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Antisense hTERT Inhibits Thyroid Cancer Cell Growth

Department of Surgery (L.T., M.C.S., C.B.B., T.J.F.), New York Presbyterian Hospital, and Weill Medical College of Cornell University; and Strang Cancer Prevention Center (T.J.F.), New York, New York 10021

Address all correspondence and requests for reprints to: Thomas J. Fahey III, M.D., New York Presbyterian Hospital-Cornell University, Room F-2024, 525 East 68th Street, New York, New York 10021. E-mail: tjfahey{at}mail.med.cornell.edu.

Activation of telomerase represents an early step in carcinogenesis. Increased telomerase expression in malignant thyroid tumors suggests that inactivation of telomerase may represent a potential chemotherapeutic target. The purpose of this study was to inhibit the protein component of telomerase, hTERT, in a human thyroid cancer cell line in vitro and in vivo using an antisense strategy. A 235-bp fragment of hTERT cDNA was subcloned, and sense and antisense hTERT expression vectors were constructed. These vectors were transfected into a human thyroid carcinoma cell line (FRO). Tumorigenic potential was determined by cellular growth assay, rate of apoptosis, anchorage-independent growth, and tumor growth in a nude mouse model. Significant down-regulation of hTERT expression was seen in the antisense transfected cells, compared with control and those transfected with the sense vector. A decrease in telomerase activity by TRAP assay was observed in the antisense hTERT cells but not in cells transfected with the sense hTERT construct. Inhibition of cell growth was observed after approximately 20 population doublings in the antisense-hTERT clones and was associated with an increase in the rate of apoptosis and a change in cellular morphology. Moreover, anchorage-independent growth was reduced in vitro, and tumor growth rate was diminished in vivo in the antisense hTERT clones. Inhibition of telomerase activity with antisense hTERT in human thyroid cancer cells is achievable and may represent a novel target to inhibit tumor growth.

Abbreviations: FBS, Fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTT, dimethylthiazoldiphenyltetra-zoliumbromide.

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