Silencing of the Tumor Suppressor GeneSLC5A8Is Associated withBRAFMutations in Classical Papillary Thyroid Carcinomas

Abstract

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.

Potential Utility and Limitations of Thyroid Cancer Cell Lines as Models for Studying Thyroid Cancer

“…Methylation of thyroid-specific genes, such as NIS (23,44), TSH-R (25), the genes for the putative thyroid follicular cell apical iodide transporters, solute carrier family 26 member 4 (SLC26A4 or pendrin) (45), and SLC5A8 (46,47), is also common in thyroid cancer and thyroid cell lines.…”

Enhancement of sodium/iodide symporter expression in thyroid and breast cancer

“…Direct stimulation of the TSH receptor in Graves' disease by antibody (Saito et al 1997, Caillou et al 1998, Castro et al 1999, Lazar et al 1999, constitutive activating mutations of the TSH receptor in a hyperfunctioning thyroid adenoma (Mian et al 2001), or the weak agonist human chorionic gonadotropin (hCG; Hershman 1999, Arturi et al 2002, activate the cAMP pathway and result in marked NIS expression. In contrast, the expression of AIT is not increased in hyperfunctioning thyroid adenomas or Graves' disease (Lacroix et al 2004, Porra et al 2005. The expression of pendrin protein is increased in hyperfunctioning thyroid tissues, possibly due to post-transcriptional upregulation by TSHR signaling (Bidart et al 2000, Mian et al 2001.…”

Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features

“…Thyroid tissue samples were taken from the Lyon Thyroid Tumor Bank, previously described (Porra et al 2005), which is a part of the Biological Resources Center (BRC) of the Lyon University Hospital. The rules of tissue collection by the BRC include the informed consent of patients.…”

“…The thymine to adenine transversion at nucleotide 1799 of the BRAF gene was detected by a real-time, allele-specific PCR method (Jarry et al 2004) adapted to cDNA as previously described (Porra et al 2005).…”

“…PAX8 and FOXE1 transcript levels were decreased (about threefold) in PTC with the BRAF T1799A mutation and in PTC with a RET/PTC gene rearrangement but were within the normal range in PTC-ga(K). Data from a previous study on NIS gene expression in PTC (Porra et al 2005) were revisited after determination of the presence or absence of BRAF or RET/PTC gene alterations. NIS gene expression exhibited a 20-fold reduction in PTC-ga(C) and only a twofold decrease in PTC-ga(K) (data not shown).…”