Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.
SLC5A8, proposed as a thyroid apical iodide transporter, was recently defined as a Na+-coupled transporter of short-chain fatty acid. To document the expression pattern of SLC5A8 in the thyroid, we analyzed the regulation of its expression in normal human thyrocytes in culture and in tissues with distinct functional activity. To determine whether SLC5A8 expression is altered in all thyroid carcinomas or only in particular subtypes, we investigated the level of its expression in a series of 50 hypofunctioning tumors. SLC5A8 expression was studied at the transcript level and compared with that of SLC26A4 or Pendrin and SLC5A5 or Na+/iodide symporter. SLC5A8 expression, unlike that of SLC5A5 and SLC26A4, was not regulated by TSH in normal human thyrocytes in culture and was not related to the functional state of thyroid tissue; toxic adenomas and adjacent resting tissues exhibited the same SLC5A8 transcript content. SLC5A8 expression was selectively down-regulated (40-fold) in papillary thyroid carcinomas of classical form (PTC-cf.). Methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of PTC-cf. and in about 20% of other papillary thyroid carcinomas. In a series of 52 PTC-cf., a low SLC5A8 expression was highly significantly associated with the presence of BRAF T1796A mutation. These data identify a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the T1796A point mutation of the BRAF gene in the PTC-cf. subtype of thyroid carcinomas.
Porra
Valérie
V
Institut Fédératif de Recherche 62, Faculté de Médecine Lyon-RTH Laennec, France.
Ferraro-Peyret
Carole
C
Durand
Christine
C
Selmi-Ruby
Samia
S
Giroud
Hélène
H
Berger-Dutrieux
Nicole
N
Decaussin
Myriam
M
Peix
Jean-Louis
JL
Bournaud
Claire
C
Orgiazzi
Jacques
J
Borson-Chazot
Françoise
F
Dante
Robert
R
Rousset
Bernard
B
D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D027501:Monocarboxylic Acid Transporters; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000076988:Sulfate Transporters; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics*
D033742:Adenine Nucleotide Translocator 2; D027682:Cation Transport Proteins; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C085609:SLC26A4 protein, human; C476760:SLC5A8 protein, human; D000076988:Sulfate Transporters; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf