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https://www.readbyqxmd.com/read/29452455/complex-hur-function-in-pancreatic-cancer-cells
#1
REVIEW
Jonathan R Brody, Dan A Dixon
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal patient outcomes. The underlying core genetic drivers of disease have been identified in human tumor specimens and described in genetically engineered mouse models. These genetic drivers of PDAC include KRAS signaling, TP53 mutations, and genetic loss of the SMAD4 tumor suppressor protein. Beyond the known mutational landscape of PDAC genomes, alternative disrupted targets that extend beyond conventional genetic mutations have been elusive and understudied in the context of PDAC cell therapeutic resistance and survival...
February 16, 2018: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/29452147/combination-of-kras-activation-and-pten-deletion-contributes-to-murine-hepatopancreatic-ductal-malignancy
#2
Yun-Kai Lin, Zheng Fang, Tian-Yi Jiang, Zheng-Hua Wan, Yu-Fei Pan, Yun-Han Ma, Yuan-Yuan Shi, Ye-Xiong Tan, Li-Wei Dong, Yong-Jie Zhang, Hong-Yang Wang
Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma...
February 13, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29451340/therapeutic-neural-stem-cells-engineered-during-different-stages-of-reprogramming-reveal-varying-therapeutic-efficacies
#3
Deepak Bhere, Rajiv Kumar Khajuria, William T Hendriks, Antara Bandyopadhyay, Tugba Bagci-Onder, Khalid Shah
Stem cells are emerging as promising treatment strategies for several brain disorders and pathologies including brain tumors. In this study, we explored the potential of creating induced pluripotent stem cell (iPSC) derived therapeutic NSCs (ipNSC) by using either unmodified or gene-modified somatic cells and tested their fate and therapeutic efficacies in vitro and in vivo. We show that cells engineered in somatic state lose transgene-expression during the neural induction process, which is partially restored by HDAC inhibitor (i) treatment whereas cells engineered at the ipNSC state have sustained expression of transgenes...
February 16, 2018: Stem Cells
https://www.readbyqxmd.com/read/29449633/a-competitive-cell-permeable-peptide-impairs-nme-1-ndpk-a-and-prune-1-interaction-therapeutic-applications-in-cancer
#4
Veronica Ferrucci, Francesco Paolo Pennino, Roberto Siciliano, Fatemeh Asadzadeh, Massimo Zollo
The understanding of protein-protein interactions is crucial in order to generate a second level of functional genomic analysis in human disease. Within a cellular microenvironment, protein-protein interactions generate new functions that can be defined by single or multiple modes of protein interactions. We outline here the clinical importance of targeting of the Nme-1 (NDPK-A)-Prune-1 protein complex in cancer, where an imbalance in the formation of this protein-protein complex can result in inhibition of tumor progression...
February 15, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29449614/decreased-succinate-dehydrogenase-b-in-human-hepatocellular-carcinoma-accelerates-tumor-malignancy-by-inducing-the-warburg-effect
#5
Po-Lin Tseng, Wei-Hsuan Wu, Tsung-Hui Hu, Chih-Wei Chen, Hung-Chi Cheng, Chien-Feng Li, Wen-Hui Tsai, Hui-Ju Tsai, Meng-Che Hsieh, Jiin-Haur Chuang, Wen-Tsan Chang
Changes in TCA cycle enzymes or respiratory activity are possible mechanisms of aerobic glycolysis that contributes to tumor progression. To clarify whether the decrease of succinate dehydrogenase B (SDHB) alters energy metabolism, induces the Warburg effect and results in tumor malignancy, SDHB expression was examined and modulated in hepatocellular carcinoma (HCC) tissues and cells, respectively. SDHB level was often decreased in malignant HCC cells and tissues. Furthermore, the reduced SDHB expression was associated with advanced tumor stage and poor survival rate...
February 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29449553/nuclear-factor-90-promotes-angiogenesis-by-regulating-hif-1%C3%AE-vegf-a-expression-through-the-pi3k-akt-signaling-pathway-in-human-cervical-cancer
#6
Wenqian Zhang, Zhengai Xiong, Tianqin Wei, Qiumeng Li, Ying Tan, Li Ling, Xiushan Feng
Vascular endothelial growth factor A (VEGF-A), a fundamental component of angiogenesis, provides nutrients and oxygen to solid tumors, and enhances tumor cell survival, invasion, and migration. Nuclear factor 90 (NF90), a double-stranded RNA-binding protein, is strongly expressed in several human cancers, promotes tumor growth by reducing apoptosis, and increasing cell cycle process. The mechanisms by which cervical cancer cells inducing VEGF-A expression and angiogenesis upon NF90 upregulation remain to be fully established...
February 15, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29449436/mixed-species-rnaseq-analysis-of-human-lymphoma-cells-adhering-to-mouse-stromal-cells-identifies-a-core-gene-set-that-is-also-differentially-expressed-in-the-lymph-node-microenvironment-of-mantle-cell-lymphoma-and-chronic-lymphocytic-leukemia-patients
#7
Gustav Arvidsson, Johan Henriksson, Birgitta Sander, Anthony P Wright
A subset of hematological cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion mediated drug resistance is an important mechanism, whereby cancer cells receive survival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture...
February 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29449372/ligand-mediated-protein-degradation-reveals-functional-conservation-among-sequence-variants-of-the-cul4-type-e3-ligase-substrate-receptor-cereblon
#8
Afua A Akuffo, Aileen Y Alontaga, Rainer Metcalf, Matthew S Beatty, Andreas Becker, Jessica M McDaniel, Rebecca S Hesterberg, William E Goodheart, Steven Gunawan, Muhammad Ayaz, Yan Yang, Md Rezaul Karim, Morgan E Orobello, Kenyon Daniel, Wayne Guida, Jeffrey A Yoder, Anjali M Rajadhyaksha, Ernst Schonbrunn, Harshani R Lawrence, Nicholas J Lawrence, Pearlie K Epling-Burnette
Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteasomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3-ubiquitin ligase in human cells but not in mouse cells suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBNs activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBNs non-primate sequence variations...
February 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29448954/new-therapeutic-strategies-to-treat-human-cancers-expressing-mutant-p53-proteins
#9
REVIEW
Giovanni Blandino, Silvia Di Agostino
The tumor suppressor p53 plays a critical role to preserve DNA fidelity from diverse insults through the regulation of cell-cycle checkpoints, DNA repair, senescence and apoptosis. The TP53 is the most frequently inactivated gene in human cancers. This leads to the production of mutant p53 proteins that loose wild-type p53 tumor suppression functions and concomitantly acquire new oncogenic properties among which deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis and several other pro-oncogenic activities...
February 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29448247/knockdown-of-magea6-activates-amp-activated-protein-kinase-ampk-signaling-to-inhibit-human-renal-cell-carcinoma-cells
#10
Xueting Ye, Jing Xie, Hang Huang, Zhexian Deng
BACKGROUND/AIMS: Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). METHODS: MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively...
February 9, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29448044/safety-evaluation-of-a-human-chimeric-monoclonal-antibody-that-recognizes-the-extracellular-loop-domain-of-claudin-2
#11
Yosuke Hashimoto, Tomoyuki Hata, Minoru Tada, Manami Iida, Akihiro Watari, Yoshiaki Okada, Takefumi Doi, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
Claudin-2 (CLDN-2), a pore-forming tight-junction protein with a tetra-transmembrane domain, is involved in carcinogenesis and the metastasis of some cancers. Although CLDN-2 is highly expressed in the tight junctions of the liver and kidney, whether CLDN-2 is a safe target for cancer therapy remains unknown. We recently generated a rat monoclonal antibody (mAb, clone 1A2) that recognizes the extracellular domains of human and mouse CLDN-2. Here, we investigated the safety of CLDN-2-targeted cancer therapy by using 1A2 as a model therapeutic antibody...
February 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29447458/e-cadherin-loss-accelerates-tumor-progression-and-metastasis-in-a-mouse-model-of-lung-adenocarcinoma
#12
Kerstin W Sinkevicius, Kelly J Bellaria, Juliana Barrios, Patrizia Pessina, Manav Gupta, Christine Fillmore Brainson, Roderick T Bronson, Carla F Kim
Metastatic disease is the primary cause of death of lung cancer patients, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation...
February 15, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29445239/the-urokinase-receptor-induces-a-mesenchymal-gene-expression-signature-in-glioblastoma-cells-and-promotes-tumor-cell-survival-in-neurospheres
#13
Andrew S Gilder, Letizia Natali, Danielle M Van Dyk, Cristina Zalfa, Michael A Banki, Donald P Pizzo, Huawei Wang, Richard L Klemke, Elisabetta Mantuano, Steven L Gonias
PLAUR encodes the urokinase receptor (uPAR), which promotes cell survival, migration, and resistance to targeted cancer therapeutics in glioblastoma cells in culture and in mouse model systems. Herein, we show that patient survival correlates inversely with PLAUR mRNA expression in gliomas of all grades, in glioblastomas, and in the subset of glioblastomas that demonstrate the mesenchymal gene expression signature. PLAUR clusters with genes that define the more aggressive mesenchymal subtype in transcriptome profiles of glioblastoma tissue and glioblastoma cells in neurospheres, which are enriched for multipotent cells with stem cell-like qualities...
February 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29445099/pharmacokinetic-pharmacodynamic-correlations-in-the-development-of-ginger-extract-as-an-anticancer-agent
#14
Rao Mukkavilli, Chunhua Yang, Reenu Singh Tanwar, Roopali Saxena, Sushma R Gundala, Yingyi Zhang, Ahmed Ghareeb, Stephan D Floyd, Subrahmanyam Vangala, Wei-Wen Kuo, Padmashree C G Rida, Ritu Aneja
Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice...
February 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29444979/irreversible-inhibition-of-cytosolic-thioredoxin-reductase-1-as-a-mechanistic-basis-for-anticancer-therapy
#15
William C Stafford, Xiaoxiao Peng, Maria Hägg Olofsson, Xiaonan Zhang, Diane K Luci, Li Lu, Qing Cheng, Lionel Trésaugues, Thomas S Dexheimer, Nathan P Coussens, Martin Augsten, Hanna-Stina Martinsson Ahlzén, Owe Orwar, Arne Östman, Sharon Stone-Elander, David J Maloney, Ajit Jadhav, Anton Simeonov, Stig Linder, Elias S J Arnér
Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets...
February 14, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29444034/label-free-cell-nuclear-imaging-by-gr%C3%A3-neisen-relaxation-photoacoustic-microscopy
#16
Xiaowei Liu, Terence T W Wong, Junhui Shi, Jun Ma, Qing Yang, Lihong V Wang
Photoacoustic microscopy (PAM) with ultraviolet (UV) laser illumination has recently been demonstrated as a promising tool that provides fast, label-free, and multilayered histologic imaging of human breast tissue. Thus far, the axial resolution has been determined ultrasonically. To enable optically defined axial resolution, we exploit the Grüneisen relaxation (GR) effect. By imaging mouse brain slices, we show that GRUV-PAM reveals detailed information about three-dimensional cell nuclear distributions and internal structures, which are important diagnostic features for cancers...
February 15, 2018: Optics Letters
https://www.readbyqxmd.com/read/29440498/structure-of-a-zosuquidar-and-uic2-bound-human-mouse-chimeric-abcb1
#17
Amer Alam, Raphael Küng, Julia Kowal, Robert A McLeod, Nina Tremp, Eugenia V Broude, Igor B Roninson, Henning Stahlberg, Kaspar P Locher
The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29439916/new-histone-demethylase-lsd1-inhibitor-selectively-targets-teratocarcinoma-and-embryonic-carcinoma-cells
#18
Nam Hoang, Xuan Zhang, Chunxiao Zhang, Van Vo, Feng Leng, Lovely Saxena, Feng Yin, Fei Lu, Guangrong Zheng, Pradip Bhowmik, Hui Zhang
LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4...
February 7, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29439259/downregulation-of-prame-suppresses-proliferation-and-promotes-apoptosis-in-hepatocellular-carcinoma-through-the-activation-of-p53-mediated-pathway
#19
Hanzhang Zhu, Jingrui Wang, Junjie Yin, Bei Lu, Qijun Yang, Yafeng Wan, Changku Jia
BACKGROUND/AIMS: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. METHODS: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro...
February 7, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29437870/cpt2-downregulation-adapts-hcc-to-lipid-rich-environment-and-promotes-carcinogenesis-via-acylcarnitine-accumulation-in-obesity
#20
Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki Otsuka, Keisuke Tateishi, Kazuhiko Koike
OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated...
February 6, 2018: Gut
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