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Molecular Cancer Research: MCR

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https://www.readbyqxmd.com/read/28720588/ews-fli-is-a-master-regulator-of-metabolic-reprogramming-in-ewing-sarcoma
#1
Jason M Tanner, Claire Bensard, Peng Wei, Nathan M Krah, John C Schell, Jamie D Gardiner, Joshua D Schiffman, Stephen L Lessnick, Jared Rutter
Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology...
July 18, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28710231/tuberin-regulates-prostaglandin-receptor-mediated-viability-via-rheb-in-mtorc1-hyperactive-cells
#2
Chenggang Li, Xiaolei Liu, Yang Liu, Erik Zhang, Kantha Medepalli, Kohei Masuda, Na Li, Elizabeth J Kopras, David J Kwiatkowski, Michael T Borchers, Kathryn A Wikenheiser-Brokamp, Andrew Osterburg, Maxwell Mays, Yang Sun, David R Plas, Julia L Sun, David N Franz, Jamie K Capal, Anya Alayev, Marina K Holz, Darcy A Krueger, Brian J Siroky, Jane J Yu
Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2 resulting in hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulate that the action of excess PGE2 and its cognate receptors (EPs) contribute to cell survival...
July 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28710230/the-tissue-reconstructing-ability-of-colon-cscs-is-enhanced-by-fk506-and-suppressed-by-gsk3-inhibition
#3
Ryo Ishida, Michiyo Koyanagi-Aoi, Nobu Oshima, Yoshihiro Kakeji, Takashi Aoi
Cancer stem cells (CSCs) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2 and KLF4, and we have designated such cells as induced cancer stem cells (iCSCs). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them...
July 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28698359/egfr-down-regulation-after-anti-egfr-therapy-predicts-the-anti-tumor-effect-in-colorectal-cancer
#4
Yasuyuki Okada, Tetsuo Kimura, Tadahiko Nakagawa, Koichi Okamoto, Akira Fukuya, Takahiro Goji, Shota Fujimoto, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Yasushi Tsuji, Toshiya Okahisa, Tetsuji Takayama
Anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is reported to induce EGFR internalization in colorectal cancer (CRC) cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to anti-tumor activity in CRC cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by trypan blue-exclusion, in 10 RAS, BRAF wild-type CRC cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect...
July 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28698358/integrative-cage-and-dna-methylation-profiling-identify-epigenetically-regulated-genes-in-nsclc
#5
Masafumi Horie, Bogumil Kaczkowski, Mitsuhiro Ohshima, Hirotaka Matsuzaki, Satoshi Noguchi, Yu Mikami, Marina Lizio, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R R Forrest, Daiya Takai, Yoko Yamaguchi, Patrick Micke, Akira Saito, Takahide Nagase
Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 non-small cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells...
July 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28684637/interferon-stimulated-genes-are-transcriptionally-repressed-by-pr-in-breast-cancer
#6
Katherine Walter, Merit L Goodman, Hari Singhal, Jade Hall, Tianbao Li, Sean Holloran, Gloria Trinca, Katelin Gibson, Victor X Jin, Geoffrey Greene, Christy Hagan
The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, interferon-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors...
July 6, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28684636/foxc1-regulates-fgfr1-isoform-switching-to-promote-invasion-following-tgf%C3%AE-induced-emt
#7
Alexander Hopkins, Mackenzie L Coatham, Fred B Berry
Epithelial-to-mesenchymal transition (EMT) is an important physiological process that drives tissue formation during development, but also contributes to disease pathogenesis including fibrosis and cancer metastasis. Elevated expression of the FOXC1 transcription factor has been detected in several metastatic cancers that have undergone EMT. Therefore, mechanistic insight into the role of FOXC1 in the initiation of the EMT process was sought. It was determined that although Foxc1 transcript expression was elevated following TGF-β1 induced EMT of NMuMG cells, FOXC1 was not required for this induction...
July 6, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28679779/molecular-effects-of-stromal-selective-targeting-by-upar-retargeted-oncolytic-virus-in-breast-cancer
#8
Yuqi Jing, Valery Chavez, Yuguang Ban, Nicolas Acquavella, Dorraya El-Ashry, Alexey Pronin, Xi Chen, Jaime R Merchan
The tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MVs) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal selective targeting by uPAR retargeted MVs were investigated. In vitro infection, virus-induced GFP expression and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer associated fibroblasts (CAFs) in a species-specific manner...
July 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28655712/braf-inhibitor-associated-mek-mutations-increase-raf-dependent-and-independent-enzymatic-activity
#9
Caroline M Emery, Kelli-Ann Monaco, Ping Wang, Marissa N Balak, Alyson Freeman, Jodi Meltzer, Scott Delach, Daniel Rakiec, David A Ruddy, Joshua M Korn, Jacob Haling, Michael G Acker, Giordano Caponigro
Alterations in MEK1/2 occur in cancers, both in the treatment naïve state and following targeted therapies, most notably BRAF and MEK inhibitors in BRAF-V600E mutant melanoma and colorectal cancer. Efforts were undertaken to understand the effects of these mutations, based upon protein structural location, and MEK1/2 activity. Two categories of MEK1/2 alterations were evaluated, those associated with either the allosteric pocket or helix-A. Clinically, MEK1/2 alterations of the allosteric pocket are rare and we demonstrate that they confer resistance to MEK inhibitors, whilst retaining sensitivity to BRAF inhibition...
June 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28652265/a-massively-parallel-fluorescence-assay-to-characterize-the-effects-of-synonymous-mutations-on-tp53-expression
#10
Geetha Bhagavatula, Matthew S Rich, David L Young, Maximillian Marin, Stanley Fields
Although synonymous mutations can affect gene expression, they have generally not been considered in genomic studies that focus on mutations that increase the risk of cancer. However, mounting evidence implicates some synonymous mutations as driver mutations in cancer. Here a massively parallel assay, based on cell sorting of a reporter containing a segment of p53 fused to green fluorescent protein (GFP), was used to measure the effects of nearly all synonymous mutations in exon 6 of TP53. In this reporter context, several mutations within the exon caused strong expression changes including mutations that may cause potential gain or loss of function...
June 26, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28637905/p120-catenin-downregulation-and-pik3ca-mutations-cooperate-to-induce-invasion-through-mmp1-in-hnscc
#11
Michal Kidacki, Heather L Lehman, Michelle V Green, Joshua I Warrick, Douglas B Stairs
Despite recent improvements in treatment for Head and Neck Squamous Cell Carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within five years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Since p120-catenin (CTNND1/P120CTN) downregulation and PIK3CA mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion...
June 21, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28634226/phostine-pst3-1a-targets-mgat5-and-inhibits-glioblastoma-initiating-cell-invasiveness-and-proliferation
#12
Zahra Hassani, Ali Saleh, Soumaya Turpault, Salim Khiati, Willy Morelle, Jacques Vignon, Jean-Philippe Hugnot, Emmanuelle Uro-Coste, Philippe Legrand, Marcel Delaforge, Séverine Loiseau, Ludovic Clarion, Marc Lecouvey, Jean-Noël Volle, David Virieux, Jean-Luc Pirat, Hugues Duffau, Norbert Bakalara
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell based assays it is demonstrated that PST3...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28634225/homeobox-transcription-factor-nkx2-1-promotes-cyclin-d1-transcription-in-lung-adenocarcinomas
#13
Masanori Harada, Satoshi Sakai, Tatsuya Ohhata, Kyoko Kitagawa, Masashi Mikamo, Koji Nishimoto, Chiharu Uchida, Hiroyuki Niida, Yojiro Kotake, Haruhiko Sugimura, Takafumi Suda, Masatoshi Kitagawa
The known oncogene cyclin D1 (CCND1) participates in progression of the cell cycle from G1 to S phase. Expression of cyclin D1 is frequently promoted in multiple human cancers including non-small cell lung cancer (NSCLC). However, a relationship between cyclin D1 expression and the prognosis of NSCLC has not been confirmed. NKX2-1 is a homeobox transcription factor involved in pulmonary development as a differentiation-promoting factor. In NSCLC, it acts as a metastasis suppressor and correlates with a good prognosis...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28634224/igh-myc-translocation-associates-with-brca2-deficiency-and-synthetic-lethality-to-parp1-inhibitors
#14
Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Katherine Sullivan, Samantha K Langer, Reza Nejadi, Yashodhara Dasgupta, Michael Hulse, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena N Lupey-Green, Huaqing Zhao, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Burkitt lymphoma/leukemia (BL) cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate a high number of potentially lethal DNA double-strand breaks (DSBs) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28611083/inhibition-of-ciliogenesis-promotes-hedgehog-signaling-tumorigenesis-and-metastasis-in-breast-cancer
#15
Nadia B Hassounah, Martha Nunez, Colleen A Fordyce, Denise J Roe, Raymond B Nagle, Thomas Allen Bunch, Kimberly Marie McDermott
Primary cilia are chemosensors that play a dual role to either activate or repress Hedgehog signaling, depending on presence or absence of ligand respectively. While inhibition of ciliogenesis has been shown to be characteristic of breast cancers, the functional consequence is unknown. Here, for the first time, inhibition of ciliogenesis led to earlier tumor formation, faster tumor growth rate, higher-grade tumor formation and increased metastasis in the polyoma middle T (PyMT) mouse model of breast cancer...
June 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28607007/synergistic-activity-with-notch-inhibition-and-androgen-ablation-in-erg-positive-prostate-cancer-cells
#16
Ahmed A Mohamed, Shyh-Han Tan, Charles P Xavier, Shilpa Katta, Wei Huang, Lakshmi Ravindranath, Muhammad Jamal, Hua Li, Meera Srivastava, Eri S Srivatsan, Taduru L Sreenath, David G McLeod, Alagarsamy Srinivasan, Gyorgy Petrovics, Albert Dobi, Shiv Srivastava
The oncogenic activation of the ETS related gene (ERG) due to gene fusions is present in over half of prostate cancer (CaP) in Western countries. Due to its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for CaP. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified; confirming that NOTCH factors are direct transcriptional targets of ERG...
June 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28607006/nr4a2-promotes-dna-double-strand-break-repair-upon-exposure-to-uvr
#17
Kelvin Yin, Yash Chhabra, Romain Tropée, Yi Chieh Lim, Mitchell Fane, Eloise Dray, Richard Sturm, Aaron G Smith
Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV-lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV-lesions can lead to several complex phenomena, such as the formation of DNA double strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signalling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV-lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA biding domain at position 337...
June 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28596419/intra-tumor-heterogeneity-novel-approaches-for-resolving-genomic-architecture-and-clonal-evolution
#18
Ravi G Gupta, Robert A Somer
High-throughput genomic technologies have revealed a remarkably complex portrait of intra-tumor heterogeneity in cancer and have shown that tumors evolve through a reiterative process of genetic diversification and clonal selection. This discovery has challenged the classical paradigm of clonal dominance and brought attention to subclonal tumor cell populations that contribute to the cancer phenotype. Dynamic evolutionary models may explain how these populations grow within the ecosystem of tissues, including linear, branching, neutral and punctuated patterns...
June 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28596418/err%C3%AE-maintains-mitochondrial-oxidative-metabolism-and-constitutes-an-actionable-target-in-pgc1%C3%AE-elevated-melanomas
#19
Pere Puigserver, Chi Luo, Eduardo Balsa, Ajith Thomas, Maximilian Hatting, Mark Jedrychowski, Steven P Gygi, Hans R Widlund
The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1α function to sustain their mitochondrial energy-dependent survival...
June 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28592703/real-time-transferrin-based-pet-detects-myc-positive-prostate-cancer
#20
Rahul Aggarwal, Spencer C Behr, Pamela L Paris, Charles Truillet, Matthew F L Parker, Loc T Huynh, Junnian Wei, Byron Hann, Jack Youngren, Jiaoti Huang, Gayatri Premasekharan, Nimna Ranatunga, Emily Chang, Kenneth T Gao, Charles J Ryan, Eric J Small, Michael J Evans
Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether (68)Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with (68)Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether (68)Ga-citrate can detect MYC-positive prostate cancer...
June 7, 2017: Molecular Cancer Research: MCR
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