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MiRNA regulation of TRAIL expression exerts selective cytotoxicity to prostate carcinoma cells

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Abstract

Prostate carcinoma is the most common cancer for men and among the leading cancer-related causes. Many evidences have shown that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) potently induces apoptosis in cancer cells, and thus, is a promising biologic agent for prostate carcinoma therapy. However, TRAIL expression mediated by the current vectors lacks tumor specificity, thereby exerting cytotoxicity to normal cells. To solve this problem, we inserted miRNA response elements (MREs), miR-143 and miR-145, expression levels of which were reduced in prostate carcinoma, as well as that of miR-122, which is specifically expressed in hepatic cells, into adenoviral vectors to control TRAIL expression (Ad-TRAIL-M3). qPCR data confirmed that miR-143, miR-145, and miR-122 levels were all decreased in prostate carcinoma cell lines and prostate cancer samples from patients. Luciferase assays showed that MREs-regulated luciferase expression was potently suppressed in normal cells, but not in prostate cancer cells. Ad-TRAIL-M3, which expresses TRAIL in a MREs-regulated manner, produced high level of TRAIL and suppressed the survival of prostate cancer cells by inducing apoptosis, while Ad-TRAIL-M3 had no TRAIL expression in normal cells and thus exerted no cytotoxicity to them. The studies on PC-3 tumor xenograft in mice further confirmed that Ad-TRAIL-M3 was able to inhibit the growth of tumors and possessed high biosafety. In conclusion, we successfully generated an adenoviral vector that expresses TRAIL in miRNA-regulated mechanism. This miRNA-based gene therapy may be promising for prostate carcinoma treatment.

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Acknowledgments

The authors thank Dr. Zhao at the General Hospital of Chengdu Military Area Command of Chinese PLA, Chengdu, China. for his kind gift of adenoviral vector, Ad-TRAIL, and Ad-EGFP.

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Authors and Affiliations

  1. Department of Urology, China Japan Union Hospital of Jilin University, Changchun, 130033, China

    Wei Huo, Ning Jin, Li Fan & Weihua Wang

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  1. Wei Huo
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Correspondence to Weihua Wang.

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Huo, W., Jin, N., Fan, L. et al. MiRNA regulation of TRAIL expression exerts selective cytotoxicity to prostate carcinoma cells. Mol Cell Biochem 388, 123–133 (2014). https://doi.org/10.1007/s11010-013-1904-3

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  • DOI: https://doi.org/10.1007/s11010-013-1904-3

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