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Gal‐3 is stimulated by gain‐of‐function p53 mutations and modulates chemoresistance in anaplastic thyroid carcinomas
Author(s) -
Lavra Luca,
Ulivieri Alessandra,
Rinaldo Cinzia,
Dominici Roberto,
Volante Marco,
Luciani Emidio,
Bartolazzi Armando,
Frasca Francesco,
Soddu Silvia,
Sciacchitano Salvatore
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2510
Subject(s) - cancer research , apoptosis , biology , mutation , cell culture , gene , genetics
Galectin‐3 (Gal‐3) is an anti‐apoptotic molecule of the β‐galactoside‐binding lectin family. Gal‐3 is down‐regulated by wt‐p53 and this repression is required for p53‐induced apoptosis. Since poorly differentiated thyroid carcinomas (PDTCs) and anaplastic thyroid carcinomas (ATCs) frequently harbour p53 mutations, we asked whether Gal‐3 expression and activity could be influenced by such mutations in these tumours. We found a positive correlation between Gal‐3 expression and p53 mutation in human thyroids and in thyroid carcinoma cell lines (TCCLs) harbouring different p53 mutations. Gal‐3 was over‐expressed in most ATCs and TCCLs, especially those with the most frequently detected p53 mutation ( p 53 R 273 H ). Over‐expression of p53 R273H in two p53 ‐null cells (SAOS‐2 and SW‐1736) as well as in two wt‐p53 ‐carrying TCCLs (TPC‐1 and K1), stimulated Gal‐3 expression, while interference with p53 R273H endogenous expression in ARO cells down‐regulated Gal‐3 expression. Conversely, over‐expression of wt‐p53 in ARO cells restored the inhibitory effect on Gal‐3 expression. ARO cells are highly resistant to apoptosis and express both p53 and Gal‐3, which are increased upon cisplatin treatment. Interference with Gal‐3 expression in these cells stimulated their chemosensitivity. In conclusion, gain‐of‐function p53 mutant acquires the de novo ability to stimulate Gal‐3 expression and to increase chemoresistance in ATCs. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.