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Oncogene

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https://www.readbyqxmd.com/read/27893719/novel-kdm1a-inhibitors-induce-differentiation-and-apoptosis-of-glioma-stem-cells-via-unfolded-protein-response-pathway
#1
G R Sareddy, S Viswanadhapalli, P Surapaneni, T Suzuki, A Brenner, R K Vadlamudi
Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893718/foxo3-is-essential-for-cd44-expression-in-pancreatic-cancer-cells
#2
M Kumazoe, M Takai, J Bae, S Hiroi, Y Huang, K Takamatsu, Y Won, M Yamashita, S Hidaka, S Yamashita, S Yamada, M Murata, S Tsukamoto, H Tachibana
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer and the 5-year survival rate is only 5%. Several studies have suggested that cancer stem cells (CSCs) are thought to be involved in recurrence and metastasis and so it is essential to establish an approach targeting CSCs. Here we have demonstrated that cyclic guanosine monophosphate (cGMP) suppressed CD44 expression and the properties of CSCs in PDAC. Microarray analysis suggested that cGMP inhibited Forkhead box O3 (FOXO3), which is known as a tumor suppressor...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893717/androgen-and-ar-contribute-to-breast-cancer-development-and-metastasis-an-insight-of-mechanisms
#3
J Feng, L Li, N Zhang, J Liu, L Zhang, H Gao, G Wang, Y Li, Y Zhang, X Li, D Liu, J Lu, B Huang
The role of androgen and androgen receptor (AR) in breast carcinogenesis has long been a disputed issue. This report provides a mechanistic insight into how androgen and AR contributes to invasion and metastasis of breast cancer. We find that dihydrotestosterone (DHT) is able to induce the epithelial-to-mesenchymal transition in breast cancer cells in an AR-dependent/estrogen receptor-independent manner. This process is dependent on the demethylation activity of lysine-specific demethylase 1A (LSD1) by epigenetically regulating the target genes E-cadherin and vimentin...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893716/hic-5-remodeling-of-the-stromal-matrix-promotes-breast-tumor-progression
#4
G J Goreczny, J L Ouderkirk-Pecone, E C Olson, M Krendel, C E Turner
The remodeling of the stromal extracellular matrix (ECM) has a crucial, but incompletely understood role during tumor progression and metastasis. Hic-5, a focal adhesion scaffold protein, has previously been implicated in tumor cell invasion, proliferation and metastasis. To investigate the role of Hic-5 in breast tumor progression in vivo, Hic-5(-/-) mice were generated and crossed with the Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen mouse. Tumors from the Hic-5(-/-);PyMT mice exhibited increased latency and reduced growth, with fewer lung metastases, as compared with Hic-5(+/-);PyMT mice...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893715/tgf%C3%AE-promotes-mesenchymal-phenotype-of-pancreatic-cancer-cells-in-part-through-epigenetic-activation-of-vav1
#5
P-H Huang, P-J Lu, L-Y Ding, P-C Chu, W-Y Hsu, C-S Chen, C-C Tsao, B-H Chen, C-T Lee, Y-S Shan, C-S Chen
The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893714/the-lim-protein-ajuba-promotes-colorectal-cancer-cell-survival-through-suppression-of-jak1-stat1-ifit2-network
#6
H Jia, L Song, Q Cong, J Wang, H Xu, Y Chu, Q Li, Y Zhang, X Zou, C Zhang, Y E Chin, X Zhang, Z Li, K Zhu, B Wang, H Peng, Z Hou
The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893713/phosphorylation-of-nfat3-by-cdk3-induces-cell-transformation-and-promotes-tumor-growth-in-skin-cancer
#7
T Xiao, J J Zhu, S Huang, C Peng, S He, J Du, R Hong, X Chen, A M Bode, W Jiang, Z Dong, D Zheng
The nuclear factor of activated T cells (NFAT) family proteins are transcription factors that regulate the expression of pro-inflammatory cytokines and other genes during the immune response. Although the NFAT proteins have been extensively investigated in the immune system, their role in cancer progression remains controversial. Here, we report that NFAT3 is highly expressed in various skin cancer cell lines and tumor tissues. Knockdown of endogenous NFAT3 expression by short hairpin RNA (shRNA) significantly inhibited tumor cell proliferation, colony formation and anchorage-independent cell growth...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893712/blood-vessel-endothelium-directed-tumor-cell-streaming-in-breast-tumors-requires-the-hgf-c-met-signaling-pathway
#8
E Leung, A Xue, Y Wang, P Rougerie, V P Sharma, R Eddy, D Cox, J Condeelis
During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893711/the-induction-of-mig6-under-hypoxic-conditions-is-critical-for-dormancy-in-primary-cultured-lung-cancer-cells-with-activating-egfr-mutations
#9
H Endo, J Okami, H Okuyama, Y Nishizawa, F Imamura, M Inoue
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893710/muc1-c-activates-bmi1-in-human-cancer-cells
#10
M Hiraki, T Maeda, A Bouillez, M Alam, A Tagde, K Hinohara, Y Suzuki, T Markert, M Miyo, K Komura, R Ahmad, H Rajabi, D Kufe
B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893709/identification-of-myst3-as-a-novel-epigenetic-activator-of-er%C3%AE-frequently-amplified-in-breast-cancer
#11
L Yu, Y Liang, X Cao, X Wang, H Gao, S-Y Lin, R Schiff, X-S Wang, K Li
Estrogen receptor α (ERα) is a master driver of a vast majority of breast cancers. Breast cancer cells often develop resistance to endocrine therapy via restoration of the ERα activity through survival pathways. Thus identifying the epigenetic activator of ERα that can be targeted to block ERα gene expression is a critical topic of endocrine therapy. Here, integrative genomic analysis identified MYST3 as a potential oncogene target that is frequently amplified in breast cancer. MYST3 is involved in histone acetylation via its histone acetyltransferase domain (HAT) and, as a result, activates gene expression by altering chromatin structure...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893708/tgf-%C3%AE-upregulates-the-translation-of-usp15-via-the-pi3k-akt-pathway-to-promote-p53-stability
#12
W-T Liu, K-Y Huang, M-C Lu, H-L Huang, C-Y Chen, Y-L Cheng, H-C Yu, S-Q Liu, N-S Lai, H-B Huang
Crosstalk between transforming growth factor beta (TGF-β) signaling and p53 has a critical role in cancer progression. TGF-β signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-β signaling. However, it remains unknown whether p53 stability is regulated by TGF-β...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893707/blockade-of-the-il-6-trans-signalling-stat3-axis-suppresses-cachexia-in-kras-induced-lung-adenocarcinoma
#13
A Miller, L McLeod, S Alhayyani, A Szczepny, D N Watkins, W Chen, P Enriori, W Ferlin, S Ruwanpura, B J Jenkins
Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130(F/F) knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893706/microrna-383-located-in-frequently-deleted-chromosomal-locus-8p22-regulates-cd44-in-prostate-cancer
#14
N Bucay, K Sekhon, T Yang, S Majid, V Shahryari, C Hsieh, Y Mitsui, G Deng, Z L Tabatabai, S Yamamura, G A Calin, R Dahiya, Y Tanaka, S Saini
A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27869172/a-redox-state-dictated-signalling-pathway-deciphers-the-malignant-cell-specificity-of-cd40-mediated-apoptosis
#15
C J Dunnill, K Ibraheem, A Mohamed, J Southgate, N T Georgopoulos
CD40, a member of the tumour necrosis factor receptor (TNFR) superfamily, has the capacity to cause extensive apoptosis in carcinoma cells, while sparing normal epithelial cells. Yet, apoptosis is only achieved by membrane-presented CD40 ligand (mCD40L), as soluble receptor agonists are but weakly pro-apoptotic. Here, for the first time we have identified the precise signalling cascade underpinning mCD40L-mediated death as involving sequential TRAF3 stabilisation, ASK1 phosphorylation, MKK4 (but not MKK7) activation and JNK/AP-1 induction, leading to a Bak- and Bax-dependent mitochondrial apoptosis pathway...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869171/epigenetic-activation-of-the-prostaglandin-receptor-ep4-promotes-resistance-to-endocrine-therapy-for-breast-cancer
#16
J F Hiken, J I McDonald, K F Decker, C Sanchez, J Hoog, N D VanderKraats, K L Jung, M Akinhanmi, L E Rois, M J Ellis, J R Edwards
Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869170/androgen-receptor-promotes-melanoma-metastasis-via-altering-the-mirna-539-3p-usp13-mitf-axl-signals
#17
Y Wang, Z Ou, Y Sun, S Yeh, X Wang, J Long, C Chang
Early studies demonstrated that male melanoma patients have worse survival than female patients, yet the detailed mechanisms for this gender difference remain unclear. We analyzed around 100 cases of human melanoma and found that androgen receptor (AR) positive melanoma patients have worse survival outcomes compared with AR-negative melanoma patients. Here we report that AR can have positive roles to increase melanoma cell invasion in multiple cell lines in vitro and a mouse model in vivo. Mechanism dissection suggest that AR increases melanoma cell invasion via modulating the MITF-AXL signals via altering the miRNA-539-3p/USP13 signaling to increase MITF protein degradation through a reduction of de-ubiquitination...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869169/critical-role-of-the-pot1-ob-domain-in-maintaining-genomic-stability
#18
T K Pandita
Oligonucleotide/oligosaccharide-binding (OB) domain-containing proteins have been identified as critical for telomere maintenance, DNA repair, transcription and other DNA metabolism processes. Protection of telomere 1 (POT1), a telomere binding protein, has an OB domain like single-strand binding protein (SSB1). In this issue of Oncogene, Gu et al. present evidence that POT1, like SSB1, is required to maintain genomic stability. This work, in conjunction with results from previous investigators, highlights the importance of POT1 in telomere metabolism...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869168/mir-127-promotes-emt-and-stem-like-traits-in-lung-cancer-through-a-feed-forward-regulatory-loop
#19
L Shi, Y Wang, Z Lu, H Zhang, N Zhuang, B Wang, Z Song, G Chen, C Huang, D Xu, Y Zhang, W Zhang, Y Gao
The coordination between cellular differentiation and the mesenchymal/stem transition is essential for both embryo development and neoplasia, suggesting a mechanistic link between these two major processes. In this work we show that miR-127, an embryo-expressing lung miRNA, was prominently induced in lung adenocarcinoma and correlated with poor prognosis. Elevated miR-127 level drove a pronounced shift from the epithelial to the mesenchymal phenotype in cancer cells, and this shift was associated with their acquisition of stem-like traits, increased resistance to the epidermal growth factor receptor inhibitor and tumor-propagating potential...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27869167/cystine-addiction-of-triple-negative-breast-cancer-associated-with-emt-augmented-death-signaling
#20
X Tang, C-K Ding, J Wu, J Sjol, S Wardell, I Spasojevic, D George, D P McDonnell, D S Hsu, J T Chang, J-T Chi
Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable...
November 21, 2016: Oncogene
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