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https://www.readbyqxmd.com/read/28214899/therapeutic-targeting-of-epithelial-plasticity-programs-focus-on-the-epithelial-mesenchymal-transition
#1
Reem Malek, Hailun Wang, Kekoa Taparra, Phuoc T Tran
Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer...
2017: Cells, Tissues, Organs
https://www.readbyqxmd.com/read/28214335/the-role-of-c-ski-in-regulation-of-tgf%C3%AE-induced-human-cardiac-fibroblast-proliferation-and-ecm-protein-expression
#2
Juan Wang, Liping Guo, Difei Shen, Xiao Xu, Jiaping Wang, Suxia Han, Wen He
Cardiac fibrosis is characterized by over-deposition of extracellular matrix (ECM) proteins and over-proliferation of cardiac fibroblast, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Transforming growth factor β 1 (TGFβ1) is as an essential inducing factor of cardiac fibrosis. C-Ski protein has been identified as an inhibitory regulator of TGFβ signaling. In the present study, we revealed the repressive effect of c-Ski on TGFβ1-induced human cardiac fibroblast (HCFB) proliferation and ECM protein increase (Collagen I and α-SMA)...
February 18, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28213819/conditional-knockout-of-activin-like-kinase-1-alk-1-leads-to-heart-failure-without-maladaptive-remodeling
#3
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, Richard H Karas, S Paul Oh, Navin K Kapur
Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles...
February 17, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/28209733/dual-function-of-tgf%C3%AE-in-lens-epithelial-cell-fate-implications-for-secondary-cataract
#4
Bruce A Boswell, Anna Korol, Judith A West-Mays, Linda S Musil
The most common vision-disrupting complication of cataract surgery is posterior capsule opacification (PCO; secondary cataract). PCO is caused by residual lens cells undergoing one of two very different cell fates: either transdifferentiating into myofibroblasts, or maturing into lens fiber cells. Although TGFβ has been strongly implicated in lens cell fibrosis, the factors responsible for the latter process have not been identified. We show here for the first time that TGFβ can induce purified primary lens epithelial cells within the same culture to undergo differentiation into either lens fiber cells or myofibroblasts...
February 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28206960/an-autocrine-paracrine-circuit-of-growth-differentiation-factor-gdf-15-has-a-role-for-maintenance-of-breast-cancer-stem-like-cells
#5
Asako Sasahara, Kana Tominaga, Tatsunori Nishimura, Masao Yano, Etsuko Kiyokawa, Miki Noguchi, Masakuni Noguchi, Hajime Kanauchi, Toshihisa Ogawa, Hiroshi Minato, Keiichiro Tada, Yasuyuki Seto, Arinobu Tojo, Noriko Gotoh
Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells...
February 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28205584/a-postnatal-role-for-embryonic-myosin-revealed-by-myh3-mutations-that-alter-tgf%C3%AE-signaling-and-cause-autosomal-dominant-spondylocarpotarsal-synostosis
#6
Jennifer Zieba, Wenjuan Zhang, Jessica X Chong, Kimberly N Forlenza, Jorge H Martin, Kelly Heard, Dorothy K Grange, Merlin G Butler, Tjitske Kleefstra, Ralph S Lachman, Deborah Nickerson, Michael Regnier, Daniel H Cohn, Michael Bamshad, Deborah Krakow
Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28203226/microbial-anti-inflammatory-molecule-mam-from-faecalibacterium-prausnitzii-shows-a-protective-effect-on-dnbs-and-dss-induced-colitis-model-in-mice-through-inhibition-of-nf-%C3%AE%C2%BAb-pathway
#7
Natalia M Breyner, Cristophe Michon, Cassiana S de Sousa, Priscilla B Vilas Boas, Florian Chain, Vasco A Azevedo, Philippe Langella, Jean M Chatel
Faecalibacterium prausnitzii and its supernatant showed protective effects in different chemically-induced colitis models in mice. Recently, we described 7 peptides found in the F. prausnitzii supernatant, all belonging to a protein called Microbial Anti-inflammatory Molecule (MAM). These peptides were able to inhibit NF-κB pathway in vitro and showed anti-inflammatory properties in vivo in a DiNitroBenzene Sulfate (DNBS)-induced colitis model. In this current proof we tested MAM effect on NF-κB pathway in vivo, using a transgenic model of mice producing luciferase under the control of NF-κB promoter...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28197388/inhibition-of-tumor-growth-and-metastasis-by-emmprin-multiple-antigenic-peptide-map-vaccination-is-mediated-by-immune-modulation
#8
Elina Simanovich, Vera Brod, Maya M Rahat, Ella Drazdov, Miriam Walter, Jivan Shakya, Michal A Rahat
Previously, we have identified a new epitope in EMMPRIN, a multifunctional protein that mediates tumor cell-macrophage interactions and induces both MMP-9 and VEGF. Here, we synthesized this epitope as an octa-branched multiple antigenic peptide (MAP) to vaccinate mice implanted with subcutaneous syngeneic colon (CT26), prostate (TRAMP-C2) or renal (RENCA) cell line carcinomas. Vaccination inhibited, and sometimes regressed, tumor growth in a dose-dependent manner, reaching 94%, 71% and 72% inhibition, respectively, at a 50 μg dose (p < 0...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28197372/fam13a-is-associated-with-non-small-cell-lung-cancer-nsclc-progression-and-controls-tumor-cell-proliferation-and-survival
#9
Felix Eisenhut, Lisanne Heim, Sonja Trump, Susanne Mittler, Nina Sopel, Katerina Andreev, Fulvia Ferrazzi, Arif B Ekici, Ralf Rieker, Rebekka Springel, Vera L Assmann, Matthias Lechmann, Sonja Koch, Marina Engelhardt, Christina Warnecke, Denis I Trufa, Horia Sirbu, Arndt Hartmann, Susetta Finotto
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1α levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1α and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28196297/targeting-invasive-properties-of-melanoma-cells
#10
REVIEW
Imanol Arozarena, Claudia Wellbrock
Melanoma is a skin cancer notorious for its metastatic potential. As an initial step of the metastatic cascade melanoma cells part from the primary tumour and invade the surrounding tissue, which is crucial for their dissemination and the formation of distant secondary tumours. Over the last two decades our understanding of both, general and melanoma specific mechanisms of invasion has significantly improved, but to date no efficient therapeutic strategy tackling the invasive properties of melanoma cells has reached the clinic...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28195240/mir302-regulates-snai1-expression-to-control-mesangial-cell-plasticity
#11
L De Chiara, D Andrews, A Watson, G Oliviero, G Cagney, J Crean
Cell fate decisions are controlled by the interplay of transcription factors and epigenetic modifiers, which together determine cellular identity. Here we elaborate on the role of miR302 in the regulation of cell plasticity. Overexpression of miR302 effected silencing of the TGFβ type II receptor and facilitated plasticity in a manner distinct from pluripotency, characterized by increased expression of Snail. miR302 overexpressing mesangial cells also exhibited enhanced expression of EZH2 coincident with Snail upregulation...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28192800/molecular-profiling-of-the-developing-lacrimal-gland-reveals-putative-role-of-notch-signaling-in-branching-morphogenesis
#12
Galina Dvoriantchikova, Wensi Tao, Steve Pappas, Gabriel Gaidosh, David T Tse, Dmitry Ivanov, Daniel Pelaez
Purpose: Although normal function of the lacrimal gland is essential for vision (and thus for human well-being), the lacrimal gland remains rather poorly understood at a molecular level. The purpose of this study was to identify new genes and signaling cascades involved in lacrimal gland development. Methods: To identify these genes, we used microarray analysis to compare the gene expression profiles of developing (embryonic) and adult lacrimal glands. Differential data were validated by quantitative RT-PCR, and several corresponding proteins were confirmed by immunohistochemistry and Western blot analysis...
February 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28188225/inflammation-induced-caveolin-1-and-bmprii-depletion-promotes-endothelial-dysfunction-and-tgf%C3%AE-driven-pulmonary-vascular-remodeling
#13
Suellen Darc Santos Oliveira, Maricela Castellon, Jiwang Chen, Marcelo G Bonini, Xiaowu Gu, Michael H Elliott, Roberto F Machado, Richard D Minshall
Endothelial cell (EC) activation and vascular injury are hallmark features of Acute Lung Injury and Acute Respiratory Distress Syndrome (ALI/ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine whether the lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and whether this contributes to the onset of pulmonary vascular remodeling...
February 10, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28182006/coordinate-activities-of-brd4-and-cdk9-in-the-transcriptional-elongation-complex-are-required-for-tgf%C3%AE-induced-nox4-expression-and-myofibroblast-transdifferentiation
#14
Talha Ijaz, Mohammad Jamaluddin, Yingxin Zhao, Yueqing Zhang, Jayson Jay, Celeste C Finnerty, David N Herndon, Ronald G Tilton, Allan R Brasier
Transdifferentiation of quiescent dermal fibroblasts to secretory myofibroblasts has a central role in wound healing and pathological scar formation. This myofibroblast transdifferentiation process involves TGFβ-induced de novo synthesis of alpha smooth muscle cell actin (αSMA)+ fibers that enhance contractility as well as increased expression of extracellular matrix (ECM) proteins, including collagen and fibronectin. These processes are mediated upstream by the reactive oxygen species (ROS)-producing enzyme Nox4, whose induction by TGFβ is incompletely understood...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28181591/lumican-peptides-rational-design-targeting-alk5-tgfbri
#15
Tarsis Ferreira Gesteira, Vivien J Coulson-Thomas, Yong Yuan, Jianhua Zhang, Helena B Nader, Winston W-Y Kao
Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28181132/anti-tgf%C3%AE-1-receptor-inhibitor-mediates-the-efficacy-of-the-human-umbilical-cord-mesenchymal-stem-cells-against-liver-fibrosis-through-tgf%C3%AE-1-smad-pathway
#16
Ji Xuan, Wang Feng, Zheng-Tao An, Jian Yang, Hua-Bing Xu, Jing Li, Zhi-Fei Zhao, Wei Wen
The aim of the current investigation was to evaluate the anti-fibrosis potential of human umbilical cord mesenchymal stem cells (hUC-MSCs) and further to explore some of its underlying mechanisms. Hepatic fibrosis mice model was induced by CCl4. Liver function parameters in serum and fibrosis-associated markers in tissues were detected. Moreover, SB-431542, an anti-TGFβ-1 receptor inhibitor, was employed in vitro to reveal the underlying mechanism of TGFβ-1/Smad pathway on hUC-MSCs against liver fibrosis...
February 8, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28179110/oxidized-and-original-article-degraded-mitochondrial-polynucleotides-demps-especially-rna-are-potent-immunogenic-regulators-in-primary-mouse-macrophages
#17
Abhinav R Saxena, Linda Y Gao, Shachi Srivatsa, Elizabeth Z Bobersky, Sivakumar Periasamy, Danielle T Hunt, Kyle E Altman, Dana R Crawford
Certain mitochondrial components can act as damage-associated molecular patterns (DAMPs) or danger signals, triggering a proinflammatory response in target (usually immune) cells. We previously reported the selective degradation of mitochondrial DNA and RNA in response to cellular oxidative stress, and the immunogenic effect of this DNA in primary mouse astrocytes. Here, we extend these studies to assess the immunogenic role of both mitochondrial DNA and RNA isolated from hydrogen peroxide (HP) treated HA1 cells (designated "DeMPs" for degraded mitochondrial polynucleotides) using mouse bone marrow derived macrophages (BMDMs), a conventional immune cell type...
February 4, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28174235/an-integrated-approach-identifies-mediators-of-local-recurrence-in-head-neck-squamous-carcinoma
#18
Francesca Citron, Joshua Armenia, Giovanni Franchin, Jerry Polesel, Renato Talamini, Sara D'Andrea, Sandro Sulfaro, Carlo M Croce, William Klement, Dave Otasek, Chiara Pastrello, Tomas Tokar, Igor Jurisica, Deborah French, Riccardo Bomben, Emanuela Vaccher, Diego Serraino, Barbara Belletti, Andrea Vecchione, Luigi Barzan, Gustavo Baldassarre
PURPOSE: Head and Neck Squamous Cell Carcinomas (HNSCC) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected microRNAs (miRs) could be used as biomarkers of recurrence in HNSCC. EXPERIMENTAL DESIGN: A Nanostring array was used to identify miRs associated with locoregional recurrence in 44 HNSCC patients...
February 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28169339/dna-methylation-governs-the-dynamic-regulation-of-inflammation-by-apoptotic-cells-during-efferocytosis
#19
Clare A Notley, Christine K Jordan, Jenny L McGovern, Mark A Brown, Michael R Ehrenstein
Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus. However, activation of cells prior to apoptosis abolishes their immunoregulatory properties. Here we show using the antigen-induced model of arthritis that the degree of DNA methylation within AC confers their immunomodulatory plasticity. DNA isolated from resting and activated AC mimicked their respective immune effects. Demethylation of DNA abrogated the protective effect of AC whereas remethylation of AC DNA reversed the effects of activation and restored the ability to inhibit inflammation...
February 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28169289/the-nedd8-non-covalent-binding-region-in-the-smurf-hect-domain-is-critical-to-its-ubiquitn-ligase-function
#20
Shan He, Yu Cao, Ping Xie, Guanglong Dong, Lingqiang Zhang
Nedd8 is a ubiquitin-like protein that controls vital biological events through conjugation to target proteins. We previously identified the HECT-type ubiquitin ligase Smurf1 which controls diverse cellular processes is activated by Nedd8 through covalent neddylation. However, the effect of non-covalent binding to Nedd8 remains unknown. In this study, we demonstrate that both Smurf1 and its homologue Smurf2 carry a non-covalent Nedd8-binding site within its catalytic HECT domain. Structural analysis reveals that Smurf2 has Nedd8-binding sites within the small sub-domain of N-lobe and the C-lobe of HECT domain...
February 7, 2017: Scientific Reports
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