Department of Urology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Institute of Precision Medicine, Jining Medical University, Jining, 272000, China.
Adv Exp Med Biol. 2017;983:207-216. doi: 10.1007/978-981-10-4310-9_15.
Metastasis is the sole cause of cancer death and there is no curable means in clinic. Cellular protein CRMP4 (DPYSL3 gene) was previously defined as a metastasis suppressor in human prostate cancers since its expression is dramatically reduced in lymphatic metastatic diseases and DPYSL3 overexpression in prostate cancer cells significantly suppressed cancer cell migration and invasion. To develop a CRMP4-based antimetastasis therapeutic approach, the small activating RNA (saRNA) technique was utilized to enhance CRMP4 expression in prostate cancer cells. A total of 14 saRNAs were synthesized and screened in multiple prostate cancer cell lines. Two saRNAs targeting the isoform-2 promoter region were determined to have significant activating effect on DPYSL3 gene expression at the mRNA and protein levels. These saRNA also largely reduced prostate cancer cell migration and invasion in vitro and in vivo. Most significantly, PSMA aptamer-mediated prostate cancer cell homing of these saRNAs blocked distal metastasis in an orthotopic nude mouse model. In conclusion, our data demonstrated that saRNA-based DPYSL3 gene enhancement is capable of suppressing tumor metastasis in prostate cancer, which provides a potential therapeutic approach for cancer management.
转移是癌症死亡的唯一原因，临床上尚无治愈方法。细胞蛋白 CRMP4（DPYSL3 基因）先前被定义为人类前列腺癌的转移抑制因子，因为其在淋巴转移疾病中的表达显著降低，而 DPYSL3 在前列腺癌细胞中的过表达显著抑制了癌细胞的迁移和侵袭。为了开发基于 CRMP4 的抗转移治疗方法，利用小激活 RNA（saRNA）技术增强前列腺癌细胞中的 CRMP4 表达。总共合成并筛选了 14 种 saRNA，用于多种前列腺癌细胞系。两种靶向同种型-2 启动子区域的 saRNA 被确定在 mRNA 和蛋白水平上对 DPYSL3 基因表达具有显著的激活作用。这些 saRNA 还大大减少了前列腺癌细胞的体外和体内迁移和侵袭。最重要的是，PSMA 适体介导的这些 saRNA 的前列腺癌细胞归巢阻断了原位裸鼠模型中的远端转移。总之，我们的数据表明，基于 saRNA 的 DPYSL3 基因增强能够抑制前列腺癌的肿瘤转移，为癌症管理提供了一种潜在的治疗方法。
