Department of Pathophysiology, Norman Bethune College of Medicine and Prostate Diseases Prevention and Treatment Research Center, Jilin University, Changchun, China.
Cancer Gene Ther. 2010 Dec;17(12):844-54. doi: 10.1038/cgt.2010.41. Epub 2010 Aug 13.
The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (r(s)=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin-dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin-shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis.
前列腺癌的发生涉及多种基因改变。例如，survivin 和 p53 的改变都被报道在前列腺癌的进展中具有关键作用。然而，关于 p53 和 survivin 在前列腺癌中的相互关系知之甚少。我们的数据表明，survivin 的表达与前列腺癌和正常前列腺组织中 wtp53 蛋白的表达呈负相关（r(s)=0.548）。我们开发了一种治疗策略，其中两种抗肿瘤因子，小干扰 RNA-survivin 和 p53 蛋白，从同一个质粒中共同表达，并研究了它们对雄激素非依赖性前列腺癌细胞系 PC3 的生长的影响。当 p53 与 survivin 特异性短发夹 RNA（shRNA）共表达时，肿瘤细胞增殖明显受到抑制，发生凋亡。此外，这种组合还消除了下游靶分子如细胞周期蛋白依赖性激酶 4 和 c-Myc 的表达，同时增强了 GRIM19 的表达。与对照组或单一治疗组相比，在存在 survivin-shRNA/wtp53 的情况下，这些基因表达的变化明显。在裸鼠模型中，肿瘤内注射共表达构建体抑制了肿瘤异种移植物的生长和存活。这些研究揭示了 p53 和 survivin 蛋白之间存在相互作用的证据，以及 wtp53-survivin 通路下游的复杂信号网络积极控制肿瘤细胞增殖、存活和凋亡。
