microRNA response elements-regulated TRAIL expression shows specific survival-suppressing activity on bladder cancer
Zhao Y, Li Y, Wang L, Yang H, Wang Q, Qi H, Li S, Zhou P, Liang P, Wang Q, Li X. J Exp Clin Cancer Res. 2013 Feb 26;32:10. doi: 10.1186/1756-9966-32-10.

Source

Department of Urology, General Hospital of Chengdu Military Area Command of Chinese PLA, Chengdu 610083, Sichuan Province, People's Republic of China. zhaoyg717@163.com.

Abstract

BACKGROUND:

Bladder transitional cell carcinoma greatly threatens human health all over the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis-inducing effect on a variety of cancer cells including bladder cancer. However, adenovirus-mediated TRAIL expression still showed cytotoxicity to normal cells mainly due to lack of tumor specificity.

METHODS:

To solve the problem, we applied miRNA response elements (MREs) of miR-1, miR-133 and miR-218 to confer TRAIL expression with specificity to bladder cancer cells.

RESULTS:

Expression of miR-1, miR-133 and miR-218 was greatly decreased in bladder cancer than normal bladder tissue. Luciferase assay showed that application of the 3 MREs was able to restrain exogenous gene expression to within bladder cancer cells. Subsequently, we constructed a recombinant adenovirus with TRAIL expression regulated by MREs of miR-1, miR-133 and miR-218, namely Ad-TRAIL-MRE-1-133-218. qPCR, immunoblotting and ELISA assays demonstrated that Ad-TRAIL-MRE-1-133-218 expressed in bladder cancer cells, rather than normal bladder cells. The differential TRAIL expression also led to selective apoptosis-inducing and growth-inhibiting effect of Ad-TRAIL-MRE-1-133-218 on bladder cancers. Finally, bladder cancer xenograft in mouse models further confirmed that Ad-TRAIL-MRE-1-133-218 effectively suppressed the growth of bladder cancers.

CONCLUSIONS:

Collectively, we demonstrated that MREs-based TRAIL delivery into bladder cancer cells was feasible and efficient for cancer gene therapy.