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Molecular Cancer Research: MCR

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https://www.readbyqxmd.com/read/28637905/p120-catenin-downregulation-and-pik3ca-mutations-cooperate-to-induce-invasion-through-mmp1-in-hnscc
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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%C3%A2-detects-myc-positive-prostate-cancer
#10
Rahul Aggarwal, Spencer Behr, Pamela L Paris, Charles Truillet, Matthew F L Parker, Loc T Huynh, Junnian Wei, Byron Hann, Jack Youngren, Gayatri Premasekharan, Jiaoti Huang, Nimna Ranatunga, Emily Chang, Kenneth T Gao, Charles J Ryan, Eric J Small, Michael J Evans
Non-invasive 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 if 68Ga-citrate (which avidly binds to circulating transferrin) labeled transferrin (Tf) can detect MYC-positive prostate cancer tumors, since the transferrin receptor is a direct MYC target gene. Positron emission tomography (PET) imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA) and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer...
June 7, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28588059/near-infrared-photoimmunotherapy-targeting-prostate-cancer-with-prostate-specific-membrane-antigen-psma-antibody
#11
Tadanobu Nagaya, Yuko Nakamura, Shuhei Okuyama, Fusa Ogata, Yasuhiro Maruoka, Peter L Choyke, Hisataka Kobayashi
Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photo-absorber, IR700DX, in a PSMA expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro...
June 6, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28584024/ppar%C3%AE-reprograms-glutamine-metabolism-in-sorafenib-resistant-hcc
#12
Keun-Gyu Park, Mi-Jin Kim, Yeon-Kyung Choi, Soo Young Park, Se Young Jang, Jung Yi Lee, Hye Jin Ham, Byung-Gyu Kim, Hui-Jeon Jeon, Ji-Hyun Kim, Jung-Guk Kim, In-Kyu Lee
The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator-activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28584023/notch-represses-transcription-by-prc2-recruitment-to-the-ternary-complex
#13
Xiaoqing Han, Prathibha Ranganathan, Christos Tzimas, Kelly L Weaver, Ke Jin, Luisana Astudillo, Wen Zhou, Xiaoxia Zhu, Bin Li, David J Robbins, Anthony J Capobianco
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28584022/ikk%C3%AE-mediated-resistance-to-skin-cancer-development-is-ink4a-arf-dependent
#14
Angustias Page, Ana Bravo, Cristian Suárez-Cabrera, Josefa P Alameda, M LLanos Casanova, Corina Lorz, Carmen Segrelles, Jose C Segovia, Jesus M Paramio, Manuel Navarro, Angel Ramírez
IKKβ (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the nuclear factor kappa B (NF-κB) pathway. IKKβ exerts a pro-tumorigenic role in several animal models of lung, hepatic, intestinal and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28584021/the-landscape-of-isoform-switches-in-human-cancers
#15
Kristoffer Vitting-Seerup, Albin Sandelin
Alternative usage of transcript isoforms from the same gene has been hypothesized as an important feature in cancers. However, differential usage of gene transcripts between conditions - isoform switching - has not been comprehensively characterized in and across cancer types. To this end, we developed methods for identification and visualization of isoform switches with predicted functional consequences. Using these methods, we characterized isoform switching in RNA-seq data from >5500 cancer patients covering 12 solid cancer types...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28584020/kit-d816v-induces-src-mediated-tyrosine-phosphorylation-of-mitf-and-altered-transcription-program-in-melanoma
#16
Bengt Phung, Julhash U Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R Goding, Göran Jönsson, Jesper V Olsen, Eiríkur Steingrímsson, Lars Rönnstrand
The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KIT(D816V) has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KIT(D816V) induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28550083/normal-and-cancerous-tissues-release-extrachromosomal-circular-dna-eccdna-into-the-circulation
#17
Pankaj Kumar, Laura W Dillon, Yoshiyuki Shibata, Amir A Jazaeri, David R Jones, Anindya Dutta
Cell-free circulating linear DNA is being explored for noninvasive diagnosis and management of tumors and fetuses, the so-called liquid biopsy. Previously, we observed the presence of small extrachromosomal circular DNA (eccDNA), called microDNA, in the nuclei of mammalian tissues and cell lines. Now, we demonstrate that cell-free microDNA derived from uniquely mapping regions of the genome is detectable in plasma and serum from both mice and humans and that they are significantly longer (30%-60% >250 bases) than cell-free circulating linear DNA (∼150 bases)...
May 26, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28539329/aberrant-methylation-mediated-silencing-of-lncrna-meg3-functions-as-a-cerna-in-esophageal-cancer
#18
Zhiming Dong, Aili Zhang, Shengnan Liu, Fan Lu, Yanli Guo, Guoqiang Zhang, Fenglou Xu, Yabin Shi, Supeng Shen, Jia Liang, Wei Guo
Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), has tumor suppressor properties and its expression is lost in several human tumors. However, its biological role in esophageal squamous cell carcinoma (ESCC) tumorigenesis is poorly defined. The present study determined the role and methylation status of MEG3 in esophageal cancer cells and ESCC clinical specimens, and further observed the competing endogenous RNA (ceRNA) activity of MEG3 in the pathogenesis and development of ESCC. Significant down-regulation of MEG3 was detected in esophageal cancer cells and ESCC tissues and the expression level of MEG3 was significantly increased in cancer cells after treated with the DNA methyltransferase inhibitor 5-Aza-dC...
May 24, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28536143/aurora-kinase-a-promotes-ar-degradation-via-the-e3-ligase-chip
#19
Sukumar Sarkar, David L Brautigan, James M Larner
Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer (CRPC). Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation...
May 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28536142/augmented-tme-o-glcnacylation-promotes-tumor-proliferation-through-the-inhibition-of-p38-mapk
#20
Kazumasa Moriwaki, Michio Asahi
O-GlcNAcylation is a dynamic O-linked glycosylation event that plays a crucial role in regulating cellular signaling. Recent studies indicate that increased O-GlcNAcylation is a general feature in cancer and contributes to various cancer phenotypes, including cell proliferation, survival, invasion, metastasis, and energy metabolism. However, the role of O-GlcNAcylation in the tumor microenvironment (TME) is not fully elucidated. Here, B16 melanoma cells were subcutaneously transplanted into O-GlcNAc transferase transgenic (Ogt-Tg) mice exhibiting elevated O-GlcNAcylation to examine the effect of O-GlcNAcylation in the TME on tumor progression...
May 23, 2017: Molecular Cancer Research: MCR
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