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Down-regulation of TSC-22 (Transforming Growth Factor ß-stimulated Clone 22) Markedly Enhances the Growth of a Human Salivary Gland Cancer Cell Line in Vitro and in Vivo¹

Second Department of Oral and Maxillofacial Surgery [K-i. N., H. K., S. H., D. U., F. O., H. Y., M. S.], Department of Biochemistry [Y. M.], and Department of Pathology [H. H.], Tokushima University School of Dentistry, Tokushima 770, Japan

We have recently isolated TSC-22 (transforming growth factor ß-stimulated clone 22) cDNA as a new anticancer drug (Vesnarinone)-inducible gene in a human salivary gland cancer cell line, TYS. We conducted the present study to examine whether up-regulation or down-regulation of TSC-22 can affect the growth of TYS cells in vitro and in vivo. We constructed an expression vector containing sense- or antisense-oriented human TSC-22 cDNA under the transcriptional control of the SR promoter. We cotransfected TYS cells with the sense or antisense expression vector and pSV2neo and obtained more than 200 G418-resistant colonies in each sense or antisense transfectant. Approximately 80% of representative G418-resistant clones expressed the transcripts from transfected sense or antisense TSC-22 cDNA. To avoid the clonal heterogeneity of the cells, we mixed all of the G418-resistant colonies together in each sense or antisense transfectant and examined the expression of TSC-22 protein, in vitro growth, and the tumorigenicity in nude mice. The expression of TSC-22 protein was examined by solid-phase ELISA using a specific antibody against recombinant TSC-22 protein. The expression of TSC-22 protein was up-regulated in the sense transfectants and down-regulated in the antisense transfectants. Contrary to our expectation, up-regulation of TSC-22 protein did not affect both in vitro and in vivo growth of TYS cells. However, down-regulation of TSC-22 markedly enhanced the growth of TYS cells in vitro and in vivo. Furthermore, we examined the expression of TSC-22 mRNA in several human salivary gland tumors. The mRNA expression of TSC-22 in benign and malignant salivary gland tumors was significantly decreased when compared to that in tumor-free salivary glands (P < 0.05; one-way ANOVA), and in some salivary gland tumors, the expression of TSC-22 mRNA was not detectable by reverse transcription-PCR. These results suggest that down-regulation of TSC-22 may play a major role on salivary gland tumorigenesis.

¹ This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan, and by a Tokushima University Institutional grant.

² To whom requests for reprints should be addressed, at Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, 3-18-15 Kuramoto, Tokushima 770, Japan. Phone: 81-886-33-7354; Fax: 81-886-33-7462; E-mail: kawamata@dent.tokushima-u.ac.jp.

Received 7/17/97. Accepted 12/ 1/97.

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