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.

Anticancer Immunotoxins, Challenges, and Approaches

2020 ◽  
Vol 26 ◽  
Author(s):  
Maryam Dashtiahangar ◽  
Leila Rahbarnia ◽  
Safar Farajnia ◽  
Arash Salmaninejad ◽  
Arezoo Gowhari Shabgah ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Antibody Fragment ◽  
Clinical Use ◽  
Multiple Cancer ◽  
Main Obstacle ◽  
Cancer Types ◽  
Recombinant Immunotoxins ◽  
Cancerous Cells ◽  
High Immunogenicity ◽  
Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

scholarly journals Identification of the cross-strand chimeric RNAs generated by fusions of bi-directional transcripts

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuting Wang ◽  
Qin Zou ◽  
Fajin Li ◽  
Wenwei Zhao ◽  
Hui Xu ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Sequencing Data ◽  
Normal Tissues ◽  
Rna Transcripts ◽  
Chimeric Rnas ◽  
Dna Strands ◽  
Comprehensive Survey ◽  
The Cross ◽  
Chimeric Rna ◽  
Cancerous Cells

AbstractA major part of the transcriptome complexity is attributed to multiple types of DNA or RNA fusion events, which take place within a gene such as alternative splicing or between different genes such as DNA rearrangement and trans-splicing. In the present study, using the RNA deep sequencing data, we systematically survey a type of non-canonical fusions between the RNA transcripts from the two opposite DNA strands. We name the products of such fusion events cross-strand chimeric RNA (cscRNA). Hundreds to thousands of cscRNAs can be found in human normal tissues, primary cells, and cancerous cells, and in other species as well. Although cscRNAs exhibit strong tissue-specificity, our analysis identifies thousands of recurrent cscRNAs found in multiple different samples. cscRNAs are mostly originated from convergent transcriptions of the annotated genes and their anti-sense DNA. The machinery of cscRNA biogenesis is unclear, but the cross-strand junction events show some features related to RNA splicing. The present study is a comprehensive survey of the non-canonical cross-strand RNA junction events, a resource for further characterization of the originations and functions of the cscRNAs.

scholarly journals Functional Stratification of Cancer Drugs through Integrated Network Similarity

2022 ◽  
Author(s):  
Nurcan Tuncbag ◽  
Seyma Unsal Beyge
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Network Models ◽  
Drug Combinations ◽  
Multiple Cancer ◽  
Integrated Network ◽  
Drug Molecules ◽  
The Difference

Abstract Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.

scholarly journals Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy

2018 ◽  
Vol 115 (3) ◽  
pp. 561-566 ◽  
Author(s):  
Melin J. Khandekar ◽  
Alexander S. Banks ◽  
Dina Laznik-Bogoslavski ◽  
James P. White ◽  
Jang Hyun Choi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Peroxisome Proliferator ◽  
Multiple Cancer ◽  
P53 Signaling ◽  
Response To Chemotherapy ◽  
P53 Response ◽  
Cancer Types ◽  
Agonist Ligands

The peroxisome-proliferator receptor-γ (PPARγ) is expressed in multiple cancer types. Recently, our group has shown that PPARγ is phosphorylated on serine 273 (S273), which selectively modulates the transcriptional program controlled by this protein. PPARγ ligands, including thiazolidinediones (TZDs), block S273 phosphorylation. This activity is chemically separable from the canonical activation of the receptor by agonist ligands and, importantly, these noncanonical agonist ligands do not cause some of the known side effects of TZDs. Here, we show that phosphorylation of S273 of PPARγ occurs in cancer cells on exposure to DNA damaging agents. Blocking this phosphorylation genetically or pharmacologically increases accumulation of DNA damage, resulting in apoptotic cell death. A genetic signature of PPARγ phosphorylation is associated with worse outcomes in response to chemotherapy in human patients. Noncanonical agonist ligands sensitize lung cancer xenografts and genetically induced lung tumors to carboplatin therapy. Moreover, inhibition of this phosphorylation results in deregulation of p53 signaling, and biochemical studies show that PPARγ physically interacts with p53 in a manner dependent on S273 phosphorylation. These data implicate a role for PPARγ in modifying the p53 response to cytotoxic therapy, which can be modulated for therapeutic gain using these compounds.

scholarly journals Regulation of PD-L1 expression in the tumor microenvironment

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ming Yi ◽  
Mengke Niu ◽  
Linping Xu ◽  
Suxia Luo ◽  
Kongming Wu
Keyword(s):  
Cancer Cells ◽  
Immune Escape ◽  
Multiple Cancer ◽  
Laboratory Findings ◽  
Limiting Step ◽  
Programmed Death ◽  
Programmed Cell Death 1 ◽  
Anti Cancer ◽  
Potential Applications ◽  
Cancer Types

AbstractProgrammed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

scholarly journals TBIO-26. NON-CANONICAL OPEN READING FRAMES ENCODE FUNCTIONAL PROTEINS ESSENTIAL FOR CANCER CELL SURVIVAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii471-iii471
Author(s):  
John Prensner ◽  
Oana Enache ◽  
Victor Luria ◽  
Karsten Krug ◽  
Karl Clauser ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Protein Translation ◽  
Cancer Cell Lines ◽  
Open Reading Frames ◽  
Sequencing Analysis ◽  
Multiple Cancer ◽  
Cancer Types ◽  
Non Coding Rnas ◽  
Reading Frames

Abstract The brain is the foremost non-gonadal tissue for expression of non-coding RNAs of unclear function. Yet, whether such transcripts are truly non-coding or rather the source of non-canonical protein translation is unknown. Here, we used functional genomic screens to establish the cellular bioactivity of non-canonical proteins located in putative non-coding RNAs or untranslated regions of protein-coding genes. We experimentally interrogated 553 open reading frames (ORFs) identified by ribosome profiling for three major phenotypes: 257 (46%) demonstrated protein translation when ectopically expressed in HEK293T cells, 401 (73%) induced gene expression changes following ectopic expression across 4 cancer cell types, and 57 (10%) induced a viability defect when the endogenous ORF was knocked out using CRISPR/Cas9 in 8 human cancer cell lines. CRISPR tiling and start codon mutagenesis indicated that the biological impact of these non-canonical ORFs required their translation as opposed to RNA-mediated effects. We functionally characterized one of these ORFs, G029442—renamed GREP1 (Glycine-Rich Extracellular Protein-1)—as a cancer-implicated gene with high expression in multiple cancer types, such as gliomas. GREP1 knockout in >200 cancer cell lines reduced cell viability in multiple cancer types, including glioblastoma, in a cell-autonomous manner and produced cell cycle arrest via single-cell RNA sequencing. Analysis of the secretome of GREP1-expressing cells showed increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth inhibitory effect of GREP1 knock-out. Taken together, these experiments suggest that the non-canonical ORFeome is surprisingly rich in biologically active proteins and potential cancer therapeutic targets deserving of further study.

scholarly journals Identification of Chimeric RNAs in Pig Skeletal Muscle and Transcriptomic Analysis of Chimeric RNA TNNI2-ACTA1 V1

2021 ◽  
Vol 8 ◽  
Author(s):  
Dongyu Liu ◽  
Jiqiao Xia ◽  
Zewei Yang ◽  
Xuelian Zhao ◽  
Jiaxin Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Underlying Mechanism ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Normal Tissues ◽  
Chimeric Rnas ◽  
Chimeric Rna ◽  
Cancerous Cells

Chimeric RNA was considered a special marker of cancer. However, recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues. Here, we analyzed and predicted jointly 49 chimeric RNAs by Star-Fusion and FusionMap. One chimeric RNA, we named TNNI2-ACTA1, and its eight transcript variants were identified by reverse transcriptase–polymerase chain reaction. The overexpression of TNNI2-ACTA1 V1 inhibited the proliferation of porcine skeletal muscle satellite cells through down-regulating the mRNA expression levels of cell cycle–related genes cyclinD1. However, as parental genes, there is no such effect in the TNNI2 and ACTA1. To explore the underlying mechanism for this phenomenon, we used RNA-seq to profile the transcriptomes of PSCs with overexpression. Compared with the negative control group, 1,592 differentially expressed genes (DEGs) were upregulated and 1,077 DEGs downregulated in TNNI2 group; 1,226 DEGs were upregulated and 902 DEGs downregulated in ACTA1 group; and 13 DEGs were upregulated and 16 DEGs downregulated in TNNI2-ACTA1 V1 group, respectively. Compared with the parental gene groups, three specific genes were enriched in the TNNI2-ACTA1 V1 group (NCOA3, Radixin, and DDR2). These three genes may be the key to TNNI2-ACTA1 V1 regulating cell proliferation. Taken together, our study explores the role of chimeric RNAs in normal tissues. In addition, our study as the first research provides the foundation for the mechanism of chimeric RNAs regulating porcine skeletal muscle growth.

ApoStream, a novel device for antibody-independent capture of circulating cancercells (CCCs) from blood of patients with various types of cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13500-e13500
Author(s):  
Vishal Gupta ◽  
Insiya Jafferji ◽  
Miguel Garza ◽  
Sujita Sukumaran ◽  
Jacky Woo ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Cancer Cells ◽  
Laser Scanning ◽  
Mononuclear Cells ◽  
Metastatic Cancer ◽  
Multiple Cancer ◽  
Tumor Biopsy ◽  
Peripheral Blood Mononuclear ◽  
Skov3 Cells ◽  
Cancer Types

e13500 Background: The detection of circulating tumor cells (CTCs) using immunomagnetic EpCAM-based capture methods has been conceptually accepted as a “liquid tumor biopsy”. However, these methods have limited the recovery of CTCs for molecular profiling applications. We developed a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, ApoStream for antibody-independent capture of circulating cancer cells (CCCs), with improved recovery across multiple cancer types and preserved viability of CCCs for downstream characterization. Methods: The performance of ApoStream was demonstrated using a low EpCAM expressing cell line, SKOV3. ApoStream was further used to enrich CCCs from various cancer patient blood. Prostate, breast and NSCLC CCCs were stained for cytokeratin (CK), CD45, and DAPI; melanoma CCCs were stained with S100, CD45 and DAPI. CCC enumeration was performed using laser scanning cytometry. Results: In system precision performance studies, average inter-day recovery on the ApoStream was 80.3 ± 3.5%, CV = 4.3% when cancer cells were spiked into buffer, and 78.5 ± 3.0%, CV = 3.3% when cancer cells spiked into ~10 million healthy peripheral blood mononuclear cells (PBMCs). Linearity performance was demonstrated with spiking 5-2600 SKOV3 cells into 10 million PBMCs (R2=1). Cell viability was not affected by processing through ApoStream device. High CCC recovery from metastatic cancer patient blood samples was obtained with counts ranging from 0 - 2630 (NSCLC, n=66), 0 - 3490 (prostate, n=29), 10 - 968 (breast, n=11), and 3 - 3120 (melanoma, n=13) CCCs per 7.5 mL blood. Positive CCC counts were obtained in 90% of NSCLC samples, 93% of prostate cancer samples, 100% breast cancer and melanoma specimens. There were no CK+ cells detected in healthy donor blood controls. Conclusions: Improved CCC recovery from various cancer types was demonstrated with the ApoStream device. ApoStream provides an antibody-independent method for capture of viable CCCs that enables further downstream molecular characterization of rare cells for use in clinical applications. Acknowledgements: Funded by NCI Contract No. HHSN261200800001E.

Nanoparticle modification of microfluidic cell separation for cancer cell detection and isolation

The Analyst ◽  
2020 ◽  
Vol 145 (1) ◽  
pp. 257-267 ◽  
Author(s):  
Yun Zhou ◽  
Ziye Dong ◽  
Hermella Andarge ◽  
Wei Li ◽  
Dimitri Pappas
Keyword(s):  
Surface Modification ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Separation ◽  
Cell Detection ◽  
Multiple Cancer ◽  
Nanoparticle Surface ◽  
Nanoparticle Surface Modification ◽  
Cancer Cell Detection

We present a nanoparticle surface modification approach to improve the microfluidic performance in detecting cancer cells. Multiple cancer cell lines were included in this work, and the capture ability of the chip with surface modification reached a significant increase.

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