scholarly journals Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Neha Ahuja ◽  
Cheemala Ashok ◽  
Subhashis Natua ◽  
Deepak Pant ◽  
Anna Cherian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Transcriptional Repression ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Global Changes ◽  
Invasion And Metastasis ◽  
New Paradigm ◽  
Mesenchymal Transition ◽  
Splicing Regulator

Abstract Hypoxic microenvironment heralds epithelial–mesenchymal transition (EMT), invasion and metastasis in solid tumors. Deregulation of alternative splicing (AS) of several cancer-associated genes has been instrumental in hypoxia-induced EMT. Our study in breast cancer unveils a previously unreported mechanism underlying hypoxia-mediated AS of hMENA, a crucial cytoskeleton remodeler during EMT. We report that the hypoxia-driven depletion of splicing regulator ESRP1 leads to skipping of hMENA exon 11a producing a pro-metastatic isoform, hMENAΔ11a. The transcriptional repression of ESRP1 is mediated by SLUG, which gets stimulated via hypoxia-driven TGF-β signaling. Interestingly, RBFOX2, an otherwise RNA-binding protein, is also found to transcriptionally repress ESRP1 while interacting with SLUG. Similar to SLUG, RBFOX2 gets upregulated under hypoxia via TGF-β signaling. Notably, we found that the exosomal delivery of TGF-β contributes to the elevation of TGF-β signaling under hypoxia. Moreover, our results show that in addition to hMENA, hypoxia-induced TGF-β signaling contributes to global changes in AS of genes associated with EMT. Overall, our findings reveal a new paradigm of hypoxia-driven AS regulation of hMENA and insinuate important implications in therapeutics targeting EMT.

scholarly journals Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Mohammad S. Esfahani ◽  
Luke J. Lee ◽  
Young-Jun Jeon ◽  
Ryan A. Flynn ◽  
Henning Stehr ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Wide Distribution ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Wild Type Counterpart ◽  
Lung Adenocarcinomas ◽  
Splice Junctions

AbstractThe functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3′ splice junctions. The presence of S34F caused a shift in cross-linking at 3′ splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

scholarly journals Epithelial Splicing Regulator Protein 1 and Alternative Splicing in Somatotroph Adenomas

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3331-3343 ◽  
Author(s):  
Tove Lekva ◽  
Jens Petter Berg ◽  
Robert Lyle ◽  
Ansgar Heck ◽  
Geir Ringstad ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Importance ◽  
Somatostatin Analog ◽  
Gh3 Cells ◽  
Mesenchymal Transition ◽  
Regulator Protein ◽  
Splicing Pattern ◽  
Splicing Regulator ◽  
Granulation Pattern

Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.

scholarly journals Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Ziqian Yan ◽  
Zhimei Sheng ◽  
Yuanhang Zheng ◽  
Ruijun Feng ◽  
Qinpei Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model

AbstractStudies have shown that cancer-associated fibroblasts (CAFs) play an irreplaceable role in the occurrence and development of tumors. Therefore, exploring the action and mechanism of CAFs on tumor cells is particularly important. In this study, we compared the effects of CAFs-derived exosomes and normal fibroblasts (NFs)-derived exosomes on breast cancer cells migration and invasion. The results showed that exosomes from both CAFs and NFs could enter into breast cancer cells and CAFs-derived exosomes had a more enhancing effect on breast cancer cells migration and invasion than NFs-derived exosomes. Furthermore, microRNA (miR)-18b was upregulated in CAFs-derived exosomes, and CAFs-derived exosomes miR-18b can promote breast cancer cell migration and metastasis by specifically binding to the 3′UTR of Transcription Elongation Factor A Like 7 (TCEAL7). The miR-18b-TCEAL7 pathway promotes nuclear Snail ectopic activation by activating nuclear factor-kappa B (NF-κB), thereby inducing epithelial-mesenchymal transition (EMT) and promoting cell invasion and metastasis. Moreover, CAFs-derived exosomes miR-18b could promote mouse xenograft model tumor metastasis. Overall, our findings suggest that CAFs-derived exosomes miR-18b promote nuclear Snail ectopic by targeting TCEAL7 to activate the NF-κB pathway, thereby inducing EMT, invasion, and metastasis of breast cancer. Targeting CAFs-derived exosome miR-18b may be a potential treatment option to overcome breast cancer progression.

scholarly journals The Estrogen Receptor α Signaling Pathway Controls Alternative Splicing in the Absence of Ligands in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6261
Author(s):  
Jamal Elhasnaoui ◽  
Giulio Ferrero ◽  
Valentina Miano ◽  
Santina Cutrupi ◽  
Michele De De Bortoli
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Disease Free Survival ◽  
Estrogen Receptor Α ◽  
Functional Enrichment ◽  
Expression Change ◽  
Mesenchymal Transition

Background: The transcriptional activity of estrogen receptor α (ERα) in breast cancer (BC) is extensively characterized. Our group has previously shown that ERα controls the expression of a number of genes in its unliganded form (apoERα), among which a large group of RNA-binding proteins (RBPs) encode genes, suggesting its role in the control of co- and post-transcriptional events. Methods: apoERα-mediated RNA processing events were characterized by the analysis of transcript usage and alternative splicing changes in an RNA-sequencing dataset from MCF-7 cells after siRNA-induced ERα downregulation. Results: ApoERα depletion induced an expression change of 681 RBPs, including 84 splicing factors involved in translation, ribonucleoprotein complex assembly, and 3′end processing. ApoERα depletion results in 758 isoform switching events with effects on 3′end length and the splicing of alternative cassette exons. The functional enrichment of these events shows that post-transcriptional regulation is part of the mechanisms by which apoERα controls epithelial-to-mesenchymal transition and BC cell proliferation. In primary BCs, the inclusion levels of the experimentally identified alternatively spliced exons are associated with overall and disease-free survival. Conclusion: Our data supports the role of apoERα in maintaining the luminal phenotype of BC cells by extensively regulating gene expression at the alternative splicing level.

scholarly journals MicroRNAs regulate the epithelial–mesenchymal transition and influence breast cancer invasion and metastasis

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769168 ◽  
Author(s):  
Min Zhao ◽  
Lin Ang ◽  
Jin Huang ◽  
Jin Wang
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Breast Cancer Invasion ◽  
Proliferation And Apoptosis ◽  
Post Transcriptional Regulation

MicroRNAs are small RNA molecules that play a major role in the post-transcriptional regulation of genes and influence the development, differentiation, proliferation, and apoptosis of cells and the development and progression of tumors. The epithelial–mesenchymal transition is a process by which epithelial cells morphologically transform into cells with a mesenchymal phenotype. The epithelial–mesenchymal transition plays a highly important role in tumor invasion and metastasis. Increasing evidence indicates that microRNAs are tightly associated with epithelial–mesenchymal transition regulation in tumor cells. In breast cancer, various microRNA molecules have been identified as epithelial–mesenchymal transition inducers or inhibitors, which, through different mechanisms and signaling pathways, participate in the regulation of breast cancer invasion and metastasis among various biological behaviors. The epithelial–mesenchymal transition–related microRNAs in breast cancer provide valuable molecules for researching cell invasion and metastasis, and they also provide candidate targets that may be significant for the targeted therapy of breast cancer.

scholarly journals Co-regulation of alternative splicing by hnRNPM and ESRP1 during EMT

2018 ◽  
Author(s):  
Samuel E. Harvey ◽  
Yilin Xu ◽  
Xiaodan Lin ◽  
Xin D. Gao ◽  
Yushan Qiu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Cancer Metastasis ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Mesenchymal Transition ◽  
Cancer Subtypes ◽  
Functional Relationships ◽  
Splicing Regulators

ABSTRACTThe epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome-scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they co-regulate a set of cassette exon events, with the majority showing discordant splicing regulation. hnRNPM discordantly regulated splicing events show a positive correlation with splicing during EMT while concordant splicing events do not, highlighting the antagonistic role of hnRNPM and ESRP1 during EMT. Motif enrichment analysis near co-regulated exons identifies guanine-uridine rich motifs downstream of hnRNPM-repressed and ESRP1-enhanced exons, supporting a model of competitive binding to these cis-elements to antagonize alternative splicing. The set of co-regulated exons are enriched in genes associated with cell-migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of co-regulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtypes. These data identify complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.

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