Acquisition of an oncogenic fusion protein is sufficient to globally alter the landscape of miRNA expression to inhibit myogenic differentiation

Loupe, Jacob M.; Miller, Patrick J. O.; Crabtree, Judy S.; Zabaleta, Jovanny; Hollenbach, Andrew D.

doi:10.18632/oncotarget.19693

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…Finally, the fusion protein promotes aneuploidy by inducing gene expression changes that override regulatory cell cycle checkpoints and dysregulate maintenance of chromosome number and structure (Loupe et al, 2016b). In addition to protein-encoding target genes, PAX3-FOXO1 also regulates expression of a series of microRNAs that impact on the above-described cellular functions, such as differentiation (Loupe et al, 2016a; Loupe et al, 2016b; Loupe et al, 2017; Hanna et al, 2018).…”

Section: Pax3 In Human Diseasementioning

confidence: 99%

The expression and function of PAX3 in development and disease

Boudjadi

Chatterjee

Sun

et al. 2018

Gene

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The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.

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Section: Pax3 In Human Diseasementioning

confidence: 99%

The expression and function of PAX3 in development and disease

Boudjadi

Chatterjee

Sun

et al. 2018

Gene

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“…Such downstream effectors of PAX3-FOXO1 include transcription factors such as MYCN 6,8 , growth effectors such as MET 9 , CB1 10 , FGFR4, ALK1, IGF1R, PDGFR-alpha 11,12 , CDKN1B, CDKN1C 13,14 , proteins regulating apoptosis such as Bcl-XL, bcl-2 15,16 , and epigenetic regulators such as JARID2 17 . In addition, PAX3-FOXO1 was shown to regulate a number of miRNA, to enhance oncologic properties such as invasion and proliferation 18,19 . Importantly, the majority of work has focused on autocrine functions of PAX3-FOXO1 expression, with lack of data regarding effects on paracrine communication.…”

Section: Introductionmentioning

confidence: 99%

The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486

Ghamloush

Ghayad

Rammal

et al. 2019

Sci Rep

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The alveolar subtype (ARMS) is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 that drives oncogenic cellular properties. Exosomes are small, secreted vesicles that affect paracrine signaling. We show that PAX3-FOXO1 transcript alters exosome content of C2C12 myoblasts, leading to pro-tumorigenic paracrine effects in recipient cells. Microarray analysis revealed alteration in miRNA content of exosomes, affecting cellular networks involved in cell metabolism, growth signaling, and cellular invasion. Overexpression and knockdown studies showed that miR-486-5p is an effector of PAX3-FOXO1, and mediates its paracrine effects in exosomes, including promoting recipient cell migration, invasion, and colony formation. Analysis of human RMS cells showed miR-486-5p is enriched in both cells and exosomes, and to a higher extent in ARMS subtypes. Analysis of human serum samples showed that miR-486-5p is enriched in exosomes of patients with RMS, and follow-up after chemotherapy showed decrease to control values. Our findings identify a novel role of both PAX3-FOXO1 and its downstream effector miR-486-5p in exosome-mediated oncogenic paracrine effects of RMS, and suggest its possible use as a biomarker.

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“…Indeed, patients with fusion-positive ARMS present with advanced disease, and have high rates of tumor recurrence and poorer survival [ 131 ], despite current multimodality therapy. PAX3-FOXO1 acts as a transcriptional regulator and alters a number of genes involved in myogenic and developmental processes, proliferation, survival, migration, and metastasis [ 132 ], as well as several miRNA [ 133 , 134 ].…”

Section: Clinical Utility Of Exosomes Detection In Liquid Biopsymentioning

confidence: 99%

Exosome-Based Liquid Biopsy Approaches in Bone and Soft Tissue Sarcomas: Review of the Literature, Prospectives, and Hopes for Clinical Application

Agnoletto

Pignochino

Caruso

et al. 2023

IJMS

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The knowledge of exosome impact on sarcoma development and progression has been implemented in preclinical studies thanks to technological advances in exosome isolation. Moreover, the clinical relevance of liquid biopsy is well established in early diagnosis, prognosis prediction, tumor burden assessment, therapeutic responsiveness, and recurrence monitoring of tumors. In this review, we aimed to comprehensively summarize the existing literature pointing out the clinical relevance of detecting exosomes in liquid biopsy from sarcoma patients. Presently, the clinical utility of liquid biopsy based on exosomes in patients affected by sarcoma is under debate. The present manuscript collects evidence on the clinical impact of exosome detection in circulation of sarcoma patients. The majority of these data are not conclusive and the relevance of liquid biopsy-based approaches in some types of sarcoma is still insufficient. Nevertheless, the utility of circulating exosomes in precision medicine clearly emerged and further validation in larger and homogeneous cohorts of sarcoma patients is clearly needed, requiring collaborative projects between clinicians and translational researchers for these rare cancers.

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Acquisition of an oncogenic fusion protein is sufficient to globally alter the landscape of miRNA expression to inhibit myogenic differentiation

Cited by 4 publications

References 36 publications

The expression and function of PAX3 in development and disease

The expression and function of PAX3 in development and disease

The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486

Exosome-Based Liquid Biopsy Approaches in Bone and Soft Tissue Sarcomas: Review of the Literature, Prospectives, and Hopes for Clinical Application

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