Gal-3 is stimulated by gain-of-function p53 mutations and modulates chemoresistance in anaplastic thyroid carcinomas.
Galectin-3 (Gal-3) is an anti-apoptotic molecule of the beta-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 (p53(R273H)). 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.
Lavra
Luca
L
S. Pietro Fatebenefratelli Hospital, Rome, Italy.
Ulivieri
Alessandra
A
Rinaldo
Cinzia
C
Dominici
Roberto
R
Volante
Marco
M
Luciani
Emidio
E
Bartolazzi
Armando
A
Frasca
Francesco
F
Soddu
Silvia
S
Sciacchitano
Salvatore
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003114:Colony-Forming Units Assay; D019008:Drug Resistance, Neoplasm; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D034622:RNA Interference; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000970:Antineoplastic Agents; D037502:Galectin 3; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin