Chen N, Szentirmay M N, Pawar S A, Sirito M, Wang J, Wang Z, Zhai Q, Yang H-X, Peehl D M, Ware J L, Sawadogo M
Department of Molecular Genetics, The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
Oncogene. 2006 Jan 26;25(4):579-87. doi: 10.1038/sj.onc.1209079.
Although the transcription factor USF2 has been implicated in the regulation of cellular growth and proliferation, it is unknown whether alterations in USF2 contribute to tumorigenesis and tumor development. We examined the role of USF2 in prostate tumorigenesis. Western blot analysis revealed markedly decreased USF2 levels in three androgen-independent prostate cancer cell lines, PC-3, DU145, and M12, as compared to nontumorigenic prostate epithelial cells or the androgen-dependent cell line, LNCaP. Ectopic expression of USF2 in PC-3 cells did not affect the cell proliferation rate of PC-3 cells on plastic surfaces. However, it dramatically decreased anchorage-independent growth of PC-3 cells in soft agar (90-98% inhibition) and the invasion capability (80% inhibition) of PC-3 cells in matrix gel assay. Importantly, expression of USF2 in PC-3 cells inhibited the tumorigenicity of PC-3 cells in an in vivo nude mice xenograft model (80-90% inhibition). These results suggest that USF2 has tumor-suppression function. Consistent with its function in tumor suppression, we found that the USF2 protein is present in normal prostate epithelial cells but absent in 18 of 42 (43%) human prostate cancer tissues (P = 0.015). To further examine the functional role of USF2 in vivo, we generated mice with genetic deletion of USF2 gene. We found that USF2-null mice displayed marked prostate hyperplasia at a young age, suggesting that USF2 is involved in the normal growth and differentiation of prostate. Together, these studies demonstrate that USF2 has tumor-suppressor function and plays a role in prostate carcinogenesis.
尽管转录因子USF2与细胞生长和增殖的调控有关，但尚不清楚USF2的改变是否有助于肿瘤发生和肿瘤发展。我们研究了USF2在前列腺肿瘤发生中的作用。蛋白质印迹分析显示，与非致瘤性前列腺上皮细胞或雄激素依赖性细胞系LNCaP相比，三种雄激素非依赖性前列腺癌细胞系PC-3、DU145和M12中的USF2水平显著降低。在PC-3细胞中异位表达USF2并不影响PC-3细胞在塑料表面的增殖率。然而，它显著降低了PC-3细胞在软琼脂中的非锚定依赖性生长（抑制率为90%-98%）以及在基质胶试验中PC-3细胞的侵袭能力（抑制率为80%）。重要的是，在体内裸鼠异种移植模型中，PC-3细胞中USF2的表达抑制了PC-3细胞的致瘤性（抑制率为80%-90%）。这些结果表明USF2具有肿瘤抑制功能。与其在肿瘤抑制中的功能一致，我们发现USF2蛋白存在于正常前列腺上皮细胞中，但在42个人前列腺癌组织中的18个（43%）中不存在（P = 0.015）。为了进一步研究USF2在体内的功能作用，我们构建了USF2基因缺失的小鼠。我们发现USF2基因缺失的小鼠在年轻时出现明显的前列腺增生，这表明USF2参与前列腺的正常生长和分化。总之，这些研究表明USF2具有肿瘤抑制功能，并在前列腺癌发生中发挥作用。
