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B Boulianne, N Feldhahn
Transcription is an essential process in all living cells. However, transcription also sensitises genomic DNA to damage from a number of endogenous sources. Although various mechanisms protect the integrity of DNA during transcription, transcription-associated genomic instability occurs in normal and malignant cells and, if unrepaired, can result in genomic alterations. Numerous studies have implicated genomic alterations found in cancer genomes to transcription. Hence, transcription-associated genomic instability can be considered as a major driver of cancer development...
November 6, 2017: Oncogene
Y Zhou, L Wang, X Ban, T Zeng, Y Zhu, M Li, X-Y Guan, Y Li
Esophageal squamous cell carcinoma (ESCC) is highly prevailing in Asia and it is ranked in the most aggressive squamous cell carcinomas. High-frequency loss of heterozygosity occurred in chromosome 14q11.2 in many tumors including ESCC, suggesting that one or more tumor-suppressor genes might exist within this region. In this study, we identified the tumor-suppressing role of DHRS2 (short-chain dehydrogenase/reductase family, member 2) at 14q11.2 in ESCCs. Downregulation of DHRS2 occurred in 30.8% of primary ESCC tumor tissues vs paired non-tumorous tissues...
November 6, 2017: Oncogene
Y Li, M Zhao, C Guo, H Chu, W Li, X Chen, X Wang, Y Li, Y Jia, S Koussatidjoa, F Zhu, J Wang, X Wang, Q Wang, W Zhao, Y Shi, W Chen, L Zhang
IL-37, a newly found anti-inflammatory cytokine of the IL-1 family, has both extracellular and intracellular functions. Accumulating evidences indicate that it is also involved in tumor progression. However, the mechanism and its intracellular target are unclear. In this study, clinical data from 84 patients showed that loss or reduced expression of IL-37 in lung adenocarcinoma tissues was significantly associated with tumor metastasis. We further provided evidence that IL-37 inhibited effectively tumor metastasis in vitro and in vivo...
November 6, 2017: Oncogene
S H Song, M S Jeon, J W Nam, J K Kang, Y J Lee, J Y Kang, H P Kim, S W Han, G H Kang, T Y Kim
Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6...
November 6, 2017: Oncogene
F Peng, J-H Wang, W-J Fan, Y-T Meng, M-M Li, T-T Li, B Cui, H-F Wang, Y Zhao, F An, T Guo, X-F Liu, L Zhang, L Lv, D-K Lv, L-Z Xu, J-J Xie, W-X Lin, E W-F Lam, J Xu, Q Liu
Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH(+) subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival...
November 6, 2017: Oncogene
M Qi, M Jiao, X Li, J Hu, L Wang, Y Zou, M Zhao, R Zhang, H Liu, J Mi, L Zhang, L Liu, Y Gong, B Han
Cullin 4B (CUL4B) is a scaffold protein overexpressed in several solid malignancies. It is known to silence tumor suppressor through post-transcriptional manner. However, its clinical significance and underlying molecular mechanisms in gastric cancer (GC) remain largely unknown. In this study, we found that CUL4B was significantly overexpressed in GC tissues and its overexpression was correlated with lymph node metastasis and poor prognosis. Through gain- and loss-of-function experiments, we showed that CUL4B promotes GC cell invasion and epithelial-mesenchymal transition (EMT) in vitro, as well as tumor growth and metastasis in vivo...
November 6, 2017: Oncogene
T Monteverde, J Tait-Mulder, A Hedley, J R Knight, O J Sansom, D J Murphy
NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1...
November 6, 2017: Oncogene
S-J Zhao, Y-Q Jiang, N-W Xu, Q Li, Q Zhang, S-Y Wang, J Li, Y-H Wang, Y-L Zhang, S-H Jiang, Y-J Wang, Y-J Huang, X-X Zhang, G-A Tian, C-C Zhang, Y-Y Lv, M Dai, F Liu, R Zhang, D Zhou, Z-G Zhang
Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/β-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT-receptor complex stabilization...
October 30, 2017: Oncogene
E M Langer, N D Kendsersky, C J Daniel, G M Kuziel, C Pelz, K M Murphy, M R Capecchi, R C Sears
During normal tumor growth and in response to some therapies, tumor cells experience acute or chronic deprivation of nutrients and oxygen and induce tumor vascularization. While this occurs predominately through sprouting angiogenesis, tumor cells have also been shown to directly contribute to vessel formation through vascular mimicry (VM) and/or endothelial transdifferentiation. The extrinsic and intrinsic mechanisms underlying tumor cell adoption of endothelial phenotypes, however, are not well understood...
October 30, 2017: Oncogene
A L Schroyer, N W Stimes, W F Abi Saab, D N Chadee
Mixed lineage kinase 3 (MLK3) functions in migration and/or invasion of several human cancers; however, the role of MLK3 in colorectal cancer (CRC) invasion is unknown. MLK3 is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) which activates MAPK pathways through either kinase-dependent or -independent mechanisms. Human colorectal tumors display increased levels of reactive oxygen species (ROS) or oxidative stress. ROS, such as H2O2, are important for carcinogenesis and activate MAPK signaling pathways...
October 30, 2017: Oncogene
L Knopfová, E Biglieri, N Volodko, M Masařík, M Hermanová, J F Glaus Garzón, M Dúcka, T Kučírková, K Souček, J Šmarda, P Beneš, L Borsig
Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels...
October 30, 2017: Oncogene
D Ma, X Chen, P-Y Zhang, H Zhang, L-J Wei, S Hu, J-Z Tang, M-T Zhou, C Xie, R Ou, Y Xu, K-F Tang
Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumors; however, the mechanisms responsible for DR-mediated antitumor effects have not been unequivocally identified. Here, we report that DR suppresses xenograft tumor growth by upregulating a novel signaling pathway. DR led to upregulated aldolase A (ALDOA) expression in xenograft tumors. ALDOA physically interacted with the catalytic subunit of DNA-dependent protein kinase (DNA-PK) and promoted DNA-PK activation. Activated DNA-PK phosphorylated p53 and increased its activity...
October 30, 2017: Oncogene
T Mitamura, S Pradeep, M McGuire, S Y Wu, S Ma, H Hatakeyama, Y A Lyons, T Hisamatsu, K Noh, A Villar-Prados, X Chen, C Ivan, C Rodriguez-Aguayo, W Hu, G Lopez-Berestein, R L Coleman, A K Sood
Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors...
October 23, 2017: Oncogene
A J Lucanus, G W Yip
Breast cancer pathobiology is known to be influenced by the differential expression of a group of proteins called the kinesin superfamily (KIFs), which is instrumental in the intracellular transport of chromosomes along microtubules during mitosis. During cellular division, kinesins are strictly regulated through temporal synthesis so that they are present only when needed. However, their misregulation may contribute to uncontrolled cell growth owing to premature sister chromatid separation, highlighting their importance in cancer...
October 23, 2017: Oncogene
H Zhou, Y Qin, S Ji, J Ling, J Fu, Z Zhuang, X Fan, L Song, X Yu, P J Chiao
SRY (sex determining region Y)-box 9 (SOX9) is required for oncogenic Kras-mediated acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasias (PanINs) and ultimately pancreatic ductal adenocarcinoma (PDAC). However, how oncogenic Kras affects SOX9 activity is not yet understood, and SOX9-associated genes in PDAC are also unknown at all. Here, we investigated the mechanistic link between SOX9 and oncogenic Kras, studied biological function of SOX9, and identified SOX9-related genes and their clinical significance in patients with PDAC...
October 23, 2017: Oncogene
F Shi, L Shang, L-Y Yang, Y-Y Jiang, X-M Wang, J-J Hao, Y Zhang, D-K Huang, Y Cai, X Xu, Q-M Zhan, X-M Jia, Y Cao, M-R Wang
Neuropilin-1 (NRP1) is a non-kinase receptor recently implicated in tumor progression. Here we revealed that over-expression of NRP1 correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). NRP1-knockdown suppressed ESCC cell proliferation and xenograft tumor growth. Reduced NRP1 expression downregulated P65 mRNA and protein expression, and ectopic expression of P65-restored cell proliferation in NRP1-silenced cells. NRP1 regulates P65 transcription by activating cAMP responsive element binding protein (CREB)...
October 23, 2017: Oncogene
D Araiza-Olivera, Y Feng, G Semenova, T Y Prudnikova, J Rhodes, J Chernoff
Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1...
October 23, 2017: Oncogene
Y Liu, H Zhou, R Zhu, F Ding, Y Li, X Cao, Z Liu
Epithelial-mesenchymal transition (EMT) is a process during which normal epithelial cells acquire mesenchymal characteristics. EMT has a critical role in various human diseases especially in cancer. EMT facilitates tumor initiation and progression by mediating cancer cell stemness and motility. Zinc finger transcription factor SNAIL is one of the most important initiators of EMT. Therefore, it is of great significance to understand the regulating mechanism of SNAIL. In this study, we carried out a luciferase-based genome-wide screening using small interfering RNA library against ~200 of E3 ligases and ubiquitin-related genes and identified SOCS box protein SPSB3 as a novel E3 ligase component that targets SNAIL into polyubiquitination and degradation in response to GSK-3β phosphorylation of SNAIL...
October 23, 2017: Oncogene
E Cuyàs, S Fernández-Arroyo, S Verdura, R Á-F García, J Stursa, L Werner, E Blanco-González, M Montes-Bayón, J Joven, B Viollet, J Neuzil, J A Menendez
The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity...
October 23, 2017: Oncogene
Q Heydt, C Larrue, E Saland, S Bertoli, J-E Sarry, A Besson, S Manenti, C Joffre, V Mansat-De Mas
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines...
October 23, 2017: Oncogene
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