scholarly journals Exonic variants undergoing allele-specific selection in cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiyuan Li ◽  
Yuanyuan Zeng ◽  
Janet Wang ◽  
Hongkun Fang ◽  
Jintao Guo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Allelic Imbalance ◽  
Healthy Population ◽  
Biological Processes ◽  
Complementary Method ◽  
Allele Specific ◽  
Cancer Types ◽  
Allele Specificity ◽  
Gains And Losses

Abstract Background Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. Results We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. Conclusions In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

Molecular pathways of Interferon–Stimulated Gene 15: Implications in cancer

2020 ◽  
Vol 21 ◽  
Author(s):  
Angeles C. Tecalco–Cruz
Keyword(s):  
Posttranslational Modification ◽  
Human Interferon ◽  
Molecular Pathways ◽  
Biological Processes ◽  
Small Protein ◽  
Target Proteins ◽  
Central Elements ◽  
Cancer Types ◽  
Interferon Stimulated Gene 15

Abstract:: Human interferon–stimulated gene 15 (ISG15) is a 15–kDa ubiquitin–like protein that can be detected as either free ISG15 or covalently associated with its target proteins through a process termed ISGylation. Interestingly, extracellular free ISG15 has been proposed as a cytokine–like protein, whereas ISGylation is a posttranslational modification. ISG15 is a small protein with implications in some biological processes and pathologies that include cancer. This review highlights the findings of both free ISG15 and protein ISGylation involved in several molecular pathways, emerging as central elements in some cancer types.

Study of NSCLC cell migration promoted by NSCLC-Derived Extracellular Vesicle using atomic force microscopy

2021 ◽  
Author(s):  
Shuwei Wang ◽  
Jiajia Wang ◽  
Tuoyu Ju ◽  
Kaige Qu ◽  
Fan Yang ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
Cell Migration ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Extracellular Vesicle ◽  
Cancer Microenvironment ◽  
Biological Processes ◽  
Force Microscopy ◽  
Atomic Force ◽  
Cellular Components

Extracellular Vesicles (EVs) secreted by cancer cells have a key role in the cancer microenvironment and progression. Previous studies have mainly focused on molecular functions, cellular components and biological processes...

scholarly journals Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

2021 ◽  
Author(s):  
Stacey J. Scott ◽  
Xiaodun Li ◽  
Sriganesh Jammula ◽  
Ginny Devonshire ◽  
Catherine Lindon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Cell Biology ◽  
Time Lapse ◽  
Rna Seq ◽  
Cancer Evolution ◽  
Mitotic Slippage ◽  
Quantitative Immunofluorescence ◽  
Cancer Types ◽  
Eac Cells

AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

scholarly journals Replicate sequencing libraries are important for quantification of allelic imbalance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Asia Mendelevich ◽  
Svetlana Vinogradova ◽  
Saumya Gupta ◽  
Andrey A. Mironov ◽  
Shamil R. Sunyaev ◽  
...  
Keyword(s):  
Allelic Imbalance ◽  
False Positive Rate ◽  
Error Rates ◽  
Differential Analysis ◽  
Rna Seq ◽  
Specific Expression ◽  
Technical Noise ◽  
Specific Analysis ◽  
Positive Rate ◽  
Allele Specific

AbstractA sensitive approach to quantitative analysis of transcriptional regulation in diploid organisms is analysis of allelic imbalance (AI) in RNA sequencing (RNA-seq) data. A near-universal practice in such studies is to prepare and sequence only one library per RNA sample. We present theoretical and experimental evidence that data from a single RNA-seq library is insufficient for reliable quantification of the contribution of technical noise to the observed AI signal; consequently, reliance on one-replicate experimental design can lead to unaccounted-for variation in error rates in allele-specific analysis. We develop a computational approach, Qllelic, that accurately accounts for technical noise by making use of replicate RNA-seq libraries. Testing on new and existing datasets shows that application of Qllelic greatly decreases false positive rate in allele-specific analysis while conserving appropriate signal, and thus greatly improves reproducibility of AI estimates. We explore sources of technical overdispersion in observed AI signal and conclude by discussing design of RNA-seq studies addressing two biologically important questions: quantification of transcriptome-wide AI in one sample, and differential analysis of allele-specific expression between samples.

scholarly journals Life after Cell Death—Survival and Survivorship Following Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2942
Author(s):  
Tamara Mc Erlain ◽  
Aileen Burke ◽  
Cristina M. Branco
Keyword(s):  
Cancer Cells ◽  
Surgical Excision ◽  
Tumour Burden ◽  
Physical Damage ◽  
Term Care ◽  
Treatment Practices ◽  
Number Of Patients ◽  
Cancer Types

To prevent cancer cells replacing and outnumbering their functional somatic counterparts, the most effective solution is their removal. Classical treatments rely on surgical excision, chemical or physical damage to the cancer cells by conventional interventions such as chemo- and radiotherapy, to eliminate or reduce tumour burden. Cancer treatment has in the last two decades seen the advent of increasingly sophisticated therapeutic regimens aimed at selectively targeting cancer cells whilst sparing the remaining cells from severe loss of viability or function. These include small molecule inhibitors, monoclonal antibodies and a myriad of compounds that affect metabolism, angiogenesis or immunotherapy. Our increased knowledge of specific cancer types, stratified diagnoses, genetic and molecular profiling, and more refined treatment practices have improved overall survival in a significant number of patients. Increased survival, however, has also increased the incidence of associated challenges of chemotherapy-induced morbidity, with some pathologies developing several years after termination of treatment. Long-term care of cancer survivors must therefore become a focus in itself, such that along with prolonging life expectancy, treatments allow for improved quality of life.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

scholarly journals Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinfen Wei ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Ziqing He ◽  
Dawei Jiang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Matrix Remodeling ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Associated Macrophage ◽  
Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

scholarly journals MBNL1 alternative splicing isoforms play opposing roles in cancer

2018 ◽  
Vol 1 (5) ◽  
pp. e201800157 ◽  
Author(s):  
Tommaso Tabaglio ◽  
Diana HP Low ◽  
Winnie Koon Lay Teo ◽  
Pierre Alexis Goy ◽  
Piotr Cywoniuk ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Gene Function ◽  
Dominant Negative ◽  
Individual Gene ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Isoform Switching ◽  
And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

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