scholarly journals Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shou Liu ◽  
Wenjian Cao ◽  
Yichi Niu ◽  
Jiayi Luo ◽  
Yanhua Zhao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Wide Spectrum ◽  
Intraepithelial Neoplasia ◽  
Human Cell Line ◽  
Global Changes ◽  
Epigenetic Landscape ◽  
Sequencing Data ◽  
Driving Mechanisms ◽  
Chromatin Remodeling Complex ◽  
A Subunit

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species (ROS). As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.

scholarly journals Single-PanIN-seq Unveils that ARID1A Deficiency Promotes Pancreatic Tumorigenesis by Attenuating KRAS Induced Senescence

2020 ◽  
Author(s):  
Shou Liu ◽  
Wenjian Cao ◽  
Yichi Niu ◽  
Jiayi Luo ◽  
Yanhua Zhao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Drug Target ◽  
Wide Spectrum ◽  
Intraepithelial Neoplasia ◽  
Global Changes ◽  
Stem Cell Markers ◽  
Epigenetic Landscape ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Cancer Stem Cell Markers ◽  
Driving Mechanisms

ABSTRACTARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency upregulates the expression of Aldehyde dehydrogenase ALDH1A1, which plays an essential role in attenuating the senescence induced by oncogenic KRAS. Despite that ALDH proteins have been commonly used as cancer stem cell markers, their effect in promoting attenuation of senescence is not known before. Therefore, ALDH proteins could be considered a potential adjuvant drug target in treating pancreatic cancer.

scholarly journals OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps

2017 ◽  
Author(s):  
Le Li ◽  
Tsz-Piu Kwok ◽  
Alden King-Yung Leung ◽  
Yvonne Y. Y. Lai ◽  
Iris K. Pang ◽  
...  
Keyword(s):  
Single Molecule ◽  
Wide Spectrum ◽  
Simulated Data ◽  
High Sensitivity ◽  
Human Cell Line ◽  
Read Length ◽  
Sequencing Data ◽  
Structural Variations ◽  
Promising Alternative ◽  
Optical Maps

AbstractHuman genomes contain structural variations (SVs) that are associated with various phenotypic variations and diseases. SV detection by sequencing is incomplete due to limited read length. Nanochannel-based optical mapping (OM) allows direct observation of SVs up to hundreds of kilo-bases in size on individual DNA molecules, making it a promising alternative technology for identifying large SVs. SV detection from optical maps is non-trivial due to complex types of error present in OM data, and no existing methods can simultaneously handle all these complex errors and the wide spectrum of SV types. Here we present a novel method, OMSV, for accurate and comprehensive identification of SVs from optical maps. OMSV detects both homozygous and heterozygous SVs, SVs of various types and sizes, and SVs with and without creating/destroying restriction sites. In an extensive series of tests based on real and simulated data, OMSV achieved both high sensitivity and specificity, with clear performance gains over the latest existing method. Applying OMSV to a human cell line, we identified hundreds of SVs >2kbp, with 65% of them missed by sequencing-based callers. Independent experimental validations confirmed the high accuracy of these SVs. We also demonstrate how OMSV can incorporate sequencing data to determine precise SV break points and novel sequences in the SVs not contained in the reference. We provide OMSV as open-source software to facilitate systematic studies of large SVs.

scholarly journals Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

2021 ◽  
Vol 10 (13) ◽  
pp. 2745
Author(s):  
Tiemo S. Gerber ◽  
Fabian Bartsch ◽  
Daniel C. Wagner ◽  
Mario Schindeldecker ◽  
Lisa-Katharina Heuft ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Intrahepatic Cholangiocarcinoma ◽  
Intraepithelial Neoplasia ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Recurrence Free Survival ◽  
Cancer Genes ◽  
Sequencing Data ◽  
Free Survival ◽  
Normal Tissues

Background: Syndecan-1 (CD138; SDC1) is a heparan sulfate proteoglycan that has been attributed a key role in cancer progression in ductal adenocarcinoma of the pancreas. We therefore aimed to investigate the role of syndecan-1 in cholangiocarcinoma. Methods: We analyzed syndecan-1 expression in a large, clinicopathologically well-characterized collective of 154 intrahepatic cholangiocarcinoma, 221 extrahepatic cholangiocarcinomas, and 95 gallbladder carcinomas as well as respective normal tissues and precursor lesions by immunohistochemistry with digital image analysis and correlated with recurrence-free survival and prognostic markers. Furthermore, we conducted an analysis of cancer genes in the cholangiocarcinoma cohort of The Cancer Genome Atlas (TCGA). Results: During cholangiocarcinogenesis, syndecan-1-expression decreased when compared to normal bile ducts and biliary intraepithelial neoplasia; however, syndecan-1 levels were found to be elevated in lymph node metastases. In the TCGA cohort, high mRNA SDC1 levels were associated with poor prognosis in intrahepatic cholangiocarcinoma. However, in our large cohort, the immunohistochemical syndecan-1 expression did not significantly correlate with recurrence-free survival. Conclusions: Syndecan-1 was found to be downregulated during cholangiocarcinogenesis, yet we could not show significant effects on prognosis on protein level. Further analyses are needed to further depict its specific role.

scholarly journals Human papillomavirus and human telomerase RNA component gene in cervical cancer progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yang Liu ◽  
Pianping Fan ◽  
Yingying Yang ◽  
Changjun Xu ◽  
Yajuan Huang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Progression ◽  
Invasive Cervical Cancer ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Cancer Group ◽  
Potential Marker ◽  
Significant Difference ◽  
Human Telomerase

Abstract This study aimed to examine hTERC gene in different grades of cervical intraepithelial neoplasia (CIN) and cervical cancer, and the association between hTERC and high risk-human papillomavirus (HR-HPV) infection. Patients who underwent cervical cancer screening at the Second Affiliated Hospital of Kunming Medical University between October 2010 and December 2011 were enrolled. All patients underwent liquid-based cytology test and hybrid capture 2 (HC2) for HPV detection. hTERC was examined using fluorescence in situ hybridization (FISH). Cervical colposcopy biopsy was performed if any of the three results was positive. HC2, FISH, and pathology were compared. A total of 1200 women underwent screening, 150 patients underwent cervical biopsy: 32 in the normal group, 38 in the CIN1 group, 66 in the CIN2/3 group, and 14 in the invasive cervical cancer group. More patients had HR-HPV infection in the CIN2/3 group and ICC group compared with the CIN1 group. hTERC increased with increasing histological dysplasia. There was significant difference in hTERC positive rate between each of the three groups. More patients with hTERC gene amplification were observed in the positive HR-HPV group than in the HR-HPV negative group. In conclusion, hTERC is a potential marker for precancerous cervical cancer lesions. hTERC might be correlated with HR-HPV infection in cervical diseases.

scholarly journals Primary Cilium in Cancer Hallmarks

2019 ◽  
Vol 20 (6) ◽  
pp. 1336 ◽  
Author(s):  
Lucilla Fabbri ◽  
Frédéric Bost ◽  
Nathalie Mazure
Keyword(s):  
Cancer Progression ◽  
Primary Cilium ◽  
Mammalian Cells ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Cancer Hallmarks ◽  
Mutual Regulation ◽  
Ultrastructure And Function ◽  
And Function ◽  
External Stimuli

The primary cilium is a solitary, nonmotile and transitory appendage that is present in virtually all mammalian cells. Our knowledge of its ultrastructure and function is the result of more than fifty years of research that has dramatically changed our perspectives on the primary cilium. The mutual regulation between ciliogenesis and the cell cycle is now well-recognized, as well as the function of the primary cilium as a cellular “antenna” for perceiving external stimuli, such as light, odorants, and fluids. By displaying receptors and signaling molecules, the primary cilium is also a key coordinator of signaling pathways that converts extracellular cues into cellular responses. Given its critical tasks, any defects in primary cilium formation or function lead to a wide spectrum of diseases collectively called “ciliopathies”. An emerging role of primary cilium is in the regulation of cancer development. In this review, we seek to describe the current knowledge about the influence of the primary cilium in cancer progression, with a focus on some of the events that cancers need to face to sustain survival and growth in hypoxic microenvironment: the cancer hallmarks.

scholarly journals gpps: an ILP-based approach for inferring cancer progression with mutation losses from single cell data

2020 ◽  
Vol 21 (S1) ◽  
Author(s):  
Simone Ciccolella ◽  
Mauricio Soto Gomez ◽  
Murray D. Patterson ◽  
Gianluca Della Vedova ◽  
Iman Hajirasouliha ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Progression ◽  
False Negative ◽  
Fixed Number ◽  
Phylogeny Reconstruction ◽  
Sequencing Data ◽  
Progression Model ◽  
Great Specificity ◽  
Cell Data ◽  
Tumor Phylogeny

Abstract Background Cancer progression reconstruction is an important development stemming from the phylogenetics field. In this context, the reconstruction of the phylogeny representing the evolutionary history presents some peculiar aspects that depend on the technology used to obtain the data to analyze: Single Cell DNA Sequencing data have great specificity, but are affected by moderate false negative and missing value rates. Moreover, there has been some recent evidence of back mutations in cancer: this phenomenon is currently widely ignored. Results We present a new tool, , that reconstructs a tumor phylogeny from Single Cell Sequencing data, allowing each mutation to be lost at most a fixed number of times. The General Parsimony Phylogeny from Single cell () tool is open source and available at https://github.com/AlgoLab/gpps. Conclusions provides new insights to the analysis of intra-tumor heterogeneity by proposing a new progression model to the field of cancer phylogeny reconstruction on Single Cell data.

scholarly journals Transcriptomics Signature from Next-Generation Sequencing Data Reveals New Transcriptomic Biomarkers Related to Prostate Cancer

2019 ◽  
Vol 18 ◽  
pp. 117693511983552 ◽  
Author(s):  
Abedalrhman Alkhateeb ◽  
Iman Rezaeian ◽  
Siva Singireddy ◽  
Dora Cavallo-Medved ◽  
Lisa A Porter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Next Generation Sequencing ◽  
Cancer Progression ◽  
Machine Learning Techniques ◽  
Next Generation Sequencing Data ◽  
Prognostic Indicators ◽  
Next Generation ◽  
Sequencing Data ◽  
Cancer Data ◽  
Generation Sequencing

Prostate cancer is one of the most common types of cancer among Canadian men. Next-generation sequencing using RNA-Seq provides large amounts of data that may reveal novel and informative biomarkers. We introduce a method that uses machine learning techniques to identify transcripts that correlate with prostate cancer development and progression. We have isolated transcripts that have the potential to serve as prognostic indicators and may have tremendous value in guiding treatment decisions. Analysis of normal versus malignant prostate cancer data sets indicates differential expression of the genes HEATR5B, DDC, and GABPB1-AS1 as potential prostate cancer biomarkers. Our study also supports PTGFR, NREP, SCARNA22, DOCK9, FLVCR2, IK2F3, USP13, and CLASP1 as potential biomarkers to predict prostate cancer progression, especially between stage II and subsequent stages of the disease.

scholarly journals The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

2020 ◽  
Vol 48 (7) ◽  
pp. 3816-3831 ◽  
Author(s):  
Tao Liu ◽  
Qinglv Wei ◽  
Jing Jin ◽  
Qingya Luo ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rna Modification ◽  
Dependent Manner ◽  
The Novel ◽  
A Subunit

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

scholarly journals Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

2008 ◽  
Vol 19 (10) ◽  
pp. 4260-4272 ◽  
Author(s):  
Yang Lu ◽  
Chang Su ◽  
Xuming Mao ◽  
Prashna Pala Raniga ◽  
Haoping Liu ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Chromatin Immunoprecipitation ◽  
Pathogenic Fungus ◽  
Dependent Manner ◽  
Hyphal Development ◽  
Chromatin Remodeling Complex ◽  
A Subunit ◽  
Human Pathogenic Fungus ◽  
Incandida Albicans

Efg1 is essential for hyphal development and virulence in the human pathogenic fungus Candida albicans. How Efg1 regulates gene expression is unknown. Here, we show that Efg1 interacts with components of the nucleosome acetyltransferase of H4 (NuA4) histone acetyltransferase (HAT) complex in both yeast and hyphal cells. Deleting YNG2, a subunit of the NuA4 HAT module, results in a significant decrease in the acetylation level of nucleosomal H4 and a profound defect in hyphal development, as well as a defect in the expression of hypha-specific genes. Using chromatin immunoprecipitation, Efg1 and the NuA4 complex are found at the UAS regions of hypha-specific genes in both yeast and hyphal cells, and Efg1 is required for the recruitment of NuA4. Nucleosomal H4 acetylation at the promoters peaks during initial hyphal induction in an Efg1-dependent manner. We also find that Efg1 bound to the promoters of hypha-specific genes is critical for recruitment of the Swi/Snf chromatin remodeling complex during hyphal induction. Our data show that the recruitment of the NuA4 complex by Efg1 to the promoters of hypha-specific genes is required for nucleosomal H4 acetylation at the promoters during hyphal induction and for subsequent binding of Swi/Snf and transcriptional activation.

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