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Differential Gene Expression of Medullary Thyroid Carcinoma Reveals Specific Markers Associated with Genetic Conditions

Authors :
Luis J Leandro-García
L. Inglada-Pérez
Aguirre A. de Cubas
David G. Pisano
Xavier Matias-Guiu
Mariangela Zane
A Cascón
Isabella Merante-Boschin
Giuseppe Opocher
Maria Rosa Pelizzo
Iñigo Landa
Cristina Rodríguez-Antona
Salud Borrego
Mercedes Robledo
Rocío Letón
Gonzalo Gómez-López
Mario Encinas
Esmeralda Castelblanco
Cristina Álvarez-Escolá
Álvaro Gómez-Graña
Leticia de la Vega
Francesca Schiavi
Anna Macià
Agnieszka Maliszewska
University of Texas
Source :
Digital.CSIC. Repositorio Institucional del CSIC, instname
Publication Year :
2013
Publisher :
American Society for Investigative Pathology, 2013.

Abstract

Maliszewska, Agnieszka et al.<br />Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RETM918T and GAL as related to RET634 mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTCM918T group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RETM918T, caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.<br />MZ-CRC-1 cells were a generous gift of Dr. Robert F. Gagel (MD Anderson Cancer Center, University of Texas, Houston, TX).

Details

Database :
OpenAIRE
Journal :
Digital.CSIC. Repositorio Institucional del CSIC, instname
Accession number :
edsair.doi.dedup.....8b24724bd74bcebed893cddd22046540