Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis.
Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis.
复制标题
DOI：
10.18632/oncotarget.8290
复制
发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Li C;Jiang W;Hu Q;Li LC;Dong L;Chen R;Zhang Y;Tang Y;Thrasher JB;Liu CB;Li B
为了探索一种新的抑制肿瘤转移的策略，我们利用最近的RNA激活（RNAa）理论，使用与靶基因启动子互补的小双链RNA分子，称为小激活RNA（saRNA），来增强转移抑制基因的转录。本研究中的靶基因是二氢嘧啶酶样3（DPYSL 3，蛋白质名称CRMP 4），其被鉴定为前列腺癌的转移抑制因子。DPYSL 3基因在人类基因组中存在两种转录变体，其中变体2为显性转录（DPYSL 3v 2，CRMP 4a），但在原发性前列腺癌中也显著下调。在多种前列腺癌细胞系中测试了DPYSL 3v 1的总共8种saRNA和DPYSL 3v 2的14种saRNA。虽然saRNA均未显著改变DPYSL 3v 1表达，但4种saRNA显示出对DPYSL 3v 2表达的强烈增强作用，导致体外细胞迁移率降低。为了实现用于体内测试的前列腺癌特异性递送，我们将最有效的saV 2 -9 RNA分子与前列腺特异性膜抗原（PSMA）靶向适体A10-3.2缀合。缀合物成功地增加了PSMA阳性但非PSMA阴性前列腺癌细胞中的DPYSL 3v 2基因表达。在携带前列腺癌原位异种移植物的裸鼠中，与对照saRNA相比，用saV 2 -9缀合物连续治疗10天显著抑制远端转移。异种移植组织的分析揭示，与对照组相比，在saV 2 -9缀合物处理组中DPYSL 3v 2表达大大增加。总之，DPYSL 3v 2启动子靶向的saRNA分子可用作抑制前列腺癌转移的连续疗法。
To explore a novel strategy in suppressing tumor metastasis, we took the advantage of a recent RNA activation (RNAa) theory and used small double-strand RNA molecules, termed as small activating RNAs (saRNA) that are complimentary to target gene promoter, to enhance transcription of metastasis suppressor gene. The target gene in this study is Dihydro-pyrimidinase-like 3 (DPYSL3, protein name CRMP4), which was identified as a metastatic suppressor in prostate cancers. There are two transcriptional variants of DPYSL3 gene in human genome, of which the variant 2 is the dominant transcript (DPYSL3v2, CRMP4a) but is also significantly down-regulated in primary prostate cancers. A total of 8 saRNAs for DPYSL3v1 and 14 saRNAs for DPYSL3v2 were tested in multiple prostate cancer cell lines. While none of the saRNAs significantly altered DPYSL3v1 expression, 4 saRNAs showed a strong enhancing effect on DPYSL3v2 expression, resulting in reduced cell mobility in vitro. To achieve a prostate cancer-specific delivery for in vivo testing, we conjugated the most potent saV2-9 RNA molecule with the prostate-specific membrane antigen (PSMA)-targeting aptamer A10-3.2. The conjugates successful increased DPYSL3v2 gene expression in PSMA-positive but not PSMA-negative prostate cancer cells. In nude mice bearing orthotopic xenograft of prostate cancer, a 10-day consecutive treatment with the saV2-9 conjugates significantly suppress distal metastasis compared to the control saRNAs. Analysis of xenograft tissues revealed that DPYSL3v2 expression was largely increased in saV2-9 conjugate-treated group compared to the control group. In conclusion, DPYSL3v2 promoter-targeted saRNA molecules might be used as an adjunctive therapy to suppress prostate cancer metastasis.
登录
查看更多内容
影响因子：
11.2
作者：
Mukherjee, Joydeep;DeSouza, Leroi V.;Guha, Abhijit
通讯作者：
Guha, Abhijit
影响因子：
46.9
作者：
Dassie, Justin P.;Liu, Xiu-ying;Thomas, Gregory S.;Whitaker, Ryan M.;Thiel, Kristina W.;Stockdale, Katie R.;Meyerholz, David K.;McCaffrey, Anton P.;McNamara, James O., II;Giangrande, Paloma H.
通讯作者：
Giangrande, Paloma H.
DOI：
10.3390/molecules14041353
发表时间：
2009-03-27
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Pan W;Clawson GA
通讯作者：
Clawson GA
影响因子：
11.2
作者：
Kang, Moo Rim;Yang, Glen;Li, Long-Cheng
通讯作者：
Li, Long-Cheng
影响因子：
64.8
作者：
GOSHIMA, Y;NAKAMURA, F;STRITTMATTER, SM
通讯作者：
STRITTMATTER, SM