Targeted knockdown of Bcl2 in tumor cells using a synthetic TRAIL 3'-UTR microRNA.
Targeted knockdown of Bcl2 in tumor cells using a synthetic TRAIL 3'-UTR microRNA.
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DOI：
10.1002/ijc.24821
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发表时间：
2010-05-01
影响因子：
6.4
通讯作者：
Ge, Shengfang
中科院分区：
文献类型：
--
作者：
Zhang, Jianjun;Huang, Shenglin;Zhang, He;Wang, Haibo;Guo, Haiyan;Qian, Guanxiang;Fan, Xianqun;Lu, Jian;Hoffman, Andrew R.;Hu, Ji-Fan;Ge, Shengfang
通过RNAi靶向肿瘤相关的抗凋亡Bcl2蛋白的过表达已被认为是一种潜在的治疗癌症的方法。然而，RNAi的稳定性及其递送仍然是Bcl2 RNAi临床检测的主要障碍。在这里，我们探索了在肿瘤坏死因子相关凋亡诱导配体（TRAIL）的3 '非翻译区（UTR）表达合成Bcl2 microRNA （smRNA）的新策略，TRAIL是一种在正常细胞中无明显毒性作用的凋亡诱导蛋白。TRAIL是由在许多人类肿瘤中活跃的人类端粒酶逆转录酶启动子（pTRT）特异性表达的。通过这种方法，我们证明了pTRT驱动Bcl2 smRNA的肿瘤特异性表达，该表达被宿主RNAi机制处理，并沉默了肿瘤细胞中内源性Bcl2的表达。Bcl2 smRNA通过激活caspase-3诱导肿瘤细胞凋亡，导致肿瘤细胞对trail诱导的凋亡显着增敏，而正常细胞则不受影响。我们还发现，TRAIL诱导的细胞凋亡和Bcl2下调联合治疗优于TRAIL或Bcl2 smRNA单独治疗。本研究证明了利用3 ' UTR microRNA技术治疗癌症的一般范例。
Targeting tumor-related overexpression of anti-apoptotic Bcl2 protein by RNAi has been suggested as a potential treatment for cancer. However, the stability of RNAi and its delivery are still major obstacles to the clinical testing of Bcl2 RNAi. Here we explore a novel strategy of expressing a synthetic Bcl2 microRNA (smRNA) in the 3’ untranslated region (UTR) of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an apoptosis-inducing protein without apparent toxic effects in normal cells. TRAIL was specifically expressed from the human telomerase reverse transcriptase promoter (pTRT) that is active in many human tumors. Using this approach, we demonstrated that pTRT drove the tumor-specific expression of Bcl2 smRNA, which was processed by the host RNAi machinery and silenced endogenous Bcl2 expression in tumor cells. Bcl2 smRNA induced tumor cell apoptosis by activating caspase-3 and led to significant sensitization of tumor cells to TRAIL-induced apoptosis, while normal cells were spared. We also showed that the combined therapy of TRAIL-induced apoptosis and Bcl2 down-regulation was superior to the mono-therapy of TRAIL or Bcl2 smRNA alone. This study proves a general paradigm for cancer therapy by using 3’ UTR microRNA technology.
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影响因子：
4.7
作者：
Parris GE
通讯作者：
Parris GE
影响因子：
4.8
作者：
Hu, JF;Vu, TH;Hoffman, AR
通讯作者：
Hoffman, AR
影响因子：
14.9
作者：
Chung KH;Hart CC;Al-Bassam S;Avery A;Taylor J;Patel PD;Vojtek AB;Turner DL
通讯作者：
Turner DL
影响因子：
3.4
作者：
Knox, J. J.;Chen, X. E.;Moore, M.
通讯作者：
Moore, M.
影响因子：
8.2
作者：
Huang, SL;Wu, Y;Zhao, HF
通讯作者：
Zhao, HF