GENE EXPRESSION PROFILE IN THYROID FOLLICULAR NEOPLASIA: A TOOL FOR DIAGNOSIS AND A TARGET FOR THERAPEUTICS

CAMACHO, CLÉBER P.; MACIEL, RUI M. B.; OLER, GISELE; LATINI, FLAVIA R.M.; ANDRADE, VICTOR P. DE; HOJAIJ, FLAVIO C.; RIGGINS, GREGORY J.; CERUTTI, JANETE M.

Federal University of São Paulo, SP, Brazil

SUMMARY

Surgery and radioiodine are effective in treating differentiated thyroid cancers. However, a significant percentage of locally advanced and metastatic follicular thyroid carcinoma does not respond to conventional therapeutic approach and treatment options are then limited. Establishing more effective treatment of follicular thyroid tumors requires an understanding of the molecular events, which lead to the initiation and progression of this disease. Comparison of gene expression profile in follicular carcinomas with those seen in normal and follicular adenoma tissues can, in turn, provide knowledge to a more efficient diagnostic procedure or to new therapeutic strategies.

Using serial analysis of gene expression (SAGE), we found out that NR4A1, CCND1 and FOSB genes were differentially expressed in follicular carcinoma, follicular adenoma and normal human thyroid libraries. Real time-PCR was used to validate our findings in a set of 27 normal human tissues, 10 follicular adenomas, 14 follicular carcinomas and 3 cell lines. Lithium, valproic acid and carbamazepine were used to test whether or not the level of expression of these three genes was induced or repressed after drug treatment in a follicular thyroid carcinoma cell line.
    NR4A1, CCND1 and FOSB were differentially expressed between normal and carcinoma tissue. All cell lines lost the expression of NR4A1 and FOSB. CCND1 was overexpressed in WRO line. A decrease in NR4A1 and an increase in CCND1 expressions, through Odds Ratio analysis, demonstrate a risk for follicular carcinoma tumorigenesis. The lithium experiment showed a different pattern of RNA expression for all three genes, depending on time, concentration and presence of TSH. These results were confirmed by immunocytochemistry (ICQ). The expression of 3 genes was partially restored by lithium, valproic acid and carbamazepine.
    These results reveal the possibility of using drugs already known in order to alter gene expression and try to re-establish the normal physiology or to promote the cellular death when in association with other therapeutic approach.