U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3.
U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3.
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DOI：
10.1186/1475-2867-5-19
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发表时间：
2005-06-22
影响因子：
5.8
通讯作者：
Rosenthal LJ
中科院分区：
文献类型：
--
作者：
Ifon ET;Pang AL;Johnson W;Cashman K;Zimmerman S;Muralidhar S;Chan WY;Casey J;Rosenthal LJ
晚期前列腺癌对雄激素消融治疗的不敏感性是临床实践中的一个严重问题，因为它与侵袭性进展和不良预后相关。靶向治疗药物发现的努力由于缺乏与前列腺肿瘤发生相关的基因的足够知识而受阻。因此，有必要进行研究，为有针对性的干预措施提供线索。本研究表明，人疱疹病毒6A型（HHV-6A）编码的抑癌基因U94的稳定表达可以改变基因表达，从而抑制PC 3细胞系的致瘤性。U94重组PC 3细胞系的基因表达谱芯片可以揭示前列腺癌生物学的基因，并有希望确定潜在的治疗靶点。U94基因在PC 3细胞系中的稳定表达抑制了其在培养中的病灶形成和在裸鼠体内的成瘤性。此外，基因表达谱显示在U94重组PC 3细胞系中FN 1（纤连蛋白，91 ± 16倍）的显著上调和ANGPTL 4（血管生成素样-4，20 ± 4倍）的显著下调。实时荧光定量聚合酶链反应（QRT-PCR）分析显示FN 1和ANGPTL 4 mRNA的表达模式与芯片数据一致。基于先前的报道，本研究中的发现暗示U94的抗肿瘤活性中FN 1的上调和ANGPTL 4的下调。具有癌症抑制活性的基因也被上调，包括SERPINE 2（丝氨酸/半胱氨酸蛋白酶抑制剂2，增加7 ± 1倍）和ADAMTS 1（具有血小板反应蛋白1型基序的解整合素样和金属蛋白酶，增加7 ± 2倍）。此外，促肿瘤发生的SPUVE 23（丝氨酸蛋白酶23）显著下调（10 ± 1倍）。在稳定表达U94的PC 3细胞系中，FN 1基因的显著上调和ANGPTL 4基因的显著下调暗示了在U94的抗肿瘤活性中FN 1的上调和ANGPTL 4的下调。因此，有必要进一步研究U94重组PC 3细胞系中差异表达基因的功能，以期为前列腺癌的治疗提供新的靶点。
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. 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). 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.
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影响因子：
2.8
作者：
BUTTYAN, R;SAWCZUK, IS;OLSSON, CA
通讯作者：
OLSSON, CA
影响因子：
5.8
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64.8
作者：
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通讯作者：
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