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Yvonne de Jong, David Monderer, Emeline Brandinelli, Morgane Monchanin, Brendy E van den Akker, Jolieke G van Oosterwijk, Jean Yves Blay, Aurélie Dutour, Judith V M G Bovée
Chondrosarcomas are malignant cartilage tumors showing relative resistance to conventional chemo- and radiotherapy. Previous studies showed that chondrosarcoma cells could be sensitized to chemotherapy by inhibiting the Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w using ABT-737. In this study we explored the specific role of Bcl-2 family members to identify the most important player in chondrosarcoma cell survival and chemo resistance. Immunohistochemistry was performed on tissue microarrays containing 137 conventional chondrosarcomas of different grades...
September 21, 2018: Oncogenesis
Stefanie Tiede, Nathalie Meyer-Schaller, Ravi Kiran Reddy Kalathur, Robert Ivanek, Ernesta Fagiani, Philip Schmassmann, Patrick Stillhard, Simon Häfliger, Norbert Kraut, Norbert Schweifer, Irene C Waizenegger, Ruben Bill, Gerhard Christofori
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that regulates a plethora of downstream signaling pathways essential for cell migration, proliferation and death, processes that are exploited by cancer cells during malignant progression. These well-established tumorigenic activities, together with its high expression and activity in different cancer types, highlight FAK as an attractive target for cancer therapy. We have assessed and characterized the therapeutic potential and the biological effects of BI 853520, a novel small chemical inhibitor of FAK, in several preclinical mouse models of breast cancer...
September 20, 2018: Oncogenesis
Mal Irvine, Ashleigh Stewart, Bernadette Pedersen, Suzanah Boyd, Richard Kefford, Helen Rizos
Nearly all patients with BRAF-mutant melanoma will progress on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy within the first year of therapy. In the vast majority of progressing melanomas, resistance occurs via the re-activation of MAPK signalling, commonly via alterations in BRAF, NRAS and MEK1/2. A small proportion of resistant melanomas rely on the activation of the compensatory PI3K/AKT signalling cascade, although activation of this pathway does not preclude patient responses to BRAF/MEK inhibition...
September 20, 2018: Oncogenesis
Johannes Grimm, Anita Hufnagel, Marion Wobser, Andreas Borst, Sebastian Haferkamp, Roland Houben, Svenja Meierjohann
Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e...
September 20, 2018: Oncogenesis
A'dem Bokhari, Vincent Jonchere, Anaïs Lagrange, Romane Bertrand, Magali Svrcek, Laetitia Marisa, Olivier Buhard, Malorie Greene, Anastasia Demidova, Jieshuang Jia, Eric Adriaenssens, Thierry Chassat, Denis S Biard, Jean-François Flejou, Fabrice Lejeune, Alex Duval, Ada Collura
Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7...
September 19, 2018: Oncogenesis
Hongbo Fang, Kaifeng Niu, Dongliang Mo, Yuqi Zhu, Qunsong Tan, Di Wei, Yueyang Li, Zixiang Chen, Shuchen Yang, Adayabalam S Balajee, Yongliang Zhao
Human RecQL4 helicase plays critical roles in the maintenance of genomic stability. Mutations in RecQL4 helicase results in three clinically related autosomal recessive disorders: Rothmund-Thomson syndrome (RTS), RAPADILINO, and Baller-Gerold syndrome. In addition to several premature aging features, RTS patients are characterized by aneuploidy involving either loss or gain of a single chromosome. Chromosome mosaicism and isochromosomes involving chromosomes 2, 7, and 8 have been reported in RecQL4-deficient RTS patients, but the precise role of RecQL4 in chromosome segregation/stability remains to be elucidated...
September 12, 2018: Oncogenesis
Jamie L King, Baotong Zhang, Yixiang Li, Kathy P Li, Jianping J Ni, Harold I Saavedra, Jin-Tang Dong
Abnormal expression of TTK kinase has been associated with the initiation, progression, and therapeutic resistance of breast and other cancers, but its roles remain to be clarified. In this study, we examined the role of TTK in triple negative breast cancer (TNBC), and found that higher TTK expression correlated with mesenchymal and proliferative phenotypes in TNBC cells. Pharmacologic inhibition and genomic silencing of TTK not only reversed the epithelial-to-mesenchymal transition (EMT) in TNBC cells, but also increased the expression of KLF5, an effector of TGF-β signaling and inhibitor of EMT...
September 12, 2018: Oncogenesis
Lin Lin, Dapeng Ding, Yanmei Jiang, Yan Li, Shijun Li
Mutations in BRAF are common to many cancers, including CRC. The MEK inhibitors are being investigated in BRAF-mutant CRC. In this study, we aimed to investigate how MEK inhibitor suppresses growth of BRAF-mutated CRC cells as well as its potential mechanisms. Our findings indicated that MEK inhibitor promote PUMA expression via ERK/FoxO3a signaling pathway. In addition, PUMA induction is essential for MEK inhibitor-induced apoptosis. Moreover, PUMA induction is required for MEK inhibitors to induced apoptosis in combination with cisplatin, dabrafenib, or Gefitinib...
September 7, 2018: Oncogenesis
Viktor Brovkovych, Yasir Izhar, Jeanne M Danes, Oleskii Dubrovskyi, Isin T Sakallioglu, Lauren M Morrow, G Ekin Atilla-Gokcumen, Jonna Frasor
Given the dependence of cancers on de novo lipogenesis, we tested the effect of fatostatin, a small molecule thought to target this pathway by blocking activation of SREBP transcription factors, in breast cancer cell lines and xenograft tumors. We found that estrogen receptor (ER) positive cells were more sensitive to fatostatin than ER negative cells and responded with cell cycle arrest and apoptosis. Surprisingly, we found that rather than inhibiting lipogenesis, fatostatin caused an accumulation of lipids as a response to endoplasmic reticulum stress rather than inhibition of SREBP activity...
August 24, 2018: Oncogenesis
Veronica Gatti, Claudia Fierro, Mirco Compagnone, Federica Giangrazi, Elke Katrin Markert, Lucilla Bongiorno-Borbone, Gerry Melino, Angelo Peschiaroli
Triple negative breast cancers (TNBC) represent the most aggressive and clinically relevant breast carcinomas. On the basis of specific molecular signature, the majority of TNBC can be classified as basal-like breast carcinoma. Here, we report data showing that in basal-like breast carcinoma cells ΔNp63 is capable of sustaining the production of the hyaluronic acid (HA), one of the major component of the extracellular matrix (ECM). At molecular level, we found that ΔNp63 regulates the expression of HA-related genes, such as the HA synthase HAS3, the hyaluronidase HYAL-1 and CD44, the major HA cell membrane receptor...
August 24, 2018: Oncogenesis
Eric Dietel, Alexander Brobeil, Claudia Tag, Stefan Gattenloehner, Monika Wimmer
Breast cancer is the most common female cancerous disease and the second most cause of cancer death in women. About 20-30% of these tumors exhibit an amplification of the HER2/ErbB2 receptor, which is coupled to a more aggressive and invasive growth of the cancer cells. Recently developed tyrosine kinase inhibitors and therapeutic antibodies targeting the HER2 receptor improved the overall survival time compared with sole radio- and chemotherapy. Upcoming resistances against the HER2-targeted therapy make a better understanding of the receptor associated downstream pathways an absolute need...
August 24, 2018: Oncogenesis
Zehua Bian, Jiwei Zhang, Min Li, Yuyang Feng, Surui Yao, Mingxun Song, Xiaowei Qi, Bojian Fei, Yuan Yin, Dong Hua, Zhaohui Huang
This article was originally published under Nature Research's License to Publish, but now has been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
August 16, 2018: Oncogenesis
Qianqian He, Bijin Au, Madhura Kulkarni, Yang Shen, Kah J Lim, Jiamila Maimaiti, Cheng Kit Wong, Monique N H Luijten, Han C Chong, Elaine H Lim, Giulia Rancati, Indrajit Sinha, Zhiyan Fu, Xiaomeng Wang, John E Connolly, Karen C Crasta
Chromosomal instability (CIN), a high rate of chromosome loss or gain, is often associated with poor prognosis and drug resistance in cancers. Aneuploid, including near-polyploid, cells contain an abnormal number of chromosomes and exhibit CIN. The post-mitotic cell fates following generation of different degrees of chromosome mis-segregation and aneuploidy are unclear. Here we used aneuploidy inducers, nocodazole and reversine, to create different levels of aneuploidy. A higher extent of aneuploid and near-polyploid cells in a given population led to senescence...
August 15, 2018: Oncogenesis
Jianming Tang, Guansheng Zhong, Jianhui Wu, Haiyan Chen, Yongshi Jia
SOX2 is a transcription factor that contributes to transcription modification and cancer, but the mechanism by which SOX2 regulates nasopharyngeal carcinoma cell proliferation is not well understood. Here, we identify a SOX2 signaling pathway that facilitates nasopharyngeal carcinoma, where it is upregulated. SOX2 expression was associated with nasopharyngeal carcinoma patient survival. SOX2 knockdown inhibited cell proliferation, colony formation, and tumorigenesis in an subcutaneous mouse xenograft model system...
August 15, 2018: Oncogenesis
Salsabiel El Nagar, Almahdi Chakroun, Coralie Le Greneur, Dominique Figarella-Branger, Thomas Di Meglio, Thomas Lamonerie, Nathalie Billon
The developmental gene OTX2 is expressed by cerebellar granule cell precursors (GCPs), a cell population which undergoes massive expansion during the early postnatal period in response to sonic hedgehog (Shh). GCPs are thought to be at the origin of most medulloblastomas, a devastating paediatric cancer that arises in the developing cerebellum. OTX2 is overexpressed in all types of medulloblastomas, except in Shh-dependent type 2 medulloblastomas, although it has GCPs as cell-of-origin. This has led to the current view that OTX2 is not involved in tumorigenesis of this subgroup...
August 13, 2018: Oncogenesis
Hao-Yu Lin, Yuan-Ke Liang, Xiao-Wei Dou, Chun-Fa Chen, Xiao-Long Wei, De Zeng, Jing-Wen Bai, Yu-Xian Guo, Fang-Fang Lin, Wen-He Huang, Cai-Wen Du, Yao-Chen Li, Min Chen, Guo-Jun Zhang
Notch3 and GATA binding protein 3 (GATA-3) have been, individually, shown to maintain luminal phenotype and inhibit epithelial-mesenchymal transition (EMT) in breast cancers. In the present study, we report that Notch3 expression positively correlates with that of GATA-3, and both are associated with estrogen receptor-α (ERα) expression in breast cancer cells. We demonstrate in vitro and in vivo that Notch3 suppressed EMT and breast cancer metastasis by activating GATA-3 transcription. Furthermore, Notch3 knockdown downregulated GATA-3 and promoted EMT; while overexpression of Notch3 intracellular domain upregulated GATA-3 and inhibited EMT, leading to a suppression of metastasis in vivo...
August 13, 2018: Oncogenesis
Ji Hye Shin, Chang Wook Park, Gyesoon Yoon, Sun Mi Hong, Kwan Yong Choi
Nicotinamide N-methyl transferase (NNMT) transfers a methyl group from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM), producing 1-methylnicotinamide (1MNA). NNMT has been implicated in several cancer types and recently in metabolism, but its role in autophagy regulation has not yet been investigated. In this study, we determined that NNMT negatively regulated autophagy at the stage of ULK1 activation through protein phosphatase 2A (PP2A) activity. Specifically, NNMT knockdown increased PP2A methylation and subsequently enhanced phosphatase activity...
August 10, 2018: Oncogenesis
Xiangfei Wang, Xiumin Wang, Yang Liu, Yating Dong, Yanan Wang, Muzaffer Ahmad Kassab, Wufang Fan, Xiaochun Yu, Chen Wu
LGR5 plays a critical role in tissue development and the maintenance of adult stem cells in gastrointestinal tract. However, the oncogenic role of LGR5 in the development of gastric adenocarcinoma remains elusive. Here, we show that LGR5 promotes gastric adenocarcinoma cell proliferation and metastasis. We find that knock down of LGR5 or suppression of Wnt signaling pathway by inhibitor C59 arrests gastric adenocarcinoma cell proliferation and invasion. Moreover, treatment of Wnt3a, the activator of Wnt signaling pathway, partially recovers the proliferation defect observed in LGR5 knockdown gastric adenocarcinoma cells...
August 9, 2018: Oncogenesis
Imerio Angriman, Lucrezia Furian, Melania Scarpa, Matteo Fassan, Susan Morgan, Andrea Porzionato, Andromachi Kotsafti, Luca Saadeh, Cristina Silvestre, Raffaele De Caro, Amedeo Carraro, Umberto Tedeschi, Romeo Bardini, Paolo Rigotti, Massimo Rugge, Carlo Castoro, Ignazio Castagliuolo, Marco Scarpa
At the time of publication, the html version of this paper contained an error; the authors Imerio Angriman and Lucrezia Furian were not tagged as equally contributing authors. This has now been fixed in the html version of the paper, the PDF was correct at the time of publication.
July 31, 2018: Oncogenesis
Bo Wang, Dongping Li, Jody Filkowski, Rocio Rodriguez-Juarez, Quinn Storozynsky, Megan Malach, Emily Carpenter, Olga Kovalchuk
Antiestrogen resistance is a major challenge encountered during the treatment of estrogen receptor alpha positive (ERα+ ) breast cancer. A better understanding of signaling pathways and downstream transcription factors and their targets may identify key molecules that can overcome antiestrogen resistance in breast cancer. An aberrant expression of miR-22 has been demonstrated in breast cancer; however, its contribution to breast cancer resistance to fulvestrant, an antiestrogen drug, remains unknown. In this study, we demonstrated a moderate elevation in miR-22 expression in the 182R -6 fulvestrant-resistant breast cancer line we used as a model system, and this elevation was positively correlated with the expression of the miRNA biogenesis enzymes AGO2 and Dicer...
July 30, 2018: Oncogenesis
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