: We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays.

Results: Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation.

Conclusions: Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal.
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http://dx.doi.org/10.1186/s12885-017-3477-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512842PMC
July 2017