Transcriptional targeting in renal cancer cell lines via the human CXCR4 promoter.
Metastatic renal cell carcinoma (RCC) is often resistant to standard treatment, thereby requiring new therapeutic strategies. In this regard, tumor cell migration and metastasis have recently been shown to be regulated by chemokines and their respective receptors (e.g., SDF-1alpha/CXCR4). In the context of RCC, up-regulation of CXCR4 expression is closely related to the development of invasive cancer. Thus, we hypothesized that the CXCR4 pathway could be exploited for RCC targeting with gene therapy vectors. In this regard, targeting adenoviral vectors to tumor cells is critically dependent on tumor-specific gene expression. Toward the end of RCC tumor targeting, we evaluated the utility of the CXCR4 promoter in an adenoviral context. First, overexpression of CXCR4 was confirmed in several RCC cell lines. Next, an adenoviral vector was constructed, whereby the human CXCR4 promoter drives the expression of a reporter gene. We tested the activity of the CXCR4 promoter in vitro and in vivo in relevant models. Our data indicate that the human CXCR4 promoter is highly active in RCC cells but not in normal human cells. Finally, biodistribution studies in mice demonstrated dramatic repression of the CXCR4 promoter in the liver but not in the kidney. In conclusion, the unique activity of the CXCR4 promoter in RCC lines and its repression in normal human cells and in the murine liver underscore its potential utility as a novel candidate for transcriptional targeting of RCC.
Haviv
Yosef S
YS
Division of Nephrology, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel 91120. yhaviv@hadassah.org.il
van Houdt
Winan J
WJ
Lu
Baogen
B
Curiel
David T
DT
Zhu
Zeng B
ZB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
D019718:Receptors, CXCR4