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https://www.readbyqxmd.com/read/28339459/functional-classification-of-dna-variants-by-hybrid-minigenes-identification-of-30-spliceogenic-variants-of-brca2-exons-17-and-18
#1
Eugenia Fraile-Bethencourt, Beatriz Díez-Gómez, Valeria Velásquez-Zapata, Alberto Acedo, David J Sanz, Eladio A Velasco
Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants...
March 24, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28334900/cdk12-regulates-alternative-last-exon-mrna-splicing-and-promotes-breast-cancer-cell-invasion
#2
Jerry F Tien, Alborz Mazloomian, S-W Grace Cheng, Christopher S Hughes, Christalle C T Chow, Leanna T Canapi, Arusha Oloumi, Genny Trigo-Gonzalez, Ali Bashashati, James Xu, Vicky C-D Chang, Sohrab P Shah, Samuel Aparicio, Gregg B Morin
CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334867/the-silent-mutation-mlh1-c-543c-t-resulting-in-aberrant-splicing-can-cause-lynch-syndrome-a-case-report
#3
Tatsuro Yamaguchi, Tomokazu Wakatsuki, Mari Kikuchi, Shin-Ichiro Horiguchi, Kiwamu Akagi
The proband was a 67-year-old man with transverse and sigmoid colon cancer. Microsatellite instability analysis revealed a high frequency of microsatellite instability, and immunohistochemical staining showed the absence of both MLH1 and PMS2 proteins in the sigmoid colon cancer tissue specimens from the patient. DNA sequencing revealed a nucleotide substitution c.543C>T in MLH1, but this variant did not substitute an amino acid. The MLH1 c.543C>T variant was located 3 bases upstream from the end of exon 6 and created a new splice donor site 4 bases upstream from the end of exon 6...
March 1, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28334074/genome-wide-analysis-reveals-that-exon-methylation-facilitates-its-selective-usage-in-the-human-transcriptome
#4
Shengli Li, Jiwei Zhang, Shenglin Huang, Xianghuo He
DNA methylation, especially in promoter regions, is a well-characterized epigenetic marker related to gene expression regulation in eukaryotes. However, the role of intragenic DNA methylation in the usage of corresponding exons still remains elusive. In this study, we described the DNA methylome across 10 human tissues. The human genome showed both conserved and varied methylation levels among these tissues. We found that the methylation densities in promoters and first exons were negatively correlated with the corresponding gene expression level...
February 16, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28330331/identification-and-quantification-of-novel-rna-isoforms-in-horn-cancer-of-bos-indicus-by-comprehensive-rna-seq
#5
Subhash J Jakhesara, Prakash G Koringa, Neelam M Nathani, Chaitanya G Joshi
Horn cancer (HC) is a squamous cell carcinoma of horn, commonly observed in Bos indicus of the Asian countries. To elucidate the complexity of alternative splicing present in the HC, high-throughput sequencing and analysis of HC and matching horn normal (HN) tissue were carried out. A total of 535,067 and 849,077 reads were analysed after stringent quality filtering for HN and HC, respectively. Cufflinks pipeline for transcriptome analysis revealed 4786 novel splice isoforms comprising 2432 exclusively in HC, 2055 exclusively in HN and 298 in both the conditions...
December 2016: 3 Biotech
https://www.readbyqxmd.com/read/28326306/cd44-a-multifunctional-cell-surface-adhesion-receptor-is-a-regulator-of-progression-and-metastasis-of-cancer-cells
#6
REVIEW
Linda T Senbanjo, Meenakshi A Chellaiah
CD44 is a cell surface adhesion receptor that is highly expressed in many cancers and regulates metastasis via recruitment of CD44 to the cell surface. Its interaction with appropriate extracellular matrix ligands promotes the migration and invasion processes involved in metastases. It was originally identified as a receptor for hyaluronan or hyaluronic acid and later to several other ligands including, osteopontin (OPN), collagens, and matrix metalloproteinases. CD44 has also been identified as a marker for stem cells of several types...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28324225/spectrum-of-genetic-variants-of-brca1-and-brca2-in-a-german-single-center-study
#7
Cornelia Meisel, Carolin Eva Sadowski, Daniela Kohlstedt, Katja Keller, Franziska Stäritz, Nannette Grübling, Kerstin Becker, Luisa Mackenroth, Andreas Rump, Evelin Schröck, Norbert Arnold, Pauline Wimberger, Karin Kast
BACKGROUND: Determination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants. METHODS: In families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC...
March 21, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/28315669/cell-survival-interplay-between-hypoxia-and-pre-mrna-splicing
#8
Arvydas Kanopka
RNA splicing takes place in the nucleus and occurs either coor post-transcriptionally. Noncoding sequences (introns) in nuclear mRNA precursors (pre-mRNA) are removed by dedicated splicing machinery. The coding sequences (exons) are joined to generate the mature mRNA that is exported to the cytoplasm and translated into protein. Splicing events are tissue-specific. This process plays an important role in cellular differentiation and organism development. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to different developmental stages and altered cellular conditions...
March 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#9
Hanna Kędzierska, Agnieszka Piekiełko-Witkowska
SR and hnRNP proteins were initially discovered as regulators of alternative splicing: the process of controlled removal of introns and selective joining of exons through which multiple transcripts and, subsequently, proteins can be expressed from a single gene. Alternative splicing affects genes involved in all crucial cellular processes, including apoptosis. During cancerogenesis impaired apoptotic control facilitates survival of cells bearing molecular aberrations, contributing to their unrestricted proliferation and chemoresistance...
March 14, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28304396/associations-between-genetic-variants-in-mrna-splicing-related-genes-and-risk-of-lung-cancer-a-pathway-based-analysis-from-published-gwass
#10
Yongchu Pan, Hongliang Liu, Yanru Wang, Xiaozheng Kang, Zhensheng Liu, Kouros Owzar, Younghun Han, Li Su, Yongyue Wei, Rayjean J Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeböller, Albert Rosenberger, Richard S Houlston, Neil Caporaso, Maria Teresa Landi, Joachim Heinrich, Angela Risch, Xifeng Wu, Yuanqing Ye, David C Christiani, Christopher I Amos, Qingyi Wei
mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls)...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28304277/partial-loss-of-genes-might-open-therapeutic-window
#11
Bo Liu, Omar Abdel-Wahab
The loss of genes that encode RNA splicing factors weakens cancer cells in a way that could be exploited by new approaches to treatment.
March 17, 2017: ELife
https://www.readbyqxmd.com/read/28302904/pharmacological-inhibition-of-the-spliceosome-subunit-sf3b-triggers-ejc-independent-nmd
#12
Teresa Carvalho, Sandra Martins, José Rino, Sérgio Marinho, Maria Carmo-Fonseca
Spliceostatin A, meayamycin, and pladienolide B are small molecules that target the SF3b subunit of spliceosomal U2 snRNP. These compounds are attracting much attention as tools to manipulate splicing and potential anti-cancer drugs. We investigated the effects of these inhibitors on mRNA transport and stability in human cells. Upon splicing inhibition unspliced pre-mRNAs accumulated in the nucleus, particularly within enlarged nuclear speckles. Yet, a small fraction of the pre-mRNA molecules were exported to the cytoplasm...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28302793/anticancer-sulfonamides-target-splicing-by-inducing-rbm39-degradation-via-recruitment-to-dcaf15
#13
Ting Han, Maria Goralski, Nicholas Gaskill, Emanuela Capota, Jiwoong Kim, Tabitha C Ting, Yang Xie, Noelle S Williams, Deepak Nijhawan
Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity are unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with pre-mRNA splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing...
March 16, 2017: Science
https://www.readbyqxmd.com/read/28300837/a-cd44v-subpopulation-of-breast-cancer-stem-like-cells-with-enhanced-lung-metastasis-capacity
#14
Jing Hu, Gang Li, Peiyuan Zhang, Xueqian Zhuang, Guohong Hu
Cancer stem-like cells (CSCs) are a subpopulation of cancer cells responsible for tumor growth, and recent evidence suggests that CSCs also contribute to cancer metastasis. However, the heterogeneity of CSCs in metastasis capacities is still unclear in breast cancer. Here we show that among the CD24(-)/CD44(+) breast CSCs, a subset expressing the variant isoform of CD44 (CD44v) displays significantly higher capacity of lung metastasis than that expressing the standard CD44 isoform CD44s. Increasing or reducing the CD44v/CD44s ratio of breast cancer cells by regulating the expression of epithelial splicing regulatory protein 1 (ESRP1) leads to promotion or suppression of lung metastasis without influencing cancer cell stemness...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28296713/whole-exome-sequencing-identifies-recurrent-sf3b1-r625-mutation-and-comutation-of-nf1-and-kit-in-mucosal-melanoma
#15
Jennifer D Hintzsche, Nicholas T Gorden, Carol M Amato, Jihye Kim, Kelsey E Wuensch, Steven E Robinson, Allison J Applegate, Kasey L Couts, Theresa M Medina, Keith R Wells, Joshua A Wisell, Martin D McCarter, Neil F Box, Yiqun G Shellman, Rene C Gonzalez, Karl D Lewis, John J Tentler, Aik Choon Tan, William A Robinson
Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas...
March 14, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28296343/a-genome-wide-sirna-screen-for-regulators-of-tumor-suppressor-p53-activity-in-human-non-small-lung-cancer-cells-identifies-components-of-the-rna-splicing-machinery-as-targets-for-anticancer-treatment
#16
Ellen Siebring-van Olst, Maxime Blijlevens, Renee X de Menezes, Ida H van der Meulen-Muileman, Egbert F Smit, Victor W van Beusechem
Reinstating wild-type tumor suppressor p53 activity could be a valuable option for the treatment of cancer. To contribute to development of new treatment options for non-small cell lung cancer (NSCLC), we performed genome-wide siRNA screens for determinants of p53 activity in NSCLC cells. We identified many genes not previously known to be involved in regulating p53 activity. Silencing p53 pathway inhibitor genes was associated with loss of cell viability. The largest functional gene cluster influencing p53 activity was mRNA splicing...
March 13, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28289760/pten-proteoforms-in-biology-and-disease
#17
REVIEW
Prerna Malaney, Vladimir N Uversky, Vrushank Davé
Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein-protein interactions, and protein-ligand interactions, might dramatically increase the functionality of the encoded protein...
March 13, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28289330/the-heterogeneity-of-cancer-stem-like-cells-at-the-invasive-front
#18
Go J Yoshida
Cancer stem-like cells exhibit the multi-functional roles to survive and persist for a long period in the minimal residual disease after the conventional anti-cancer treatments. Cancer stem-like cells of solid malignant tumors which highly express CD44v8-10, the variant isoform of CD44 generated by alternative splicing, has a resistance to redox stress by the robust production of glutathione mediated by ESRP1-CD44v-xCT (cystine/glutamate antiporter) axis. It has been reported that CD44v and c-Myc tend to show the inversed expression pattern at the invasive front of the aggressive tumors...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28288992/identification-of-a-dna-damage-induced-alternative-splicing-pathway-that-regulates-p53-and-cellular-senescence-markers
#19
Jing Chen, John Crutchley, Dadong Zhang, Kouros Owzar, Michael B Kastan
Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here we report a novel DNA damage response pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor p53, and controls DNA damage-induced cellular senescence. In brief, ionizing irradiation (IR) inhibits the activity of hSMG-1, a phosphoinositide-3-kinase-like kinase (PIKK) family member, reducing the binding of hSMG1 to a specific region of p53 precursor mRNA near exon 9 and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA...
March 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28281569/treating-triple-negative-breast-cancer-cells-with-erlotinib-plus-a-select-antioxidant-overcomes-drug-resistance-by-targeting-cancer-cell-heterogeneity
#20
Bin Bao, Cristina Mitrea, Priyanga Wijesinghe, Luca Marchetti, Emily Girsch, Rebecca L Farr, Julie L Boerner, Ramzi Mohammad, Greg Dyson, Stanley R Terlecky, Aliccia Bollig-Fischer
Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes...
March 10, 2017: Scientific Reports
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