Postnatal expression of BRAFV600E does not induce thyroid cancer in mouse models of thyroid papillary carcinoma

摘要

The mutant BRAF (BRAFV600E) is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The oncogenicity of this mutation has been shown by some genetically engineered mouse models. However, in these mice, BRAFV600E is expressed in all the thyroid cells from the fetal periods, and suppresses thyroid function, thereby leading to TSH elevation, which by itself promotes thyroid tumorigenesis. To overcome these problems, we exploited 2 different approaches, both of which allowed temporally and spatially restricted expression of BRAFV600E in the thyroid glands. First, we generated conditional transgenic mice harboring the loxP-neoR-loxP-BRAFV600Einternal ribosome entry site-green fluorescent protein sequence [Tg(LNL-BRAFV600E)]. The double transgenic mice (LNL-BRAFV600E;TPO-Cre) were derived from a high expressor line of Tg(LNLBRAFV600E) mice and TPO-Cre mice; the latter expresses Cre DNA recombinase under the control of thyroid-specific thyroid peroxidase (TPO) promoter and developed PTC-like lesions in early life under normal serum TSH levels due to mosaic recombination. In contrast, injection of adenovirus expressing Cre under the control of another thyroid-specific thyroglobulin (Tg) promoter (Ad-TgP-Cre) into the thyroids of LNL-BRAF V600E mice did not induce tumor formation despite detection ofBRAFV600EandpERKin a small fraction of thyroid cells. Second, postnatal expression ofBRAFV600E in a smallnumberof thyroid cellswasalso achieved by injecting the lentivirus expressing loxP-green fluorescent protein-loxP-BRAFV600E into the thyroids of TPO-Cre mice; however, no tumor development was again observed. These results suggest that BRAFV600E does not appear to induce PTC-like lesions when expressed in a fraction of thyroid cells postnatally under normal TSH concentrations.