scholarly journals RNA editing in cancer impacts mRNA abundance in immune response pathways

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Tracey W. Chan ◽  
Ting Fu ◽  
Jae Hoon Bahn ◽  
Hyun-Ik Jun ◽  
Jae-Hyung Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Rna Editing ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Rna Binding Proteins ◽  
Mrna Abundance ◽  
Mesenchymal Tumors ◽  
Mesenchymal Transition ◽  
Cancer Types ◽  
Experimental Validations

Abstract Background RNA editing generates modifications to the RNA sequences, thereby increasing protein diversity and shaping various layers of gene regulation. Recent studies have revealed global shifts in editing levels across many cancer types, as well as a few specific mechanisms implicating individual sites in tumorigenesis or metastasis. However, most tumor-associated sites, predominantly in noncoding regions, have unknown functional relevance. Results Here, we carry out integrative analysis of RNA editing profiles between epithelial and mesenchymal tumors, since epithelial-mesenchymal transition is a key paradigm for metastasis. We identify distinct editing patterns between epithelial and mesenchymal tumors in seven cancer types using TCGA data, an observation further supported by single-cell RNA sequencing data and ADAR perturbation experiments in cell culture. Through computational analyses and experimental validations, we show that differential editing sites between epithelial and mesenchymal phenotypes function by regulating mRNA abundance of their respective genes. Our analysis of RNA-binding proteins reveals ILF3 as a potential regulator of this process, supported by experimental validations. Consistent with the known roles of ILF3 in immune response, epithelial-mesenchymal differential editing sites are enriched in genes involved in immune and viral processes. The strongest target of editing-dependent ILF3 regulation is the transcript encoding PKR, a crucial player in immune and viral response. Conclusions Our study reports widespread differences in RNA editing between epithelial and mesenchymal tumors and a novel mechanism of editing-dependent regulation of mRNA abundance. It reveals the broad impact of RNA editing in cancer and its relevance to cancer-related immune pathways.

scholarly journals Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

2020 ◽  
Author(s):  
Tracey Chan ◽  
Ting Fu ◽  
Jae Hoon Bahn ◽  
Hyun-Ik Jun ◽  
Jae-Hyung Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Rna Editing ◽  
Cultured Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Abundance ◽  
Mesenchymal Tumors ◽  
Rna Sequences ◽  
Mesenchymal Transition ◽  
Noncoding Regions ◽  
Cancer Types

AbstractRecent studies revealed global shifts in RNA editing, the modification of RNA sequences, across many cancers. Besides a few sites implicated in tumorigenesis or metastasis, most tumor-associated sites, predominantly in noncoding regions, have unknown function. Here, we characterize editing profiles between epithelial (E) and mesenchymal (M) phenotypes in seven cancer types, as epithelial-mesenchymal transition (EMT) is a key paradigm for metastasis. We observe distinct editing patterns between E and M tumors and EMT induction upon loss of ADAR enzymes in cultured cells. E-M differential sites are highly enriched in genes involved in immune and viral processes, some of which regulate mRNA abundance of their respective genes. We identify a novel mechanism in which ILF3 preferentially stabilizes edited transcripts. Among editing-dependent ILF3 targets is the transcript encoding PKR, a crucial player in immune response. Our study demonstrates the broad impact of RNA editing in cancer and relevance of editing to cancer-related immune pathways.

scholarly journals RNA binding protein RBM3 augments kissing loop formation with lncRNAs to enhance translational control

2021 ◽  
Author(s):  
Afreen Asif Ali Sayed ◽  
Sonali Choudhury ◽  
Dharmalingam Subramaniam ◽  
Sumedha Gunewardena ◽  
Sivapriya Ponnurangam ◽  
...  
Keyword(s):  
Translational Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Rna Binding Proteins ◽  
Tumor Xenograft ◽  
Rna Seq ◽  
Loop Formation ◽  
Mesenchymal Transition ◽  
Kissing Loop

Background and Aims: Translational regulation involve the coordinated actions of RNA binding proteins (RBPs) and non-coding RNAs. For efficient translation, the mRNA needs to be circularized. While RNA binding proteins and translation factors have been shown to regulate the circularization, the role of lncRNAs in the process is not yet defined. Methods: We first performed RNA-seq and RNA-immunoprecipitation coupled-Seq (RIP-Seq) to identify differentially expressed lncRNA and mRNA in RBM3 overexpressing cell lines. We manipulated lncRNA expression in the cells and determined effects on gene expression and cell viability and motility. The studies were confirmed in vivo in intestine specific RBM3 transgenic and RBM3 knockout mouse models. Results: In comparing the RNA-Seq and RIP-Seq datasets, we identified increased expression of lncRNA LSAMP-3 and Flii-1 that bind to RBM3. In addition, there was an increase in expression of epithelial mesenchymal transition and angiogenesis markers following RBM3 overexpression. Moreover, modeling studies suggest that these lncRNAs formed kissing-loop interactions on target mRNAs including transcripts that encode epithelial mesenchymal transition and angiogenesis. While RBM3 transgenic mice showed increased LSAMP-3 and Flii-1, this was reduced in the RBM3 knockout mice. Also, RBM3 overexpression increased tumor xenograft growth, which was suppressed by knockdown of the lncRNAs. Also, knockdown of endogenous RBM3 specifically in the intestine suppressed azoxymethane-dextran sodium sulfate driven colitis-associated cancers, with a corresponding reduction in the expression of lncRNAs and transcripts that encode epithelial mesenchymal transition and angiogenesis. Conclusion: We propose that RBPs such as RBM3 mediate their function through regulatory lncRNAs that enable circularization to control translation.

scholarly journals Identification of NOVA family proteins as novel β-catenin RNA-binding proteins that promote epithelial-mesenchymal transition

RNA Biology ◽  
2020 ◽  
Vol 17 (6) ◽  
pp. 881-891 ◽  
Author(s):  
Shulin Tang ◽  
Yurong Zhao ◽  
Xirong He ◽  
Jiahui Zhu ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Rna Binding Proteins ◽  
Mesenchymal Transition

scholarly journals RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2699
Author(s):  
Donghee Kang ◽  
Yerim Lee ◽  
Jae-Seon Lee
Keyword(s):  
Cancer Treatment ◽  
Genome Stability ◽  
Binding Proteins ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Cancer Prognosis ◽  
Mesenchymal Transition ◽  
Cellular Phenotypes

RNA-binding proteins (RBPs) crucially regulate gene expression through post-transcriptional regulation, such as by modulating microRNA (miRNA) processing and the alternative splicing, alternative polyadenylation, subcellular localization, stability, and translation of RNAs. More than 1500 RBPs have been identified to date, and many of them are known to be deregulated in cancer. Alterations in the expression and localization of RBPs can influence the expression levels of oncogenes, tumor-suppressor genes, and genome stability-related genes. RBP-mediated gene regulation can lead to diverse cancer-related cellular phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and epithelial-mesenchymal transition (EMT)/invasion/metastasis. This regulation can also be associated with cancer prognosis. Thus, RBPs can be potential targets for the development of therapeutics for the cancer treatment. In this review, we describe the molecular functions of RBPs, their roles in cancer-related cellular phenotypes, and various approaches that may be used to target RBPs for cancer treatment.

Carboxypeptidase E-ΔN promotes migration, invasiveness, and epithelial–mesenchymal transition of human osteosarcoma cells via the Wnt–β-catenin pathway

2019 ◽  
Vol 97 (4) ◽  
pp. 446-453 ◽  
Author(s):  
Shuli Fan ◽  
Xiang Gao ◽  
Peng Chen ◽  
Xu Li
Keyword(s):  
Cell Migration ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Human Osteosarcoma ◽  
Carboxypeptidase E ◽  
Human Osteosarcoma Cells ◽  
Cancer Types ◽  
Interfering Rna

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents, and metastatic OS is the major cause of OS-related death. Carboxypeptidase E (CPE) is known to be highly expressed in some cancer types, and its N-terminal truncated form, CPE-ΔN, is implicated in tumor metastasis and poor prognosis. In this study, we investigated the effect of CPE-ΔN on cell migration, invasiveness, and the epithelial–mesenchymal transition (EMT) of OS cells, and illustrated the molecular mechanisms. We first constructed CPE-ΔN overexpressing human OS cell lines (143B and U2OS cells), and found that ectopic CPE-ΔN expression in OS cells enhanced cell migration and invasiveness, and promoted the EMT process. Further, overexpression of CPE-ΔN increased the levels of c-myc and nuclear β-catenin in OS cells, which suggested the CPE-ΔN promotes activation of the Wnt–β-catenin pathway in OS cells. Treatment with β-catenin small interfering RNA (siRNA) inhibited the migration and invasiveness of CPE-ΔN-overexpressing cells, and reduced the expression of E-cadherin. Together, these results suggest that CPE-ΔN promotes migration, invasiveness, and the EMT of OS cells via the Wnt–β-catenin signaling pathway.

scholarly journals Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yarden Katz ◽  
Feifei Li ◽  
Nicole J Lambert ◽  
Ethan S Sokol ◽  
Wai-Leong Tam ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
State Regulation ◽  
Ribosome Profiling ◽  
Luminal Cell ◽  
Mesenchymal Transition ◽  
Cell State

The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types.

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.

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