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Molecular Oncology

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https://www.readbyqxmd.com/read/29337428/ap4-positively-regulates-laptm4b-to-promote-hepatocellular-carcinoma-growth-and-metastasis-whilst-reducing-chemotherapy-sensitivity
#1
Yue Meng, Lu Wang, Jianjun Xu, Qingyun Zhang
Polymorphisms of the Lysosomal-Associated Protein Transmembrane-4 beta (LAPTM4B) gene are related to various forms of tumour susceptibility, which led us to hypothesize that some unique transcription factors targeting this polymorphism region may affect the biological function of LAPTM4B in tumour progression. In this study, we found that the transcription factor AP4 directly binds to the polymorphism region of the LAPTM4B gene promoter and induces its transcription. In addition, we demonstrated that AP4 promotes hepatocellular carcinoma cell proliferation and metastasis, and depresses chemotherapy sensitivity via LAPTM4B by activating the PI3K/AKT signalling pathway and caspase-dependent pathway...
January 16, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29325228/effects-of-trastuzumab-and-afatinib-on-kinase-activity-in-gastric-cancer-cell-lines
#2
Simone Keller, Gwen Zwingenberger, Karolin Ebert, Jan Hasenauer, Jacqueline Wasmuth, Dieter Maier, Ivonne Haffner, Katrin Schierle, Gregor Weirich, Birgit Luber
The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1 and MKN7) using proteome profiling...
January 11, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29316337/a-novel-enediyne-integrated-antibody-drug-conjugate-shows-promising-anti-tumor-efficacy-against-cd30-lymphomas
#3
Rong Wang, Liang Li, Shenghua Zhang, Yi Li, Xiaofei Wang, Qingfang Miao, Yongsu Zhen
CD30 is a 120-kDa type I trans-membrane glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily. Overexpression of CD30 has been reported in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). CD30-targeted treatment with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. Lidamycin (LDM), consisting of an apoprotein LDP and an active enediyne chromaphore AE, is a member of the enediyne antibiotic family and one of the most potent antitumor agents. AE and LDP can be dissociated and reconstituted under certain conditions in vitro...
January 9, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29316250/dual-inhibition-of-wnt-and-yes-associated-protein-signaling-retards-the-growth-of-triple-negative-breast-cancer-in-both-mesenchymal-and-epithelial-states
#4
Andrew Sulaiman, Sarah McGarry, Li Li, Deyong Jia, Sarah Ooi, Christina Addison, Jim Dimitroulakos, Angel Arnaout, Carolyn Nessim, Zemin Yao, Guang Ji, Haiyan Song, Suresh Gadde, Xuguang Li, Lisheng Wang
Triple negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal-like and epithelial-like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed...
January 9, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29316219/characterization-of-a-foxg1-tle1-transcriptional-network-in-glioblastoma-initiating-cells
#5
Rola Dali, Federica Verginelli, Albena Pramatarova, Robert Sladek, Stefano Stifani
Glioblastoma (GBM) is the most common and deadly malignant brain cancer of glial cell origin, with a median patient survival of less than 20 months. Transcription factors FOXG1 and TLE1 promote GBM propagation by supporting maintenance of brain tumour initiating cells with stem-like properties. Here, we characterize FOXG1 and TLE1 target genes in glioblastoma patient-derived brain tumour initiating cells using ChIP-Seq and RNA-Seq approaches. These studies identify 150 direct FOXG1 targets, several of which are also TLE1 targets, involved in cell proliferation, differentiation, survival, chemotaxis and angiogenesis...
January 9, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29316206/inhibition-of-vegf-dependent-angiogenesis-and-tumor-angiogenesis-by-an-optimized-antibody-targeting-clec14a
#6
Taek-Keun Kim, Chang Sik Park, Jihye Jang, Mi Ra Kim, Hee-Jun Na, Kangseung Lee, Hyun Jung Kim, Kyun Heo, Byong Chul Yoo, Young-Myeong Kim, Je-Wook Lee, Su Jin Kim, Eun Sung Kim, Dae Young Kim, Kiweon Cha, Tae Gyu Lee, Sukmook Lee
The C-type lectin-like domain of CLEC14a (CLEC14a-CTLD) is a key domain that mediates endothelial cell-cell contacts in angiogenesis. However, the role of CLEC14a-CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity-determining region (CDR) grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti-angiogenic human monoclonal antibody that specifically targets CLEC14a-CTLD and that shows improved stability and homogeneity relative to the parental antibody...
January 9, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29316268/crosstalk-between-hepatitis-b-virus-x-and-high-mobility-group-box-1-facilitates-autophagy-in-hepatocytes
#7
Sha Fu, Juan Wang, Xingwang Hu, Rong-Rong Zhou, Yongming Fu, Daolin Tang, Rui Kang, Yan Huang, Lunquan Sun, Ning Li, Xue-Gong Fan
Hepatitis B virus (HBV) X (HBx) protein is a pivotal regulator of HBV-triggered autophagy. However, the role of HBx-induced epigenetic changes in autophagy remains largely unknown. The cytoplasmic high-mobility group box 1 (HMGB1) has been identified as a positive regulator of autophagy, and its cytoplasmic translocation is closely associated with its acetylation status. Here, we evaluated the function of HMGB1 in HBx-mediated autophagy and its association with histone deacetylase (HDAC). Using cell lines with enforced expression of HBx, we demonstrated that HBx upregulated the expression of HMGB1 and promoted its cytoplasmic translocation by acetylation to facilitate autophagy...
January 5, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29239100/insulin-like-growth-factor-2-expression-in-prostate-cancer-is-regulated-by-specific-promoter-methylation
#8
Stefan Küffer, Tobias Gutting, Djeda Belharazem, Christian Sauer, M S Michel, Alexander Marx, Lutz Trojan, Philipp Ströbel
Deregulation of the Insulin-like Growth Factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development- and tissue-dependent manner and has been implicated in a broad range of malignancies including prostate cancer (PCa). Loss of imprinting (LOI) usually results in bi-allelic gene expression and increased levels of IGF2...
December 14, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29215790/inhibition-of-fucosylation-in-human-invasive-ductal-carcinoma-reduces-e-selectin-ligand-expression-cell-proliferation-and-erk1-2-and-p38-mapk-activation
#9
M A Carrascal, M Silva, J S Ramalho, C Pen, M Martins, C Pascoal, C Amaral, I Serrano, M J Oliveira, R Sackstein, P A Videira
Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A ), and α-1,3/4-fucosyltransferases in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their role(s) in breast carcinogenesis is still unknown. Here, we aimed to define the contribution of the fucosylated structures, including sLeX/A , to cell adhesion, cell signaling and proliferation in invasive ductal carcinomas (IDC), the most frequent type of breast cancer...
December 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29215776/tgf-%C3%AE-transactivates-egfr-and-facilitates-breast-cancer-migration-and-invasion-through-canonical-smad3-and-erk-sp1-signaling-pathway
#10
Yuanyuan Zhao, Jing Ma, Yanling Fan, Zhiyong Wang, Ran Tian, Wei Ji, Fei Zhang, Ruifang Niu
Transforming growth factor-beta (TGF-β) functions as a potent proliferation inhibitor and apoptosis inducer in the early stages of breast cancer, yet promotes cancer aggressiveness in the advanced stages. The dual effect of TGF-β on cancer development is known as TGF-β paradox, and the remarkable functional conversion of TGF-β is a pivotal and controversial phenomenon that has been widely investigated for decades. This phenomenon may be attributed to the crosstalk between TGF-β signaling and other pathways, including epidermal growth factor receptor (EGFR) signaling during cancer progression...
December 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29193607/comparative-genomics-reveals-that-loss-of-lunatic-fringe-lfng-promotes-melanoma-metastasis
#11
Martin Del Castillo Velasco-Herrera, Louise van der Weyden, Jeremie Nsengimana, Anneliese O Speak, Marcela K Sjöberg, D Timothy Bishop, Göran Jönsson, Julia Newton-Bishop, David J Adams
Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonization are poorly understood. Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic, and their highly metastatic derivatives...
November 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29193645/mapk-inhibitors-induce-serine-peptidase-inhibitor-kazal-type-1-spink1-secretion-in-braf-v600e-mutant-colorectal-adenocarcinoma
#12
Kati Räsänen, Kien X Dang, Harri Mustonen, Tho H Ho, Susanna Lintula, Hannu Koistinen, Ulf-Håkan Stenman, Caj Haglund, Jakob Stenman
The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Over-expression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) is observed in around 50% of CRCs and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed Extendable Blocking Probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N=571) using tissue-derived RNA as the starting material...
November 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29178186/mammary-epithelium-specific-inactivation-of-v-atpase-reduces-stiffness-of-extracellular-matrix-and-enhances-metastasis-of-breast-cancer
#13
Gajendra K Katara, Arpita Kulshrestha, Liqun Mao, Xin Wang, Manoranjan Sahoo, Safaa Ibrahim, Sahithi Pamarthy, Kimiko Suzue, Gajendra S Shekhawat, Alice Gilman-Sachs, Kenneth D Beaman
Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell-associated vacuolar ATPase 'a2' isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis. Using a mammary gland-specific a2V-knockout model, we show that in the absence of a2V, breast tumors exhibit atypically soft tumor phenotype, less tumor rigidity, and necrotic tumor microenvironment...
November 27, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29160958/prognostic-value-of-an-immunohistochemical-signature-in-patients-with-esophageal-squamous-cell-carcinoma-undergoing-radical-esophagectomy
#14
Jin Meng, Junhua Zhang, Yingjie Xiu, Yan Jin, Jiaqing Xiang, Yongzhan Nie, Shen Fu, Kuaile Zhao
Here, we aimed to identify an immunohistochemical (IHC)-based classifier as a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC). A cohort of 235 patients with ESCC undergoing radical esophagectomy (with complete clinical and pathological information) were enrolled in the study. Using the least absolute shrinkage and selection operator (LASSO) regression model, we extracted six IHC features associated with progression-free survival (PFS) and then built a classifier in the discovery cohort (n=141)...
November 21, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29130642/dual-inhibition-of-dnmts-and-ezh2-can-overcome-both-intrinsic-and-acquired-resistance-of-myeloma-cells-to-imids-in-a-cereblon-independent-manner
#15
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Niels Emil Ulrich Hermansen, Casey O'Connel, Peter Gimsing, Gangning Liang, Kirsten Grønbaek
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide-resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29130628/characterization-of-genetic-intratumor-heterogeneity-in-colorectal-cancer-and-matching-patient-derived-spheroid-cultures
#16
Sigrid S Árnadóttir, Maria Jeppesen, Philippe Lamy, Jesper B Bramsen, Iver Nordentoft, Michael Knudsen, Søren Vang, Mogens R Madsen, Ole Thastrup, Jacob Thastrup, Claus L Andersen
Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, while the other half was used for DNA and RNA purification...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29124875/emerging-functions-of-the-egfr-in-cancer
#17
REVIEW
Sara Sigismund, Daniele Avanzato, Letizia Lanzetti
The physiological function of the Epidermal Growth Factor Receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms have also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, since its amplification or secondary mutations have been found to arise under drug pressure...
November 10, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29120535/mirna-profiling-identifies-deregulated-mirnas-associated-with-osteosarcoma-development-and-time-to-metastasis-in-two-large-cohorts
#18
Gitte Brinch Andersen, Alice Knudsen, Henrik Hager, Lise Lotte Hansen, Jörg Tost
Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays...
November 9, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29117471/tumor-adjacent-tissue-co-expression-profile-analysis-reveals-pro-oncogenic-ribosomal-gene-signature-for-prognosis-of-resectable-hepatocellular-carcinoma
#19
O V Grinchuk, S P Yenamandra, R Iyer, M Singh, H K Lee, K H Lim, P K H Chow, V A Kuznetsov
Currently, molecular markers are not used whilst determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). Here, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT), and adjacent non-malignant tissues (AT), that typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods...
November 8, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29112787/dabrafenib-inhibits-the-growth-of-braf-wt-cancers-through-cdk16-and-nek9-inhibition
#20
Manali Phadke, Lily L Remsing Rix, Inna Smalley, Annamarie T Bryant, Yunting Luo, Harshani R Lawrence, Braydon J Schaible, Yian A Chen, Uwe Rix, Keiran S M Smalley
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival...
November 7, 2017: Molecular Oncology
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