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Molecular Cancer Research: MCR

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https://www.readbyqxmd.com/read/29348189/cancer-stem-cell-phenotypes-in-er-breast-cancer-models-are-promoted-by-pelp1-aib1-complexes
#1
Thu H Truong, Hsiangyu Hu, Nuri A Temiz, Kyla Hagen, Brian J Girard, Nicholas J Brady, Kathryn L Schwertfeger, Carol A Lange, Julie H Ostrander
Proline, glutamic acid, and leucine rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, interacting partners unique to cytoplasmic PELP1 and the mechanisms by which these interactions promote oncogenic PELP1 signaling were sought...
January 18, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330298/stemness-is-enhanced-in-gastric-cancer-by-a-set-pp2a-e2f1-axis
#2
Shuhei Enjoji, Ryotaro Yabe, Shunya Tsuji, Kazuhiro Yoshimura, Hideyoshi Kawasaki, Masashi Sakurai, Yusuke Sakai, Hiroko Takenouchi, Shigefumi Yoshino, Shoichi Hazama, Hiroaki Nagano, Hiroko Oshima, Masanobu Oshima, Michael P Vitek, Tetsuya Matsuura, Yoshitaka Hippo, Tatsuya Usui, Takashi Ohama, Koichi Sato
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Chemotherapies against gastric cancer often fail, with cancer recurrence due potentially to the persistence of cancer stem cells. This unique subpopulation of cells in tumors possess the ability to self-renew and de-differentiate. These cancer stem cells are critical for initiation, maintenance, metastasis, and relapse of cancers; however, the molecular mechanisms supporting cancer stemness remain largely unknown...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330297/characterization-and-evidence-of-the-mir-888-cluster-as-a-novel-cancer-network-in-prostate
#3
Tsuyoshi Hasegawa, Garrison Glavich, Mary Pahuski, Aleena M Short, Oliver John Semmes, Lifang Yang, Vitold Galkin, Richard R Drake, Aurora Esquela-Kerscher
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of ~22 nucleotide non-coding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients but the mechanism of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330296/tumor-progression-is-mediated-by-thymosin-%C3%A3-4-through-a-tgf%C3%A3-mrtf-signaling-axis
#4
Tsuyoshi Morita, Kenichiro Hayashi
Although enhanced thymosin beta-ß4 (TMSBX4/Tß4) expression is associated with tumor progression and metastasis, its tumor-promoting functions remain largely unknown. Here it is demonstrated that transforming growth factor beta (TGFß) facilitates Tß4 expression and leads to the activation of myocardin-related transcription factors (MRTFs), which are co-activators of serum response factor (SRF) and regulate the expression of genes critical for the epithelial-mesenchymal transition (EMT) and tumor metastasis...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330295/epigenetic-reprogramming-of-pericentromeric-satellite-dna-in-premalignant-and-malignant-lesions
#5
Nadine H Brueckmann, Christina B Pedersen, Henrik J Ditzel, Morten F Gjerstorff
Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group (PcG) proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study, demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 (PRC1) deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330294/establishment-of-the-first-well-differentiated-human-pancreatic-neuroendocrine-tumor-model
#6
Daniel Benten, Yasmin Behrang, Ludmilla Unrau, Victoria Weissmann, Gerrit Wolters-Eisfeld, Susanne Burdak-Rothkamm, Felix R Stahl, Martin Anlauf, Patricia Grabowski, Markus Möbs, Jan Dieckhoff, Bence Sipos, Martina Fahl, Corinna Eggers, Daniel Perez, Maximilian Bockhorn, Jakob R Izbicki, Ansgar W Lohse, Joerg Schrader
Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired pre-clinical research in NET. Herein, we establish and characterize a lymph node-derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared to existing NET cell lines BON and QGP-1...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330293/differential-regulation-of-let-7-by-lin28b-isoform-specific-functions
#7
Rei Mizuno, Priya Chatterji, Sarah F Andres, Kathryn E Hamilton, Lauren Simon, Shawn W Foley, Arjun N Jeganathan, Brian D Gregory, Blair B Madison, Anil K Rustgi
The RNA binding protein LIN28B plays an important role in development, stem cell biology and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers (CRCs) and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, CRC cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330292/microenvironmental-derived-regulation-of-hif-signaling-drives-transcriptional-heterogeneity-in-glioblastoma-multiforme
#8
Dieter Henrik Heiland, Annette Gaebelein, Melanie Boerries, Jakob Woerner, Nils Pompe, Pamela Franco, Sabrina Heynckes, Mark D Bartholomä, Darren Ó hAilín, Maria Stella Carro, Marco Prinz, Stefan Weber, Irina Mader, Daniel Delev, Oliver Schnell
The evolving and highly heterogeneous nature of malignant brain tumors underlies their limited response to therapy and poor prognosis. In addition to genetic alterations, highly dynamic processes such as transcriptional and metabolic reprogramming play an important role in the development of tumor heterogeneity. The present study reports an adaptive mechanism in which the metabolic environment of malignant glioma drives transcriptional reprogramming. Multi-regional analysis of a glioblastoma patient biopsy revealed a metabolic landscape marked by varying stages of hypoxia and creatine enrichment...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330291/keap1-inhibits-metastatic-properties-of-nsclc-cells-by-stabilizing-architectures-of-f-actin-and-focal-adhesions
#9
Bo Wu, Shu Yang, Haimei Sun, Tingyi Sun, Fengqing Ji, Yurong Wang, Lie Xu, Deshan Zhou
Low expression of the tumor suppressor, Kelch-like ECH-associated protein 1 (KEAP1) in non-small cell lung cancer (NSCLC) often results in higher malignant biological behavior and poor prognosis; however, the underlying mechanism remains unclear. The present study demonstrates that overexpression of Keap1 significantly suppresses migration and invasion of three different lung cancer cells (A549, H460, and H1299). Highly-expressed Keap1, compared to the control, promotes formation of multiple stress fibers with larger mature focal adhesion complexes in the cytoplasm where only fine focal adhesions were observed in the membrane under control conditions...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330290/dual-inhibition-of-cdk4-and-cdk2-via-targeting-p27-tyrosine-phosphorylation-induces-a-potent-and-durable-response-in-breast-cancer-cells
#10
Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
Cyclin-dependent kinase 4/6 (CDK4/6) specific inhibitors, such as Palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue Palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330289/brca1-through-its-e3-ligase-activity-regulates-the-transcription-factor-oct1-and-carbohydrate-metabolism
#11
Karina Vázquez-Arreguín, Jessica Maddox, Jinsuk Kang, Dongju Park, Reuben R Cano, Rachel E Factor, Thomas Ludwig, Dean Tantin
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with pro-glycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330288/epigenetically-regulated-chromosome-14q32-mirna-cluster-induces-metastasis-and-predicts-poor-prognosis-in-lung-adenocarcinoma-patients
#12
Margarita Gonzalez-Vallinas, Manuel Rodriguez-Paredes, Marco Albrecht, Carsten Sticht, Damian Stichel, Julian Gutekunst, Adriana Pitea, Steffen Sass, Francisco J Sánchez-Rivera, Justo L Bermejo, Jennifer Schmitt, Carolina De La Torre, Arne Warth, Fabian Theis, Nikola Mueller, Norbert Gretz, Thomas Muley, Michael Meister, Darjus F Tschaharganeh, Peter Schirmacher, Franziska Matthäus, Kai Breuhahn
Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify microRNAs (miRNAs) involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis-associated miRNAs were identified in The Cancer Genome Atlas (TCGA) lung adenocarcinoma patient cohort (sequencing data; n=449) and subsequently validated by RT-qPCR in an independent clinical cohort (n=108)...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330287/targeted-akt-inhibition-in-prostate-cancer-cells-and-spheroids-reduces-aerobic-glycolysis-and-generation-of-hyperpolarized-1-13c-lactate
#13
Sui Seng Tee, Izabela Suster, Steven Truong, Sangmoo Jeong, Roozbeh Eskandari, Valentina Di Gialleonardo, Julio A Alvarez, Hannah N Aldeborgh, Kayvan Keshari
The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials and this study investigates the effect of MK2206, a non-ATP competitive inhibitor, on the cellular metabolism in the context of prostate cancer. A significant reduction in cell motility and aerobic glycolysis was observed in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes (e...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330286/agonist-induced-cxcr4-and-cb2-heterodimerization-inhibits-g%C3%AE-13-rhoa-mediated-migration
#14
Kisha A Scarlett, ElShaddai Z White, Christopher J Coke, Jada R Carter, Latoya K Bryant, Cimona V Hinton
G-protein coupled receptor (GPCR) heterodimerization has emerged as a means by which alternative signaling entities can be created; yet, how receptor heterodimers affect receptor pharmacology remains unknown. Previous observations suggested a biochemical antagonism between GPCRs, CXCR4 and CB2 (CNR2), where agonist-bound CXCR4 and agonist-bound CB2 formed a physiologically non-functional heterodimer on the membrane of cancer cells, inhibiting their metastatic potential in vitro. However, the reduced signaling entities responsible for the observed functional outputs remain elusive...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330285/foxo-dependent-par-4-upregulation-prevents-long-term-survival-of-residual-cells-following-pi3k-akt-inhibition
#15
Jeffrey S Damrauer, Stephanie N Phelps, Katie Amuchastegui, Ryan Lupo, Nathaniel W Mabe, Andrea Walens, Benjamin R Kroger, James V Alvarez
Tumor recurrence is a leading cause of death and is thought to arise from a population of residual cells that survive treatment. These residual cancer cells can persist, locally or at distant sites, for years or decades. Therefore, understanding the pathways that regulate residual cancer cell survival may suggest opportunities for targeting these cells to prevent recurrence. Previously it was observed that the pro-apoptotic protein (PAWR/Par-4) negatively regulates residual cell survival and recurrence in mice and humans...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330284/novel-intergenically-spliced-chimera-nfatc3-pla2g15-is-associated-with-aggressive-t-all-biology-and-outcome
#16
Jonathan Bond, Christine Tran Quang, Guillaume Hypolite, Mohamed Belhocine, Aurélie Bergon, Gaëlle Cordonnier, Jacques Ghysdael, Elizabeth Macintyre, Nicolas Boissel, Salvatore Spicuglia, Vahid Asnafi
Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically-spliced chimeric RNAs (ISCs) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA-sequencing (RNA-seq) was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens (n=24) and candidate T-ALL-related ISCs were identified (n=55; a median of 4 per patient)...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330283/centriole-overduplication-is-the-predominant-mechanism-leading-to-centrosome-amplification-in-melanoma
#17
Ryan A Denu, Maria Shabbir, Minakshi Nihal, Chandra K Singh, B Jack Longley, Mark E Burkard, Nihal Ahmad
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell-cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray (TMA) of human melanomas and benign nevi (n=79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330282/population-dependent-intron-retention-and-dna-methylation-in-breast-cancer
#18
Dongwook Kim, Manu Shivakumar, Seonggyun Han, Michael S Sinclair, Youngji Lee, Yonglan Zheng, Olufunmilayo I Olopade, Dokyoon Kim, Younghee Lee
Regulation of gene expression by DNA methylation in gene promoter regions is well-studied; however, the effects of methylation in the gene body (exons and introns) on gene expression are comparatively understudied. Recently, hyper-methylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hyper-methylated sites. This study examines if methylation status of an intron is correlated with how frequently the intron is retained during splicing using DNA methylation and RNA sequencing (RNA-seq) data from breast cancer tissue specimens in The Cancer Genome Atlas (TCGA)...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29233910/targeting-cdk1-and-mek-erk-overcomes-apoptotic-resistance-in-braf-mutated-human-colorectal-cancer
#19
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAFV600E mutation occurs in ~8% of human colorectal cancers (CRCs) and is associated with therapeutic resistance that is due, in part, to re-activation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells. BRAFV600E CRC cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1,2,5,9 inhibitor)...
December 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29222172/proximal-aberrant-crypt-foci-associate-with-synchronous-neoplasia-and-are-primed-for-neoplastic-progression
#20
David A Drew, Allen Mo, James J Grady, Richard G Stevens, Joel B Levine, Bruce M Brenner, Joseph C Anderson, Faripour Forouhar, Michael J O'Brien, Thomas J Devers, Daniel W Rosenberg
Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion found within the human colon. Despite their relatively high frequency in the distal colon, few studies have examined the molecular characteristics of ACF within the proximal colon. In the following study, clinical participants (n=184) were screened for ACF using high-definition chromoendoscopy with contrast dye-spray. Following pathological confirmation, ACF biopsies were subjected to laser-capture microdissection (LCM) and epithelial cells were evaluated for somatic mutations with a customized colorectal cancer mutation panel using DNA-mass spectrometry...
December 8, 2017: Molecular Cancer Research: MCR
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