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Molecular Oncology

Marta Gładych, Rafał Cylwa, Kornel Kiełczewski, Przemysław Biecek, Triantafillos Liloglou, Andrzej Mackiewicz, Urszula Oleksiewicz
The KRAB-ZNF (Krüppel-associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue-specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB-ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored...
November 15, 2018: Molecular Oncology
Takayuki Arai, Satoko Kojima, Yasutaka Yamada, Sho Sugawara, Mayuko Kato, Kazuto Yamazaki, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki
Androgen deprivation therapy is frequently used to treat prostate cancer (PCa) but resistance can occur, a condition known as castration-resistant prostate cancer (CRPC). Thus, novel approaches for identification of CRPC are important for designing effective prostate cancer (PCa) treatments. Analysis of microRNA (miRNA) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR-455 duplex (miR-455-5p and miR-455-3p, respectively) acted as anti-tumor miRNAs in PCa cells. The involvement of miRNA passenger strands in cancer pathogenesis is a novel concept for miRNA functionality...
November 15, 2018: Molecular Oncology
Chatchai Phoomak, Dayoung Park, Atit Silsirivanit, Kanlayanee Sawanyawisuth, Kulthida Vaeteewoottacharn, Marutpong Detarya, Chaisiri Wongkham, Carlito B Lebrilla, Wongkham Sopit
O-GlcNAcylation is a key post-translational modification that modifies the functions of proteins. Associations between O-GlcNAcylation, shorter survival of cholangiocarcinoma (CCA) patients and increased migration/invasion of CCA cell lines have been reported. However, the specific O-GlcNAcylated proteins (OGPs) that participate in promotion of CCA progression are poorly understood. OGPs were isolated from human CCA cell lines, KKU-213 and KKU-214, using a click chemistry-based enzymatic labeling system, identified using LC-MS/MS, and searched against an OGP database...
November 15, 2018: Molecular Oncology
Liang Shi, Hui Yan, Shuxian An, Mengqin Shen, Wenzhi Jia, Ruixue Zhang, Li Zhao, Gang Huang, Jianjun Liu
Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD+ to pyruvate, NADH, and H+ . Protons (H+ ) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we identified an important post-translational mechanism by which LDHB is regulated during autophagy in cancer cells. Mass spectrometry revealed that protein sirtuin 5 (SIRT5) is a binding partner of LDHB that deacetylated LDHB at lysine-329, thereby promoting its enzymatic activity...
November 15, 2018: Molecular Oncology
Christiane Klec, Felix Prinz, Martin Pichler
Altered expression levels of the long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) have been reported in different types of cancer. More than half of the NEAT1 studies in cancer have been published within the last two years. In this review we discuss very recent developments and insights into NEAT1 contribution to carcinogenesis. Summarizing the literature, it becomes obvious that NEAT1 is a lncRNA highly de-/ up-regulated in a variety of cancer entities, in which it primarily acts as a competing endogenous RNA (ceRNA) which sponges tumor-suppressive microRNAs (miRNA)...
November 15, 2018: Molecular Oncology
Ying Ma, Danrui Cui, Xiufang Xiong, Hiroyuki Inuzuka, Wenyi Wei, Yi Sun, Brian J North, Yongchao Zhao
The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose...
November 14, 2018: Molecular Oncology
Matheus H Dias, Cecília S Fonseca, Julianna D Zeidler, Layra L Albuquerque, Marcelo S da Silva, Eduardo Lopes-Cararo, Marcelo S Reis, Vincent Noël, Edmilson O Dos Santos, Ian A Prior, Hugo A Armelin
In malignant transformation, cellular stress response pathways are dynamically mobilized to counterbalance oncogenic activity, keeping cancer cells viable. Therapeutic disruption of this vulnerable homeostasis might change the outcome of many human cancers, particularly those for which no effective therapy is available. Here, we report the use of Fibroblast Growth Factor 2 (FGF2) to demonstrate that further mitogenic activation disrupts cellular homeostasis and strongly sensitizes cancer cells to stress-targeted therapeutic inhibitors...
November 13, 2018: Molecular Oncology
Jakub Gemperle, Michal Dibus, Lenka Koudelková, Daniel Rosel, Jan Brábek
Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3-kinase...
November 13, 2018: Molecular Oncology
Xin-Yue Hu, Rong Wang, Jie Jin, Xiu-Jun Liu, A-Long Cui, Lian-Qi Sun, Yan-Ping Li, Yi Li, Yu-Cheng Wang, Yong-Su Zhen, Qing-Fang Miao, Zhuo-Rong Li
Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR-targeted antibody-drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti-EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability...
October 29, 2018: Molecular Oncology
Junyu Cao, Jie Li, Liankang Sun, Tao Qin, Ying Xiao, Ke Chen, Weikun Qian, Wanxing Duan, Jianjun Lei, Jiguang Ma, Qingyong Ma, Liang Han
Pancreatic stellate cells (PSCs), a key component of the tumor microenvironment, contribute to tumor invasion, metastasis, and chemoresistance. Osteopontin (OPN), a phosphorylated glycoprotein, is overexpressed in pancreatic cancer. However, OPN expression in PSCs and its potential roles in tumor-stroma interactions remain unclear. The present study first showed that OPN is highly expressed and secreted in activated PSCs driven by hypoxia, and this process is in a ROS-dependent manner; in addition, OPN was shown to be involved in the PSC-induced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties of pancreatic cancer cells (PCCs)...
October 27, 2018: Molecular Oncology
Tatsuya Kitagawa, Keisuke Taniuchi, Makiko Tsuboi, Masahiko Sakaguchi, Takuhiro Kohsaki, Takehiro Okabayashi, Toshiji Saibara
Diagnostic biomarkers for the early diagnosis of pancreatic cancer are needed to improve prognosis for this disease. The aim of this study was to investigate differences in the expression of four messenger RNAs (mRNAs: CCDC88A, ARF6, Vav3, and WASF2) and five small nucleolar RNAs (snoRNAs: SNORA14B, SNORA18, SNORA25, SNORA74A, and SNORD22) in serum of patients with pancreatic cancer and control participants for use in the diagnosis of pancreatic cancer. Results were compared with the expression of sialylated Lewis (a) blood group antigen CA19-9, the standard clinical tumor biomarker...
October 25, 2018: Molecular Oncology
Cristián Ibarra, Marie Karlsson, Simone Codeluppi, Manuel Varas-Godoy, Songbai Zhang, Lauri Louhivuori, Sara Mangsbo, Arad Hosseini, Navid Soltani, Rahim Kaba, T Kalle Lundgren, Abolfazl Hosseini, Nobuyuki Tanaka, Mototsugu Oya, Peter Wiklund, Ayako Miyakawa, Per Uhlén
Bacillus Calmette-Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting pro-inflammatory cytokines, including interleukin 8 (IL-8)...
October 25, 2018: Molecular Oncology
Jun Hong, Selma Maacha, Abbes Belkhiri
AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c-MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin...
October 23, 2018: Molecular Oncology
Silke Reinartz, Sonja Lieber, Jelena Pesek, Dominique T Brandt, Alina Asafova, Florian Finkernagel, Bernard Watzer, Wolfgang Andreas Nockher, Andrea Nist, Thorsten Stiewe, Julia M Jansen, Uwe Wagner, Anne Konzer, Johannes Graumann, Robert Grosse, Thomas Worzfeld, Sabine Müller-Brüsselbach, Rolf Müller
The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl-LPA species are strongly elevated in ascites versus plasma and are associated with short relapse-free survival. Data derived from transcriptome and secretome analyses of primary ascite-derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2 ) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor-associated macrophages play an essential role as main producers of PLA2 G7 and autotaxin...
October 23, 2018: Molecular Oncology
Dong Ha Kim, Yun Jung Choi, Ki Jung Sung, Seon-A Yoo, Young Hoon Sung, Jeong Kon Kim, Chang-Min Choi, Miyong Yun, Eun Yong Lee, Yong Suk Jin, Seungho Cook, Jin Kyung Rho, Jae Cheol Lee
Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)-mutant lung cancer, which arises due to poor penetration of the brain-blood barrier by EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Although osimertinib, a third-generation EGFR-TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted...
October 23, 2018: Molecular Oncology
Lei You, Huanyu Wang, Gang Yang, Fangyu Zhao, Jingcheng Zhang, Ziwen Liu, Taiping Zhang, Zhiyong Liang, Changzheng Liu, Yupei Zhao
Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non-protein coding) (PVT1) has been reported to be an oncogenic long non-coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased cell growth in PC cells treated with gemcitabine...
October 20, 2018: Molecular Oncology
Harikrishnareddy Paluvai, Eros Di Giorgio, Claudio Brancolini
Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well-known oncogenes. We have discovered that HDAC4-TM, a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (Oncogene-induced senescence)...
October 13, 2018: Molecular Oncology
Leslie Calapre, Tindaro Giardina, Cleo Robinson, Anna L Reid, Zeyad Al-Ogaili, Michelle R Pereira, Ashleigh C McEvoy, Lydia Warburton, Nicholas K Hayward, Muhammad A Khattak, Tarek M Meniawy, Michael Millward, Benhur Amanuel, Melanie Ziman, Elin S Gray
Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for non-invasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA...
October 12, 2018: Molecular Oncology
S Hombach-Klonisch, F Kalantari, R M Medapati, S Natarajan, S N Krishnan, A Kumar-Kanojia, T Thatchawan, F Begum, F Y Xu, G M Hatch, M Los, T Klonisch
PARP1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP1 inhibitors. Expression of HMGA2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA2 and PARP1 in DNA damage-induced PARP1 activity. We used human triple negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA2 colocalizes and interacts with PARP1...
October 5, 2018: Molecular Oncology
Christina Bligaard Pedersen, Finn Cilius Nielsen, Maria Rossing, Lars Rønn Olsen
Breast cancer is a highly heterogeneous disease that can be classified into multiple subtypes based on the tumor transcriptome. Most of the subtyping schemes used in clinics today are derived from analyses of microarray data from thousands of different tumors together with clinical data for the patients from which the tumors were isolated. However, RNA sequencing (RNA-Seq) is gradually replacing microarrays as the preferred transcriptomics platform, and although transcript abundances measured by the two different technologies are largely compatible, subtyping methods developed for probe-based microarray data are incompatible with RNA-Seq as input data...
October 5, 2018: Molecular Oncology
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