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: 2.09). 06/2012; 30(3):465-72. DOI: 10.3892/ijmm.2012.1046
Source: PubMed


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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Available from: Cuong Hoang-Vu, Jun 19, 2014
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    • "Moreover, a trend of survivin delta Ex3 overexpression in tumors staged pT3/pT4 compared to pT1 was observed (P = 0,0548). Chen et al. previously showed a correlation between pT stages and the presence of lymph node metastases and distant metastases in thyroid carcinoma cases, while they did not observe any significant correlation in relation to gender, age and pathological subtype [7]. In our research, we also did not find any significant correlation in relation to age and gender. "
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    ABSTRACT: ContextThyroid cancer incidence has increased significantly during the past decades and is the most common type of endocrine malignancy. Many factors in thyroid cancers were studied as independent predictors of a poor prognosis.ObjectiveThe objective of the study was to evaluate survivin expression – BIRC5 and its splice variants: survivin delta Ex3 and survivin 2B in benign and malignant thyroid nodules.DesignThyroid tissues samples from a group of 50 patients consisting of: 29 patients with thyroid cancers (including medullary, papillary, follicular and undifferentiated types), as well as from 21 patients with non-cancerous thyroid tissues (including: 11 benign thyroid lesions and 10 healthy thyroid samples).Main Outcome MeasuresThe analysis of the survivin gene expression and evaluation of the level of splice variants were performed using quantitative RT-PCR.ResultsA statistically significant higher level of expression of survivin gene – BIRC5 was detected in thyroid malignant nodules, when compared with benign lesions and healthy thyroid samples. Moreover, the comparison of survivin relative expression in different staged tumors (pT1, pT3, and pT4) revealed a much higher amount of BIRC5 transcripts in tumor tissues of pT3/pT4. The comparison of survivin expression between benign thyroid nodules and healthy thyroid did not reveal significant differences. Importantly, high expression rate of the survivin delta Ex3 splice variant characterized thyroid carcinomas.ConclusionThe results suggest that survivin, especially survivin delta Ex3 splice variant being overexpress, is a characteristic feature of thyroid malignancy.
    PLoS ONE 06/2014; 9(6):e100534. DOI:10.1371/journal.pone.0100534 · 3.23 Impact Factor
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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 upregulation 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, using a standard linked streptavidin-biotin horseradish peroxidase technique 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 upregulated in all thyroid tumors. A statistically significant association was found between nuclear survivin expression and anaplastic thyroid cancer (mean ± SD: well-differentiated thyroid cancer, 1.22 ± 20.21; non-well-differentiated thyroid cancer, 34.00 ± 25.17; anaplastic thyroid cancer, 56.50 ± 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 upregulation of the ΔEx3 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 substantial 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 <0.0001. Conclusions: Upregulation 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.
    Thyroid: official journal of the American Thyroid Association 10/2013; 24(3). DOI:10.1089/thy.2013.0196 · 4.49 Impact Factor
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    ABSTRACT: Overexpression of survivin, an inhibitor of apoptosis protein, has been found in a variety of human cancers, and is associated with tumor aggressiveness. In this study, we analyzed the expression of survivin in papillary thyroid carcinoma (PTC) and evaluated its clinical significance for predicting an aggressive course of disease at the time of diagnosis. Survivin expression was determined by immunohistochemistry in 104 tissue specimens of PTC, confirmed by Western blot and correlated with clinicopathological parameters. Of the tumors examined, 74 (71.15%) showed high cytoplasmic survivin expression. There was no association between high survivin expression and age, gender or tumor size. On the other hand, it was closely correlated with the presence of lymph node metastasis (P=0.009), and there was a tendency for correlation with extrathyroidal invasion (P=0.062). The high risk PTC group (TNM stage III-IV) was associated with high levels of survivin (P=0.027). These results indicate that survivin is an unfavorable molecule for PTC prognosis, and that its high expression may indicate a subset of PTC patients with a more aggressive disease course. Evaluation of its expression in fine needle aspiration samples could be a useful tool for the identification of those PTC patients who require more extensive surgery, careful follow-up and therapeutic strategy.
    Pathology - Research and Practice 10/2013; 210(1). DOI:10.1016/j.prp.2013.09.014 · 1.40 Impact Factor
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