Abstract
Human telomerase reverse transcriptase (hTERT) is the key enzyme responsible for synthesizing and maintaining the telomeres on the ends of chromosomes, and it is essential for cell proliferation. This has made hTERT a focus of oncology research and an attractive target for anticancer drug development. In this study, we designed a small interfering RNA (siRNA) targeting the catalytic subunit of hTERT and tested its effects on the growth of telomerase-positive human colon carcinoma SW480 cells in vitro, as well as on the tumorigenicity of these cells in nude mice. Transient and stable transfection of hTERT siRNA into colon cancer SW480 cells suppressed hTERT expression, reduced telomerase activity and inhibited cell growth and proliferation. Knocking down hTERT expression in SW480 tumors xenografted into nude mice significantly slowed tumor growth and promoted tumor cell apoptosis. Our results suggest that hTERT is involved in carcinogenesis of human colon carcinoma, and they highlight the therapeutic potential of a hTERT knock-down approach.
Highlights
Colorectal carcinoma is the third most common cancer worldwide and the fourth most common cause of death [1,2]
reverse transcriptase (RT)-PCR showed that Human telomerase reverse transcriptase (hTERT) mRNA levels were barely detectable in DLD-1 cells and significantly higher in SW480 cells than in HT29 cells (0.82760.037 vs. 0.70560.051, P,0.05; Fig. 1A)
Index was much lower after transfection with hTERT-short hairpin RNA (shRNA) (50.661.57%) than after transfection with negative control (NC)-shRNA (59.0365.86%, P,0.05); the index was similar for all three control groups (Fig. 3A)
Summary
Colorectal carcinoma is the third most common cancer worldwide and the fourth most common cause of death [1,2]. Targeting telomerase in colon carcinoma may provide an effective alternative or complement to surgical treatment. Telomerase, a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic protein with telomere-specific reverse transcriptase activity (hTERT), extends telomeres at the end of eukaryotic chromosomes, preventing cell senescence and death. Telomerase appears to play a key role in tumor growth and proliferation: expression and activity of the enzyme are abnormally elevated in most cancers [5,6], and down-regulating the enzyme inhibits growth and proliferation [7]. While hTR is constitutively present in normal and tumor cells, hTERT is the rate-limiting component of the telomerase complex, and its expression correlates with telomerase activity [8]. Several studies indicate that telomerase may be key to immortalizing cells as a necessary step in oncogenesis [11,12], making hTERT a potentially useful clinical biomarker [13] and target for anticancer research [14]
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