Expression and Regulation of the Human CtenGene

Cten is a focal adhesion molecule and a member with smallest molecular weight of the tensin family. Little is known about cten gene transcriptional regulation and the underlying signaling mechanism in human normal and cancerous cells. This dissertation aimed to elucidate the expression patterns in human and in mouse and to characterize human cten promoter. The second aspect of this dissertation focused on identifying the effect of cten deficiency in prostate and colon cancer mouse models and exploring the expression of cten in human tissues using tissue array analysis. The ultimate goal of this study is to evaluate the utilization of cten as a biomarker for certain cancers.;In order to characterize the cten transcription system, I have identified the potential transcription initiation site and cloned the 2-kb upstream region of human cten gene, which produced higher luciferase reporter activity in the normal prostate cell lines, than other non-prostatic cell lines. The shortest functional promoter fragment between -290 and +37, which displayed relatively high activity, was applied in the generation of a transgenic mouse line, hcten-Cre. The cells with strong beta-galactosidase activity in hcten-Cre:R26R double transgenic mice were distributed in prostate epithelium and most areas of brain, whereas few activities were detected in other tissues.;EGF markedly increased cten expression at the transcriptional and translational levels in RWPE-1 prostate cells compared with untreated cells. To elucidate the components involved in EGF signaling pathway, the EGFR inhibitor and the MEK 1/2 inhibitor could significantly inhibit the upregulation of cten at the translational level upon EGF treatment. These results suggested that the MEK-ERK signaling pathway is involved in EGF-stimulated cten expression. In addition, R1881, a synthetic androgen, enhanced cten expression both at the transcriptional and translational levels in a low-cten-expressed but androgen-sensitive prostatic LNCaP cells. Furthermore, overexpression of cten in LNCaP cells significantly enhanced their migration but not cell proliferation. Differing from what was shown in prostate cancer, cten is upregulated in colon cancer, including adenocarcinonatous tissues and cancer cell lines. However, neither cten knockdown in SW480 cells, which express high levels of cten, nor cten overexpression in HCT116 cells, which express lower levels of cten, had any effect on TCF/LEF transcriptional activity.;To explore the effect of cten deficiency in prostate and colon cancers, the TRAMP and Min mouse models were used for these two diseases, respectively. However, the prostate tumor progression in TRAMP mice and the intestinal carcinomas in Min mice remained unchanged between different genotypes. In addition to the significant upregulation of cten in colon cancer specimens by tissue array analysis, it was found that expression of cten was markedly lower in renal cell carcinomas, especially in clear cell carcinoma. Thus, cten could be a positive or negative biomarker for detecting early and advanced prostate, colon and kidney cancers.;To summarize, this dissertation elucidated the expression pattern, promoter activity and signaling pathway of human cten in human cell lines and tissues. This dissertation has also augmented the understanding about cten in colon and prostate cancer progression using disease mouse models. Advanced validation of cten expression may lead to a novel biomarker for certain cancer diagnosis and targeted therapy.