1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1
1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1
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DOI：
10.1186/1471-2164-11-26
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发表时间：
2010-01-13
期刊：
影响因子：
4.4
通讯作者：
Fleet, James C.
中科院分区：
文献类型：
--
作者：
Kovalenko, Pavlo L.;Zhang, Zhentao;Fleet, James C.
背景：前列腺癌是美国男性癌症死亡的第二大原因。流行病学证据表明，高水平的维生素D可以保护男性免受前列腺癌的侵害，维生素D的活性形式1 α，25二羟基维生素D-3 (1,25（OH)(2)D）在培养的前列腺细胞中具有抗癌作用。然而，维生素d介导的前列腺癌预防的分子机制和基因靶点尚不清楚。结果：我们检测了1,25(OH)(2)D （+/-100 nM, 6, 24, 48 h）对增殖的RWPE1细胞转录谱的影响，RWPE1细胞是一种永生化的非致瘤性前列腺上皮细胞系，其生长被1,25(OH)(2)D （Affymetrix U133 Plus 2.0, n = 4/次处理每次和剂量）阻止。我们的分析显示，在5%的错误检测率下，转录本水平发生了许多变化：6小时，1571（61%上升），24小时，1816（60%上升），48小时，3566（38%上升）。288个转录本在所有时间点都受到类似的调控（182个向上，80个向下），这些转录本的许多启动子含有假定的维生素D反应元件。通过通路或基因集分析的功能分析显示WNT、Notch、NF-kB和IGF1信号的早期抑制。炎症相关转录本在6小时被抑制（如IL-1途径），促炎途径的抑制在以后的时间点继续（如IL-17和IL-6途径）。也有证据表明，维生素D可以诱导抗血管生成途径和转录物，以保护细胞免受氧化应激或维持细胞氧化还原稳态。结论：我们的数据揭示了大量潜在的新的、直接的维生素D靶基因与前列腺癌的预防有关。此外，我们的数据表明，维生素D不是具有单一的强大调节作用，而是在前列腺上皮细胞内协调一种模式的变化，从而限制或减缓癌变。
Background: Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1 alpha, 25 dihydroxyvitamin D-3 (1,25(OH)(2)D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown.Results: We examined the effect of 1,25(OH)(2)D (+/-100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)(2)D (Affymetrix U133 Plus 2.0, n = 4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60% up), 48 h, 3566 (38% up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e. g. IL-1 pathway) and suppression of proinflammatory pathways continued at later time points (e. g. IL-17 and IL-6 pathways). There was also evidence for induction of anti-angiogenic pathways and induction of transcripts for protection from oxidative stress or maintenance of cell redox homeostasis at 6 h.Conclusions: Our data reveal of large number of potential new, direct vitamin D target genes relevant to prostate cancer prevention. In addition, our data suggests that rather than having a single strong regulatory effect, vitamin D orchestrates a pattern of changes within prostate epithelial cells that limit or slow carcinogenesis.