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PRRX1 silencing is required for metastatic outgrowth in melanoma and is an independent prognostic of reduced survival in patients

Authors :
Josep R. Ferreres
Antònia Vinyals
Rafael Campos‐Martin
Roderic Espín
Sebastian Podlipnik
Raquel Ramos
Esther Bertran
Cristina Carrera
Joaquim Marcoval
Josep Malvehy
Isabel Fabregat
Susana Puig
Àngels Fabra
Source :
Molecular Oncology, Vol 18, Iss 10, Pp 2471-2494 (2024)
Publication Year :
2024
Publisher :
Wiley, 2024.

Abstract

Paired related homeobox 1 (PRRX1) is an inducer of epithelial‐to‐mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAFV600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT‐related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up‐regulation of proliferative/melanocytic genes and the expression of the neural‐crest‐like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de‐differentiate towards a neural crest stem cell (NCSC)‐like phenotype that accounts for the metastatic aggressiveness.

Details

Language :
English
ISSN :
18780261 and 15747891
Volume :
18
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Molecular Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.5169246f34c04f48978b5469fb899c63
Document Type :
article
Full Text :
https://doi.org/10.1002/1878-0261.13688