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Ribonucleic Acid Interference Targeting S100A4 (Mts1) Suppresses Tumor Growth and Metastasis of Anaplastic Thyroid Carcinoma in a Mouse Model

Departments of Genetics (Y.S., M.Z., E.Y.B.) and Biological and Medical Research (K.C., Z.A.-M., F.A.A.-M.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Osancor Biotech Inc. (N.R.F.), Watford, Herts WD17 3BY, United Kingdom

Address all correspondence and requests for reprints to: Yufei Shi, MBC 3, Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail: yufei{at}kfshrc.edu.sa.

Context: The characteristic feature of malignant neoplasm is invasion and metastasis. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality.

Objective: Our objective was to examine the effects of S100A4 expression knockdown by RNA interference on the growth and metastasis of human anaplastic thyroid carcinoma cells (ARO) and the sensibility of ARO to paclitaxel after S100A4 knockdown.

Design: A plasmid construct was made that expressed small hairpin RNA (shRNA) specific for S100A4. The construct was stably transfected into ARO cells (ARO/S100A4-shRNA). The tumorigenicity, metastatic potential, and sensibility of ARO/S100A4-shRNA to paclitaxel were investigated.

Results: S100A4 expression was reduced by 71.3 ± 4.7% in ARO/S100A4-shRNA by real-time RT-PCR analysis. The growth rate of ARO/S100A4-shRNA was reduced by 46 ± 7.6% in a cell proliferation assay. Cell cycle analysis showed increased G₂/M accumulation in ARO/S100A4-shRNA. Tumor formation and growth induced by sc injection of 5 x 10⁶ ARO/S100A4-shRNA into the nude mice were significantly reduced, and no tumor metastasis was found in any of the mice. We also demonstrated significant induction of apoptosis in ARO/S100A4-shRNA after incubation with 15 nM paclitaxel, indicating that tumor cells were sensitized to chemotherapy as a result of S100A4 knockdown.

Conclusions: These data suggest that reduction of S100A4 by RNA interference is a viable approach to inhibit tumor growth and metastasis. Given that S100A4 is overexpressed in many kinds of tumors, the current study provides the proof of concept in its therapeutic potential.

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