This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, C. M. Articles by Hung, M.-C. Search for Related Content PubMed PubMed Citation Articles by Lee, C. M. Articles by Hung, M.-C.

Selective Activation of Ceruloplasmin Promoter in Ovarian Tumors

Potential Use for Gene Therapy

Departments of ¹ Gynecologic Oncology, ² Molecular and Cellular Oncology, ³ Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Gene therapy provides a novel treatment approach to cancer patients. Ideally, expression of therapeutic genes driven by cancer-specific promoters would only target tumors resulting in minimal toxicity to normal tissues. While there is a need of more effective and tolerable treatments for ovarian cancer patients, we aimed to identify gene promoters with high activity in ovarian tumors that can be potentially used in gene therapy to drive the expression of a therapeutic gene in tumors. To identify such promoters, a literature search was performed to reveal genes that are preferentially expressed in ovarian cancer compared with normal ovarian tissue. We found that the ceruloplasmin promoter drove up to 30-fold higher luciferase expression in ovarian cancer cells compared with immortalized normal cells. Furthermore, deletion studies revealed an activator protein-1 (AP-1) site in the ceruloplasmin promoter to be critical for optimal ceruloplasmin promoter activity. Ceruloplasmin promoter activity was significantly activated by 1-O-tetradecanoyl phorbol-13-acetate, a c-jun activator, and conversely suppressed by SP600125, a c-jun inhibitor. Consistently, the ceruloplasmin AP-1 site was specifically recognized by c-jun both in vitro and in vivo. Immunohistochemical analyses of human ovarian cancer specimens showed a direct correlation (r = 0.7, P = 0.007) between expression levels of c-jun and ceruloplasmin. In nude mice carrying SKOV3.ip1 xenografts, the ceruloplasmin promoter demonstrated significantly higher activities in tumors compared with normal organs. Together, these results suggest that the ceruloplasmin promoter activity is significantly enhanced in ovarian cancer and therefore may be exploited as a promising cancer-specific promoter in developing new gene therapy strategies for ovarian cancer.

This article has been cited by other articles:

				J.-Y. Yang and M.-C. Hung A New Fork for Clinical Application: Targeting Forkhead Transcription Factors in Cancer Clin. Cancer Res., February 1, 2009; 15(3): 752 - 757. [Abstract] [Full Text] [PDF]

				S. L. Tye, A. G. Gilg, L. B. Tolliver, W. G. Wheeler, B. P. Toole, and B. L. Maria Hyaluronan Regulates Ceruloplasmin Production By Gliomas and Their Treatment-Resistant Multipotent Progenitors J Child Neurol, October 1, 2008; 23(10): 1221 - 1230. [Abstract] [PDF]

				H.-W. Lo, S.-C. Hsu, W. Xia, X. Cao, J.-Y. Shih, Y. Wei, J. L. Abbruzzese, G. N. Hortobagyi, and M.-C. Hung Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression Cancer Res., October 1, 2007; 67(19): 9066 - 9076. [Abstract] [Full Text] [PDF]

				J. Knapp, L. Olson, S. Tye, J. R. Bethard, C. A. Welsh, Z. Rumbolt, I. Takacs, and B. L. Maria Case of Desmoplastic Infantile Ganglioglioma Secreting Ceruloplasmin J Child Neurol, November 1, 2005; 20(11): 920 - 924. [Abstract] [PDF]