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Cancer AND CRISPR-Cas9

M Nazhif Zaini, Saroor A Patel, Saiful E Syafruddin, Paulo Rodrigues, Sakari Vanharanta
Tissue-specific transcriptional programs control most biological phenotypes, including disease states such as cancer. However, the molecular details underlying transcriptional specificity is largely unknown, hindering the development of therapeutic approaches. Here, we describe novel experimental reporter systems that allow interrogation of the endogenous expression of HIF2A, a critical driver of renal oncogenesis. Using a focused CRISPR-Cas9 library targeting chromatin regulators, we provide evidence that these reporter systems are compatible with high-throughput screening...
August 13, 2018: Scientific Reports
Francesco Iorio, Fiona M Behan, Emanuel Gonçalves, Shriram G Bhosle, Elisabeth Chen, Rebecca Shepherd, Charlotte Beaver, Rizwan Ansari, Rachel Pooley, Piers Wilkinson, Sarah Harper, Adam P Butler, Euan A Stronach, Julio Saez-Rodriguez, Kosuke Yusa, Mathew J Garnett
BACKGROUND: Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting CRISPR-Cas9 screens is the high false-positive rate in detecting essential genes within copy number amplified regions of the genome. We have developed the computational tool CRISPRcleanR which is capable of identifying and correcting gene-independent responses to CRISPR-Cas9 targeting. CRISPRcleanR uses an unsupervised approach based on the segmentation of single-guide RNA fold change values across the genome, without making any assumption about the copy number status of the targeted genes...
August 13, 2018: BMC Genomics
Sijie Lin, Kuancan Liu, Yongchun Zhang, Ming Jiang, Rong Lu, Christopher J Folts, Xia Gao, Mark D Noble, Tingting Zhao, Zhongren Zhou, Xiaopeng Lan, Jianwen Que
Drug repurposing with a better understanding of the underlying mechanism has provided new avenues to find treatment for malignancies. Esophageal adenocarcinoma (EAC) is a rapidly increasing cancer with a dismal 5-year survival rate of <15%. Lack of efficient treatment options contributes to the high mortality rate of EAC. To find new therapy against EAC we performed unbiased drug screening of an FDA-approved drug library and identified that the cardiac glycosides including Ouabain, Digoxin and Digitoxin efficiently inhibit the proliferation of EAC cell lines (OE33 and OE19) both in vitro and in vivo...
August 10, 2018: Cellular Signalling
Gabriele Fenini, Serena Grossi, Emmanuel Contassot, Thomas Biedermann, Ernst Reichmann, Lars E French, Hans-Dietmar Beer
By forming a protective barrier, epidermal keratinocytes represent the first line of defense against environmental insults. UVB radiation of the sun is a major challenge for the skin and can induce inflammation, aging and eventually skin cancer. UVB induces an immune response in human keratinocytes resulting in activation and secretion of the pro-inflammatory cytokines proIL-1β and -18. This is mediated by assembly of protein complexes, termed inflammasomes. However, the mechanisms underlying sensing of UVB by keratinocytes, and particularly the types of inflammasomes required for cytokine secretion, are a matter of debate...
August 7, 2018: Journal of Investigative Dermatology
Elad Prinz, Sharon Aviram, Ami Aronheim
The mitogen-activated protein kinases (MAPKs) regulate a variety of cellular processes. The three main MAPK cascades are the ERK, JNK and p38 kinases. A typical MAPK cascade is composed of MAP3K-MAP2K-MAPK kinases that are held by scaffold proteins. Scaffolds function to assemble the protein tier and contribute to the specificity and efficacy of signal transmission. WDR62 is a JNK scaffold protein, interacting with JNK, MKK7 and several MAP3Ks. The loss of WDR62 in human leadsto microcephaly and pachygyria...
August 9, 2018: Molecular Biology of the Cell
Wookjae Lee, Joon Ho Lee, Soyeong Jun, Ji Hyun Lee, Duhee Bang
Mutations within the KRAS oncogene are associated with the proliferation of various cancers. Therapeutic approaches for treating cancers with such mutations have focused on targeting the downstream protein effectors of KRAS. However, to date, no approved treatment has targeted the mutated KRAS oncogene directly. Presently, we used the selectivity of the CRISPR/Cas9 system to directly target mutated KRAS alleles. We designed single-guide RNAs (sgRNAs) to target two specific single-nucleotide missense mutations on KRAS codon-12 located in the seed region adjacent to a protospacer adjacent motif (PAM)...
August 8, 2018: Scientific Reports
Gabriele Ibba, Claudia Piu, Elena Uleri, Caterina Serra, Antonina Dolei
The human endogenous retrovirus (HERV)-K, human mouse mammary tumor virus like-2 (HML-2) subgroup of HERVs is activated in several tumors and has been related to prostate cancer progression and motor neuron diseases. The cellular splicing factor 2/alternative splicing factor (SF2/ASF) is a positive regulator of gene expression, coded by a potent proto-oncogene, amplified, and abnormally expressed in tumors. TAR DNA-binding protein-43 (TDP-43) is a DNA/RNA-binding protein, negative regulator of alternative splicing, known for causing neurodegeneration, and with complex roles in oncogenesis...
August 7, 2018: Viruses
K Blighe, L DeDionisio, K A Christie, B Chawes, S Shareef, T Kakouli-Duarte, C Chao-Shern, V Harding, R S Kelly, L Castellano, J Stebbing, J A Lasky-Su, M A Nesbit, C B T Moore
The reporting of the first draft of the human genome in 2000 brought with it much hope for the future in what was felt as a paradigm shift toward improved health outcomes. Indeed, we have now mapped the majority of variation across human populations with landmark projects such as 1000 Genomes; in cancer, we have catalogued mutations across the primary carcinomas; whilst, for other diseases, we have identified the genetic variants with strongest association. Despite this, we are still awaiting the genetic revolution in healthcare to materialise and translate itself into the health benefits for which we had hoped...
August 8, 2018: BMC Genomics
Ning Li, Minghong Chen, Yansha Cao, Hua Li, Jinping Zhao, Zhenhua Zhai, Fu Ren, Keyan Li
BACKGROUND: CRC is one of the most common malignancies worldwide, and its molecular mechanisms remain unclear. Elevated levels of BAG3 have been reported in various tumors. The present study aimed to explore the expression and function of BAG3 in CRC. METHODS: BAG3 protein expression was evaluated in 90 CRC specimens using immunohistochemistry in tissue microarrays, and the correlation between BAG3 expression and the clinicopathological features were assessed. In HCT116 cells BAG3 overexpression cell models were constructed, and CRISPR/Cas9 was used for BAG3 knockout...
August 6, 2018: BMC Cancer
Ursa Lampreht Tratar, Simon Horvat, Maja Cemazar
The use of existing mouse models in cancer research is of utmost importance as they aim to explore the casual link between candidate cancer genes and carcinogenesis as well as to provide models to develop and test new therapies. However, faster progress in translating mouse cancer model research into the clinic has been hampered due to the limitations of these models to better reflect the complexities of human tumors. Traditionally, immunocompetent and immunodeficient mice with syngeneic and xenografted tumors transplanted subcutaneously or orthotopically have been used...
2018: Frontiers in Oncology
Ilya Blokhin, Olga Khorkova, Jane Hsiao, Claes Wahlestedt
The central dogma of molecular biology, which states that the only role of long RNA transcripts is to convey information from gene to protein, was brought into question in recent years due to discovery of the extensive presence and complex roles of long noncoding RNAs (lncRNAs). Furthermore, lncRNAs were found to be involved in pathogenesis of multiple diseases and thus represent a new class of therapeutic targets. Translational efforts in the lncRNA field have been augmented by progress in optimizing the chemistry and delivery platforms of lncRNA-targeting modalities, including oligonucleotide-based drugs and CRISPR-Cas9...
August 6, 2018: Expert Opinion on Drug Discovery
Anupama Sahoo, Sanjaya K Sahoo, Piyush Joshi, Bongyong Lee, Ranjan J Perera
The clinical management of malignant melanoma remains a challenge because these tumors are intrinsically aggressive and prone to therapeutic resistance. Micro-RNA (miR)-211 is an emerging melanoma oncogene. Melanoma metabolism adapts to promote survival, including in response to BRAFV600E inhibition, but how miR-211 participates in this process is unknown. Here we generated miR-211 loss-of-function cell lines using CRISPR/Cas9 technology and show that miR-211 loss slowed growth and invasion in vitro, inhibited phosphoinositol-3-kinase (PI3K) signaling, and inhibited melanoma growth in vivo...
August 1, 2018: Journal of Investigative Dermatology
Yan-Xiang Cheng, Gan-Tao Chen, Xiao Yang, Yan-Qing Wang, Li Hong
The objectives of this study were to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudotype virus on SiHa cytobiology behavior by cutting the HPV16 E6 gene selectively and to explore the role of this system in the treatment of cervical cancer. After designing specific gRNA sequences targeting HPV16 E6, generating hCas9-EGFP and E6-gRNA-RFP plasmids, and preparing the pseudovirus of HPV16 carrying E6-gRNA and Cas9 plasmids, we determined the titer of the pseudotype virus using the TCID50 method...
April 2018: Current medical science
Justin W C Leung, Lara E Emery, Kyle M Miller
Histone H2A variants play important roles in maintaining the integrity of the genome. For example, the histone variant H2AX is phosphorylated on Ser139 (called γH2AX) at DNA double-strand breaks (DSB) and serves as a signal for the initiation of downstream DNA damage response (DDR) factor recruitment and DNA repair activities within damaged chromatin. For decades, genetic studies in human cells involving DNA damage signaling and repair factors have relied mostly on either knockdown by RNA interference (i.e...
2018: Methods in Molecular Biology
Xue Wang, Hongfei Yu, Wenjie Sun, Jianlu Kong, Lei Zhang, Jinlong Tang, Jingyu Wang, Enping Xu, Maode Lai, Honghe Zhang
BACKGROUND: Long non-coding RNAs (lncRNAs) function as key molecules in cancer progression. The lncRNA CYTOR plays oncogenic roles in multiple types of cancer, yet the detailed molecular mechanisms of those roles remain unknown. The aim of this study was to investigate the clinical significance, biological function and interacting partners of CYTOR in colorectal cancer (CRC). METHODS: A systematic and comprehensive analysis of CYTOR expression was performed in 138 CRC samples and in the TCGA and GEO databases...
July 31, 2018: Molecular Cancer
Hidekazu Nagano, Naoko Hashimoto, Akitoshi Nakayama, Sawako Suzuki, Yui Miyabayashi, Azusa Yamato, Seiichiro Higuchi, Masanori Fujimoto, Ikki Sakuma, Minako Beppu, Masataka Yokoyama, Yutaka Suzuki, Sumio Sugano, Kazuhiro Ikeda, Ichiro Tatsuno, Ichiro Manabe, Koutaro Yokote, Satoshi Inoue, Tomoaki Tanaka
The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 ( DPYSL4 ). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression...
July 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Scott J Callahan, Stephanie Tepan, Yan M Zhang, Helen Lindsay, Alexa Burger, Nathaniel R Campbell, Isabella S Kim, Travis J Hollmann, Lorenz Studer, Christian Mosimann, Richard M White
Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but these typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method called Transgene Electroporation in Adult Zebrafish (TEAZ)...
July 30, 2018: Disease Models & Mechanisms
Jeehan Lee, Hye Hyeon Yun, Seulki Kim, Sang Hee Ji, Hyo-Jeong Kuh, Jeong-Hwa Lee
BACKGROUND/AIM: High expression of the Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic protein, in various human cancers is linked to a poor outcome. The purpose of this study was to clarify whether BIS is associated with the migration and invasive characteristics of A549 cells. MATERIALS AND METHODS: BIS-knockout (KO) cells were prepared by the CRISPR/Cas9 method. The aggressive behaviors of A549 cells were analyzed by wound healing and a transwell invasion assay as well as 3D spheroid culture...
August 2018: Anticancer Research
Björn Stolte, Amanda Balboni Iniguez, Neekesh V Dharia, Amanda L Robichaud, Amy Saur Conway, Ann M Morgan, Gabriela Alexe, Nathan J Schauer, Xiaoxi Liu, Gregory H Bird, Aviad Tsherniak, Francisca Vazquez, Sara J Buhrlage, Loren D Walensky, Kimberly Stegmaier
Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background. The majority of tumors express wild-type TP53 , and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for TP53 wild-type Ewing sarcoma, we used a genome-scale CRISPR-Cas9 screening approach and identified and validated MDM2 , MDM4 , USP7, and PPM1D as druggable dependencies. The stapled peptide inhibitor of MDM2 and MDM4, ATSP-7041, showed anti-tumor efficacy in vitro and in multiple mouse models...
August 6, 2018: Journal of Experimental Medicine
Shuai Zhen, Xu Li
Long non-coding RNAs (LncRNA), a class of transcripts with lengths>200nt, play a master role in the regulation of cancer pathogenesis. Recently, the CRISPR/Cas9 system has been explored as a revolutionary genome editing tool for molecular biology. Growing evidences show that LncRNAs can be targeted by the CRISPR/Cas9 system used for evaluation the function. Thus, the CRISPR/Cas9 systems provide a novel gene-editing strategy for the modification of LncRNA expression. In this review, we summarize current knowledge of the functions and underlying mechanisms of LncRNA by CRISPR/Cas9...
July 26, 2018: Human Gene Therapy
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