U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3.
BACKGROUND
Insensitivity of advanced-stage prostate cancer to androgen ablation therapy is a serious problem in clinical practice because it is associated with aggressive progression and poor prognosis. Targeted therapeutic drug discovery efforts are thwarted by lack of adequate knowledge of gene(s) associated with prostate tumorigenesis. Therefore there is the need for studies to provide leads to targeted intervention measures. Here we propose that stable expression of U94, a tumor suppressor gene encoded by human herpesvirus 6A (HHV-6A), could alter gene expression and thereby inhibit the tumorigenicity of PC3 cell line. Microarray gene expression profiling on U94 recombinant PC3 cell line could reveal genes that would elucidate prostate cancer biology, and hopefully identify potential therapeutic targets.


RESULTS
We have shown that stable expression of U94 gene in PC3 cell line inhibited its focus formation in culture, and tumorigenesis in nude mice. Moreover gene expression profiling revealed dramatic upregulation of FN 1 (fibronectin, 91 +/- 16-fold), and profound downregulation of ANGPTL 4 (angiopoietin-like-4, 20 +/- 4-fold) in U94 recombinant PC3 cell line. Quantitative real-time polymerase chain reaction (QRT-PCR) analysis showed that the pattern of expression of FN 1 and ANGPTL 4 mRNA were consistent with the microarray data. Based on previous reports, the findings in this study implicate upregulation of FN 1 and downregulation of ANGPTL 4 in the anti tumor activity of U94. Genes with cancer inhibitory activities that were also upregulated include SERPINE 2 (serine/cysteine protease inhibitor 2, 7 +/- 1-fold increase) and ADAMTS 1 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7 +/- 2-fold increase). Additionally, SPUVE 23 (serine protease 23) that is pro-tumorigenic was significantly downregulated (10 +/- 1-fold).


CONCLUSIONS
The dramatic upregulation of FN 1 and downregulation of ANGPTL 4 genes in PC3 cell line stably expressing U94 implicate up-regulation of FN 1 and downregulation of ANGPTL 4 in anti tumor activity of U94. Further studies are necessary to determine functional roles of differentially expressed genes in U94 recombinant PC3 cell line, and hopefully provide leads to potential therapeutic targets in prostate cancer.
Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA. eti@georgetown.edu
Ekwere T
ET
Ifon
Alan L Y
AL
Pang
Warren
W
Johnson
Kathleen
K
Cashman
Sharon
S
Zimmerman
Sumitra
S
Muralidhar
Wai-Yee
WY
Chan
John
J
Casey
Leonard Jason
LJ
Rosenthal