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Molecular Cancer Research: MCR

Yukiko Kariya, Midori Oyama, Yasuhiro Hashimoto, Jianguo Gu, Yoshinobu Kariya
Malignant transformation is associated with aberrant N-glycosylation, but the role of protein N-glycosylation in cancer progression remains poorly defined. β4-integrin is a major carrier of N-glycans and is associated with poor prognosis, tumorigenesis, and metastasis. Here, N-glycosylation of β4-integrin contributes to the activation of signaling pathways that promote β4-dependent tumor development and progression. Increased expression of β1,6GlcNAc-branched N-glycans was found to be co-localized with β4-integrin in human cutaneous squamous cell carcinoma tissues, and that the β1,6GlcNAc residue was abundant on β4-integrin in transformed keratinocytes...
March 16, 2018: Molecular Cancer Research: MCR
Zhijian Zhao, Mengping Zhang, Xiaolu Duan, Yiwen Chen, Ermao Li, Lianming Luo, Wenqi Wu, Zhenwei Peng, Hui-Juan Qiu, Guohua Zeng
Transient receptor potential melastatin 7 (TRPM7) is important for the tumorigenesis and progression of several cancers. However, little is known about TRPM7 expression and its clinical significance in clear cell renal cell carcinoma (ccRCC). The expression dynamics of TRPM7 was examined in a clinical cohort of RCC specimens by quantitative PCR (qPCR), immunoblotting and immunohistochemical (IHC) staining. A series of in vitro and in vivo assays were performed to elucidate the function of TRPM7 in RCC and the underlying mechanisms...
March 15, 2018: Molecular Cancer Research: MCR
Kati Richter, Teija Paakkola, Daniela Mennerich, Kateryna Kubaichuk, Anja Konzack, Heidi Ali-Kippari, Nina Kozlova, Peppi Koivunen, Kirsi-Maria Haapasaari, Arja Jukkola-Vuorinen, Hanna-Riikka Teppo, Elitsa Y Dimova, Risto Bloigu, Zoltan Szabo, Risto Kerkelä, Thomas Kietzmann
Recent studies suggest that the ubiquitin-specific protease USP28 plays an important role in cellular repair and tissue remodeling, which implies that it has a direct role in carcinogenesis. The carcinogenic potential of USP28 was investigated in a comprehensive manner using patients, animal models, and cell culture. The findings demonstrate that overexpression of USP28 correlates with a better survival in patients with invasive ductal breast carcinoma. Mouse xenograft experiments with USP28-deficient breast cancer cells also support this view...
March 15, 2018: Molecular Cancer Research: MCR
Soyoung Park, Ah-Young Oh, Jung-Hyun Cho, Min-Ho Yoon, Tae-Guen Woo, Somi Kang, Ho-Young Lee, Yunjin Jung, Bum-Joon Park
Quinacrine (QNC), anti-protozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest anti-tumor effects of QNC through suppression of NF-κB and activation of p53. This study, demonstrates the anti-cancer effect of QNC via a novel pathway through the elimination of check point kinase 1/2 (Chk1/2) under p53 inactivated conditions. Inhibition of p53, by PFT-α or siRNA, promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells...
March 15, 2018: Molecular Cancer Research: MCR
Tie Li, Christopher D Cox, Byram Ozer, Nhung T Nguyen, Huytram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh Leia Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP), and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
Pingping Fang, Jill A Madden, Lisa Neums, K Ryan Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in poly (ADP-ribose) polymerase (PARP) inhibitor response has not yet been studied. The present study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. Based on ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
Yulei Zhao, Tess Montminy, Taha Azad, Elizabeth Lightbody, Yawei Hao, Sandip SenGupta, Eric Asselin, Christopher Jb Nicol, Xiaolong Yang
Breast cancer (BC) is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB occur in many BC cases. In recent years, activation of the Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have been found to be important for BC development and progression. However, there is no evidence that PI3K interacts with YAP/TAZ in mammary tumorigenesis. Using a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, PIK3CB was identified as a transformation inducing kinase...
March 15, 2018: Molecular Cancer Research: MCR
Hyeon Jeong Lee, Jie Li, Renee E Vickman, Junjie Li, Rui Liu, Abigail Durkes, Bennett D Elzey, Shuhua Yue, Xiaoqi Liu, Timothy L Ratliff, Ji-Xin Cheng
Dysregulation of cholesterol is a common characteristic of human cancers including prostate cancer. This study observed an aberrant accumulation of cholesteryl ester in metastatic lesions using Raman spectroscopic analysis of lipid droplets in human prostate cancer patient tissues. Inhibition of cholesterol esterification in prostate cancer cells significantly suppresses the development and growth of metastatic cancer lesions in both orthotopic and intra-cardiac injection mouse models. Gene expression profiling reveals that cholesteryl ester depletion suppresses the metastatic potential through upregulation of multiple regulators that negatively impact metastasis...
March 15, 2018: Molecular Cancer Research: MCR
Kelly Flentie, Caleb Gonzalez, Brandon Kocher, Yue Wang, Hongtu Zhu, Jayne Marasa, David Piwnica-Worms
Bacterial flagellin is a potent activator of NF-κB signaling, inflammation and host innate immunity, and recent data indicate that flagellin represents a novel anti-tumor ligand acting through toll-like receptor 5 (TLR5) and the NF-κB pathway to induce host immunity and aid in the clearance of tumor xenografts. To identify innate signaling components of TLR5 responsible for these anti-tumor effects, a loss-of-function high-throughput screen was employed utilizing carcinoma cells expressing a dynamic NF-κB bioluminescent reporter stimulated by Salmonella typhimurium expressing flagellin...
March 9, 2018: Molecular Cancer Research: MCR
Yifeng Xia, Cheng Zhan, Mingxiang Feng, Mathias Leblanc, Eugene Ke, Narayana Yeddula, Inder M Verma
Small cell lung cancer (SCLC) is the most deadly subtype of lung cancer due to its dismal prognosis. We have developed a lentiviral vector-mediated SCLC mouse model and have explored the role of both the NF-κB and CREB families of transcription factors in this model. Surprisingly, induction of NF-κB activity, which promotes tumor progression in many cancer types including non-small cell lung carcinoma (NSCLC), is dispensable in SCLC. Instead, suppression of NF-κB activity in SCLC tumors moderately accelerated tumor development...
March 9, 2018: Molecular Cancer Research: MCR
Akimitsu Yamada, Masayuki Nagahashi, Tomoyoshi Aoyagi, Wei-Ching Huang, Santiago Lima, Nitai C Hait, Aparna Maiti, Kumiko Kida, Krista P Terracina, Hiroshi Miyazaki, Takashi Ishikawa, Itaru Endo, Michael R Waters, Qianya Qi, Li Yan, Sheldon Milstien, Sarah Spiegel, Kazuaki Takabe
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathological consequences of these events to breast cancer progression and metastasis has not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients...
March 9, 2018: Molecular Cancer Research: MCR
Rebecca C Arend, Angelina I Londono, Allison M Montgomery, Haller J Smith, Zachary C Dobbin, Ashwini A Katre, Alba Martinez, Eddy S Yang, Ronald D Alvarez, Warner K Huh, Kerri S Bevis, J Michael Straughn, Jacob M Estes, Lea Novak, David K Crossman, Sara J Cooper, Charles N Landen, Charles A Leath
While high-grade serous ovarian carcinoma (HGSOC) is the most common histological subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants (by DNA next-generation sequencing [NGS] using a 50 gene Ion Torrent panel) and gene expression (using the NanoString® PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT)...
March 9, 2018: Molecular Cancer Research: MCR
Victoria Peyret, Magalí Nazar, Mariano Martin, Amado A Quintar, Elmer A Fernandez, Romina C Geysels, Cesar Fuziwara, María M Montesinos, Cristina A Maldonado, Pilar Santisteban, Edna T Kimura, Claudia G Pellizas, Juan P Nicola, Ana M Masini-Repiso
Emerging evidence suggests that unregulated Toll-like receptors (TLRs) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTCs) mainly harboring the BRAFV600E mutation was studied. TLR4 was overexpressed in PTCs compared to non-neoplastic thyroid tissue. Moreover, paired clinical specimens of primary PTC and its lymph node metastasis showed a significant upregulation of TLR4 levels in the metastatic tissues...
March 9, 2018: Molecular Cancer Research: MCR
Benjamin Yeung, Prem Khanal, Virja Mehta, Laura Trinkle-Mulcahy, Xiaolong Yang
The Hippo pathway is a signalling cascade that plays important roles in organ size control, tumorigenesis, metastasis, stress response, stem cell differentiation and renewal during development and tissue homeostasis, and mechanotransduction. Recently, we and others have shown that loss of the Hippo pathway core component LATS or overexpression of its downstream targets YAP and its paralog TAZ causes resistance of cancer cells to anti-tubulin drugs. However, YAP and TAZ mediates anti-tubulin drug-induced apoptosis independent of its upstream regulator LATS and the Hippo pathway...
March 9, 2018: Molecular Cancer Research: MCR
Michele Pellegrino, Pietro Rizza, Alessandra Nigro, Rosangela Ceraldi, Elena Ricci, Ida Perrotta, Saveria Aquila, Marilena Lanzino, Sebastiano Andò, Catia Morelli, Diego Sisci
Breast cancer (BC) is a complex and heterogeneous disease, with distinct histological features dictating the therapy. Although the clinical outcome of BC patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in BC therapy are needed. As a "faster" alternative to reach this aim, we evaluated if Lamotrigine (LTG), a broadly used anticonvulsivant, could be "repurposed" as an antitumoral drug in BC...
March 9, 2018: Molecular Cancer Research: MCR
Mohamed E Salem, Alberto Puccini, Axel Grothey, Derek Raghavan, Richard M Goldberg, Joanne Xiu, W Michael Korn, Benjamin A Weinberg, Jimmy J Hwang, Anthony F Shields, John L Marshall, Philip A Philip, Heinz-Josef Lenz
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing (NGS) was performed on genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens using the NextSeq platform...
March 9, 2018: Molecular Cancer Research: MCR
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March 9, 2018: Molecular Cancer Research: MCR
Shankha Subhra Chatterjee, Mayukh Biswas, Liberalis Debraj Boila, Debasis Banerjee, Amitava Sengupta
SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in ~ 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNFΔ...
February 26, 2018: Molecular Cancer Research: MCR
Mei Ding, Theodorus H van der Kwast, Ravi N Vellanki, Warren D Foltz, Trevor D McKee, Nahum Sonenberg, Pier Paolo Pandolfi, Marianne Koritzinsky, Bradly G Wouters
The mTOR signaling pathway is a central regulator of protein synthesis and cellular metabolism in response to the availability of energy, nutrients, oxygen, and growth factors. mTOR activation leads to phosphorylation of multiple downstream targets including the eukaryotic initiation factor 4E (eIF4E) binding proteins-1 and -2 (EIF4EBP1/4E-BP1 and EIF4EBP2/4E-BP2). These binding proteins inhibit protein synthesis, but are inactivated by mTOR to stimulate cell growth and metabolism. However, the role of these proteins in the context of aberrant activation of mTOR, which occurs frequently in cancers through loss of PTEN or mutational activation of the PI3K/AKT pathway, is unclear...
February 16, 2018: Molecular Cancer Research: MCR
Jonas Blaes, Carina M Thomé, Philipp-Niclas Pfenning, Petra Rübmann, Felix Sahm, Antje Wick, Theresa Bunse, Torsten Schmenger, Jaromir Sykora, Andreas von Deimling, Benedikt Wiestler, Christian Merz, Manfred Jugold, Uwe Haberkorn, Amir Abdollahi, Jürgen Debus, Christian Gieffers, Claudia Kunz, Martin Bendszus, Michael Kluge, Michael Platten, Harald Fricke, Wolfgang Wick, Dieter Lemke
CD95 (Fas/APO-1), a death receptor family member, activity has been linked to tumorigenicity in multiple cancers, including glioblastoma multiforme (GBM). A phase II clinical trial on relapsed glioblastoma patients demonstrated that targeted inhibition of CD95 signaling via the CD95 ligand (CD95L) binding and neutralizing Fc-fusion protein APG101 (asunercept) prolonged patient survival. While CD95 signaling may be relevant for multiple aspects of tumor growth, the mechanism of action of APG101 in glioblastoma is not clear...
February 16, 2018: Molecular Cancer Research: MCR
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