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Molecular Characterization of Human Telomerase Reverse Transcriptase-immortalized Human Fibroblasts by Gene Expression Profiling

Activation of the Epiregulin Gene^{1 ,, 2}

Department of Molecular Medicine [C. L., M. N.], Department of Medicine, Division of Hematology [M. Ho., C. Z., M. B., D. X.], Microbiology and Tumor Biology Center [M. He.], Karolinska Hospital and Institutet, SE-171 76 Stockholm, Sweden; Molecular Biology Laboratory, Medical Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino-Cho, Omiyanshi, Saitama, 330-8530 Japan [T. K.]; Shaanxi Provincial Hospital, Xian, 710068 People’s Republic of China [C. Z.]; Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912 [J. M. S.]; Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503 [B. T. T.]

Reconstitution of telomerase activity by ectopic expression of telomerase reverse transcriptase (hTERT) results in an immortal phenotype in various types of normal human cells, including fibroblasts. Despite lack of transformation characteristics, it is unclear whether hTERT-immortalized cells are physiologically and biochemically the same as their normal counterparts. Here, we compared the gene expression profiles of normal and hTERT-immortalized fibroblasts by using a cDNA microarray containing 20,736 cDNA clones and identified 172 dysregulated genes or expressed sequence tags (ESTs). One of the highly expressed genes in the hTERT-immortalized fibroblasts (hTERT-BJ cells) encodes epiregulin, a potent growth factor. Blockade of epiregulin reduced the growth of hTERT-BJ cells and colony formation of hTERT-transformed fibroblasts. Moreover, inhibition of epiregulin function in immortal hTERT-BJ cells triggered a senescence program. Our results suggest that both activation of telomerase and subsequent induction of epiregulin are required for sustained cell proliferation. Given the significant difference in gene expression profiles between normal and hTERT-immortalized fibroblasts and the close relationship between epiregulin and tumorigenesis, we conclude that hTERT-immortalized cells may not replace their normal counterparts for studies of normal cell biology and that the use of hTERT for expansion of normal human cells for therapeutic purposes must be approached with caution.

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