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: 1.88). 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: 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 · 3.53 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 · 1.56 Impact Factor
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    ABSTRACT: Papillary carcinoma of the thyroid (PTC) is generally a slow growing tumor with favorable prognosis, while anaplastic thyroid carcinoma (ATC) is highly aggressive malignancy. Genetic defects in apoptotic pathways may contribute to differences in their biological behavior. In this study, we analyzed immunohistochemically the expression of apoptosis-related molecules: galectin-3, Bcl-2, survivin (antiapoptotic), and Bax (pro-apoptotic), in archival tissue sections of PTC (n = 69) and ATC (n = 30) and correlated the results with clinicopathological parameters of these tumors. Galectin-3 and Bcl-2 showed a similar trend of down-regulation from high levels of both in PTC to low levels in ATC (p < 0.05). Bax was expressed at high levels in both type of thyroid carcinoma. Expression of survivin increased from PTC to ATC (p < 0.05), which may, at least in part, further facilitate the ability of malignant thyroid cell of ATC to escape programmed cell death despite high Bax expression. Only survivin, but not galectin-3, Bcl-2, or Bax, correlated significantly with lymph node metastasis presence and advanced stages of malignancy. In conclusion, this study documented down-regulation of galectin-3 and Bcl-2 (antiapoptotic molecules) and stepwise increase of survivin (inhibitor of apoptosis), during thyroid tumor progression from PTC to ATC. Correlation of high survivin expression with aggressive behavior implies its role in progression of thyroid tumor malignancy and suggests that survivin could be a useful tool in the prediction of aggressiveness of a subset of papillary carcinomas and a possible target for molecular therapy for ATC patients.
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