Identification of R-Spondin Gene Signature Predictive of Metastatic Progression in BRAFV 600E -Positive Papillary Thyroid Cancer.

Autor: da Silva SD; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.; Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada., Morand GB; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.; Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.; Department of Otorhinolaryngology-Head and Neck Surgery, Luzerner Kantonsspital, 6004 Lucerne, Switzerland.; Department of Otorhinolaryngology-Head and Neck Surgery, University Hospital Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland., Diesel L; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada., de Lima JM; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada., Bijian K; Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada., Kailasam S; Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada.; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada., Lefebvre F; Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada.; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada., Bourque G; Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada.; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada., Hier M; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada., Alaoui-Jamali MA; Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
Jazyk: angličtina
Zdroj: Cells [Cells] 2022 Dec 29; Vol. 12 (1). Date of Electronic Publication: 2022 Dec 29.
DOI: 10.3390/cells12010139
Abstrakt: Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and early stages are curable. However, a subset of PTCs shows an unusually aggressive phenotype with extensive lymph node metastasis and higher incidence of locoregional recurrence. In this study, we investigated a large cohort of PTC cases with an unusual aggressive phenotype using a high-throughput RNA sequencing (RNA-Seq) to identify differentially regulated genes associated with metastatic PTC. All metastatic PTC with mutated BRAF (V600E) but not BRAF wild-type expressed an up-regulation of R-Spondin Protein 4 (RSPO4) concomitant with an upregulation of genes involved in focal adhesion and cell-extracellular matrix signaling. Further immunohistochemistry validation confirmed the upregulation of these target genes in metastatic PTC cases. Preclinical studies using established PTC cell lines support that RSPO4 overexpression is associated with BRAF V600E mutation and is a critical upstream event that promote activation of kinases of focal adhesion signaling known to drive cancer cell locomotion and invasion. This finding opens up the potential of co-targeting B-Raf, RSPO and focal adhesion proteins as a pharmacological approach for aggressive BRAF V600E PTC.
Databáze: MEDLINE
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