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Neoplasia: An International Journal for Oncology Research

Jian Zhang, Zi-Qi Zheng, Ya-Wei Yuan, Pan-Pan Zhang, Ying-Qin Li, Ya-Qin Wang, Xin-Ran Tang, Xin Wen, Xiao-Hong Hong, Yuan Lei, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma, Na Liu
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo...
February 14, 2019: Neoplasia: An International Journal for Oncology Research
Małgorzata Dawidowska, Roman Jaksik, Monika Drobna, Bronisława Szarzyńska-Zawadzka, Maria Kosmalska, Łukasz Sędek, Ludomiła Machowska, Anna Lalik, Monika Lejman, Marek Ussowicz, Krzysztof Kałwak, Jerzy R Kowalczyk, Tomasz Szczepański, Michał Witt
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles...
February 11, 2019: Neoplasia: An International Journal for Oncology Research
Mehrdad Rakaee, Lill-Tove Rasmussen Busund, Simin Jamaly, Erna-Elise Paulsen, Elin Richardsen, Sigve Andersen, Samer Al-Saad, Roy M Bremnes, Tom Donnem, Thomas K Kilvaer
Macrophages are important inflammatory cells that regulate innate and adaptive immunity in cancer. Tumor-associated macrophages (TAMs) are thought to differentiate into two main phenotypes: proinflammatory M1 and protumorigenic M2. Currently, the prognostic impact of TAMs and their M1 and M2 phenotypes is unclear in non-small cell cancer (NSCLC). The present study was set up to evaluate an approach for identifying common M1 and M2 macrophage markers and explore their clinical significance in NSCLC. Using multiplex chromogenic immunohistochemistry, tissue microarrays of 553 primary tumors and 143 paired metastatic lymph nodes of NSCLC specimens were stained to detect various putative macrophage phenotypes: M1 (HLA-DR/CD68), M2 (CD163/CD68), M2 (CD204/CD68), and pan-macrophage (CD68/CK)...
February 8, 2019: Neoplasia: An International Journal for Oncology Research
Robert C Fisher, Kishan Bellamkonda, L Alex Molina, Shao Xiang, David Liska, Samaneh K Sarvestani, Susmita Chakrabarti, Annamarie Berg, Marda L Jorgensen, Denise Hatala, Sugong Chen, Alexandra Aiello, Henry D Appelman, Edward W Scott, Emina H Huang
Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion...
February 6, 2019: Neoplasia: An International Journal for Oncology Research
Peter Dietrich, Anne Gaza, Laura Wormser, Valerie Fritz, Claus Hellerbrand, Anja Katrin Bosserhoff
Inhibition of the RAS-RAF-ERK-pathway using sorafenib as a first-line and regorafenib as a second-line treatment approach is the only effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). Recent studies suggest that wild-type KRAS and HRAS isoforms could majorly contribute to HCC progression and sorafenib resistance. In contrast, the role of neuroblastoma RAS viral oncogene homolog (NRAS) in HCC remained elusive. In this study, wild-type NRAS was found to be overexpressed in HCC cell lines, preclinical HCC models, and human HCC tissues...
January 24, 2019: Neoplasia: An International Journal for Oncology Research
Svenja Bihr, Riuko Ohashi, Ariane L Moore, Jan H Rüschoff, Christian Beisel, Thomas Hermanns, Axel Mischo, Claudia Corrò, Jörg Beyer, Niko Beerenwinkel, Holger Moch, Peter Schraml
Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples...
January 16, 2019: Neoplasia: An International Journal for Oncology Research
Santosh Kumar Bharti, Samata Kakkad, Pierre Danhier, Flonne Wildes, Marie-France Penet, Balaji Krishnamachary, Zaver M Bhujwalla
Metastatic dissemination continues to be a major cause of prostate cancer (PCa) mortality, creating a compelling need to understand factors that play a role in the metastatic cascade. Since hypoxia plays an important role in PCa aggressiveness, we characterized patterns of hypoxia in the primary tumor and metastatic environments of a human PCa xenograft. We previously developed and characterized an imaging strategy based on the hypoxia response element (HRE)-driven expression of long-lived enhanced green fluorescent protein (EGFP) and short-lived luciferase (luc) fused to the oxygen-dependent degradation domain in human PCa PC-3 cells...
January 9, 2019: Neoplasia: An International Journal for Oncology Research
Ashley T Jones, Kalin Narov, Jian Yang, Julian R Sampson, Ming Hong Shen
Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to glucose and glutamine in Tsc1-/- or Tsc2-/- mouse embryonic fibroblasts (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic inhibition causes significant cell death in Tsc2-/- but not Tsc2+/+ MEFs...
January 7, 2019: Neoplasia: An International Journal for Oncology Research
Jian Jiang, Min Zheng, Mei Zhang, Xiao Yang, Li Li, Sha-Sha Wang, Jia-Shun Wu, Xiang-Hua Yu, Jing-Biao Wu, Xin Pang, Ya-Jie Tang, Ya-Ling Tang, Xin-Hua Liang
BACKGROUND: Dormancy is one characteristic of cancer cells to make patients remain asymptomatic before metastasis and relapse, which is closely related to the survival rate of cancer patients, including head and neck squamous cell carcinoma (HNSCC). PRRX1 has previously been implicated in the invasion and metastasis of the epithelial-mesenchymal transition (EMT) process in different types of human carcinoma. However, whether PRRX1 can regulate cancer dormancy and its reactivation, leading to the migration and invasion of HNSCC cells, remains elusive...
January 7, 2019: Neoplasia: An International Journal for Oncology Research
Ga Bin Park, Daejin Kim
CD97 shows a strong relationship with metastasis and poor clinical outcome in various tumors, including ovarian cancer. The expression of CD97 in metastatic ovarian cancer cells was higher than that in primary ovarian cancer cells. Mature miRNAs are frequently de-regulated in cancer and incorporated into a specific mRNA, leading to post-transcriptional silencing. In this study, we investigated whether the miR-503-5p targeting of the CD97 3'-untranslated region (3'-UTR) contributes to ovarian cancer metastasis as well as the underlying mechanism regulating cancer progression...
January 5, 2019: Neoplasia: An International Journal for Oncology Research
Musaffe Tuna, Christopher I Amos, Gordon B Mills
Smoking and alcohol intake are major risk factors in head and neck squamous cell carcinomas (HNSCCs). Although the link between TP53 mutation and smoking has been well established, very little is known about the link between acquired uniparental disomy (aUPD) and smoking and/or alcohol consumption or other clinical characteristics. We used TCGA genomic data to investigate whether smoking, alcohol intake, clinical and demographic variables, HPV status and TP53 mutation are associated with aUPD at specific chromosomal regions...
January 4, 2019: Neoplasia: An International Journal for Oncology Research
Colin Charles Tièche, Yanyun Gao, Elias Daniel Bührer, Nina Hobi, Sabina Anna Berezowska, Kurt Wyler, Laurène Froment, Stefan Weis, Ren-Wang Peng, Rémy Bruggmann, Primo Schär, Michael Alex Amrein, Sean Ralph Robert Hall, Patrick Dorn, Gregor Kocher, Carsten Riether, Adrian Ochsenbein, Ralph Alexander Schmid, Thomas Michael Marti
Cell lines are essential tools to standardize and compare experimental findings in basic and translational cancer research. The current dogma states that cancer stem cells feature an increased tumor initiation capacity and are also chemoresistant. Here, we identified and comprehensively characterized three morphologically distinct cellular subtypes in the non-small cell lung cancer cell line A549 and challenge the current cancer stem cell dogma. Subtype-specific cellular morphology is maintained during short-term culturing, resulting in the formation of holoclonal, meroclonal, and paraclonal colonies...
December 27, 2018: Neoplasia: An International Journal for Oncology Research
J D Jones, B P Sinder, D Paige, F N Soki, A J Koh, S Thiele, Y Shiozawa, L C Hofbauer, S Daignault, H Roca, L K McCauley
Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80+ CD206+ ) were identified in PCa bone resident tumors in mice...
December 23, 2018: Neoplasia: An International Journal for Oncology Research
Cho Rong Hong, William R Wilson, Kevin O Hicks
Tumor hypoxia contributes to resistance to anticancer therapies. Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells and their activity can extend to well-oxygenated areas of tumors via diffusion of active metabolites. This type of bystander effect has been suggested to be responsible for the single agent activity of the clinical-stage HAP evofosfamide (TH-302) but direct evidence is lacking. To dissect the contribution of bystander effects to TH-302 activity, we implemented a Green's function pharmacokinetic (PK) model to simulate the spatial distribution of O2 , TH-302 and its cytotoxic metabolites, bromo-isophosphoramide mustard (Br-IPM) and its dichloro derivative isophosphoramide mustard (IPM), in two digitized tumor microvascular networks...
December 23, 2018: Neoplasia: An International Journal for Oncology Research
Yongjun Cha, Sun Young Kim, Hyun Yang Yeo, Ji Yeon Baek, Moon Ki Choi, Kyung Hae Jung, Seung Myung Dong, Hee Jin Chang
Aberrant promoter methylation plays a vital role in colorectal carcinogenesis. However, its role in treatment responses is unclear, especially for metastatic disease. Here, we investigated the association between promoter methylation and treatment outcomes of irinotecan-based chemotherapy in 102 patients with metastatic colorectal cancer. Promoter methylation was examined by methylation-specific polymerase chain reaction for three loci (CHFR, WRN, and SULF2) associated with chemotherapy response and five CpG island methylator phenotype (CIMP)-specific markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1)...
December 14, 2018: Neoplasia: An International Journal for Oncology Research
Caitlin E Jones, Anisha M Hammer, YouJin Cho, Gina M Sizemore, Edna Cukierman, Lisa D Yee, Samir N Ghadiali, Michael C Ostrowski, Jennifer L Leight
The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression...
December 11, 2018: Neoplasia: An International Journal for Oncology Research
Masayuki Haruta, Yasuhito Arai, Hajime Okita, Yukichi Tanaka, Tetsuya Takimoto, Ryuichi P Sugino, Yasuhiro Yamada, Takehiko Kamijo, Takaharu Oue, Masahiro Fukuzawa, Tsugumichi Koshinaga, Yasuhiko Kaneko
To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q-, 16q-, or HACE1 loss. RFS was better for those with than those without +12 (P = ...
December 5, 2018: Neoplasia: An International Journal for Oncology Research
Mohsina Khan, Dattatraya Muzumdar, Anjali Shiras
Glioblastoma (GBM) is one of the most aggressive and lethal types of brain tumor. Despite the advancements in conventional or targeted therapies, median survival of GBM patients is less than 12 months. Amongst various signaling pathways aberrantly activated in glioma, active Wnt/β-catenin signaling pathway is one of the crucial oncogenic players. β-catenin, an important mediator of Wnt signaling pathway, gets phosphorylated by GSK3β complex. Phosphorylated β-catenin is specifically recognized by β-Trcp1, a F-box/WD40-repeat protein and with the help of Skp1 it plays a central role in recruiting phosphorylated β-catenin for degradation...
December 5, 2018: Neoplasia: An International Journal for Oncology Research
Ilaria Saltarella, Maria Antonia Frassanito, Aurelia Lamanuzzi, Arianna Brevi, Patrizia Leone, Vanessa Desantis, Lucia Di Marzo, Matteo Bellone, Daniele Derudas, Domenico Ribatti, Raffaella Chiaramonte, Maria Teresa Palano, Antonino Neri, Maria Addolorata Mariggiò, Ruggiero Fumarulo, Franco Dammacco, Vito Racanelli, Angelo Vacca, Roberto Ria
Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression...
December 4, 2018: Neoplasia: An International Journal for Oncology Research
Anne-Kathrin Knuth, Stefanie Rösler, Barbara Schenk, Lisa Kowald, Sjoerd J L van Wijk, Simone Fulda
Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNγ up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNγ transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNγ-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D...
December 3, 2018: Neoplasia: An International Journal for Oncology Research
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