Article

Targeting of the anti-apoptotic gene survivin in human thyroid carcinoma.

Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical School, Wenzhou, Zhejiang 325000, P.R. China.
International Journal of Molecular Medicine (Impact Factor: 1.96). 06/2012; 30(3):465-72. DOI: 10.3892/ijmm.2012.1046
Source: PubMed

ABSTRACT Survivin is a novel apoptosis inhibitor. Its gene is related to the baculovirus gene, which is believed to play a crucial role in fetal development and in cancer. We attempted to determine the expression of survivin in both thyroid goiter and carcinoma tissues, and to evaluate its prognostic value in human thyroid disease. In the present study, we applied small interfering RNA (siRNA) directed against survivin to determine the effects of decreasing the high constitutive levels of this protein in the FTC-133 thyroid follicular cancer cell line. Using reverse transcription PCR and immunohistochemistry, we compared the expression of survivin with relevant clinical and pathological data of 90 postsurgical specimens from patients with primary thyroid carcinoma and patients with benign goiter (33 with papillary thyroid cancer, 24 with follicular thyroid cancer, 18 with undifferentiated thyroid cancer and 15 cases with goiter). For the siRNA treatment in a human follicular thyroid carcinoma cell line, fluorescein-labeled double-stranded ultrapure siRNAs were used. RT-PCR identified the survivin transcript in 67/75 (89.3%) tumor samples and in 4/15 benign goiter samples. Immunohistochemical analysis showed positive immunoreactivity in 65/75 (86.7%) carcinomas while no expression was noted in all of the 15 benign goiter tissues. Survivin mRNA and protein levels were significantly higher in cancer tissues compared to benign goiter tissues (P<0.001). Higher survivin expression was found in the tumor tissues of pT3/pT4 and in the tumors with lymph node metastasis (P<0.05). Tumors with distant metastasis demonstrated higher survivin expression compared to the tumors without distant metastasis. Additionally, the expression of survivin in undifferentiated carcinomas was higher than that in differentiated ones. There was no significant correlation between survivin expression and age, gender, histological subtype and pathological stage. Our additional studies demonstrated that siRNA directed against survivin markedly decreased the protein expression of survivin. In conclusion, we conclude that survivin expression indicates more aggressive behavior and metastatic ability in thyroid cancer cells in vivo. Survivin can be used as a diagnostic and therapeutic marker for thyroid carcinoma and an important target in the strategy of thyroid cancer therapy. Our results of siRNA silencing indicate that siRNA may have potential as a therapeutic modality in the treatment of human thyroid cancer.

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    ABSTRACT: Background. Survivin is involved in human cancer and is responsible for aggressive biological behavior and poor clinical outcomes in several human malignancies. Thus, we hypothesized that the up-regulation of survivin protein expression may be enhanced in parallel with transition toward a poorly differentiated phenotype in human thyroid carcinomas. Methods. The expression of survivin was evaluated, by standard LSAB-HRP technique, in a series of 56 human thyroid carcinomas (42 papillary, 4 poorly differentiated and 10 anaplastic carcinomas) and thyroid carcinoma cell lines at different degrees of differentiation. Results. The cytoplasmic expression of survivin protein was significantly up-regulated in all thyroid tumors. A statistical significant association was found between nuclear survivin expression and anaplastic thyroid cancer (WDTC: mean 1.22 - SD 20.21; non-WDTC: mean 34.00 - SD 25.17; ATC: mean 56.50 - SD 22.10; p<0.001). Nuclear staining of survivin has been shown in poorly differentiated and anaplastic thyroid carcinomas and this is likely due to the up-regulation of the Ex3 survivin splicing variant as shown in poorly differentiated/anaplastic thyroid carcinoma cell lines. Of note, selected thyroid tumors characterized by a mixed population of differentiated and undifferentiated neoplastic cells, likely progressing from well to poorly differentiated and anaplastic phenotypes, exhibited cytoplasmic expression of survivin in differentiated fields and nuclear protein staining in poorly differentiated and anaplastic areas. This expression profile provides substantially added value to conventional clinical markers in predicting anaplastic cancer. The cut-off for distinguishing thyroids that developed ATC from those that remained differentiated was > 30% of nuclear survivin expression. The receiver operating characteristic (ROC) area was 0.92, with a P value of less than 0.0001. Conclusions. Up-regulation of survivin expression may be a molecular marker of dedifferentiation in thyroid epithelial carcinomas, likely being responsible for survival responses of tumor cells and, thus, favoring progression toward a poorly differentiated phenotype.
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