MiRNA Regulation Of TRAIL Expression Exerts Selective Cytotoxicity To Prostate Carcinoma Cells

Prostate carcinoma is the most common cancer for men and amongthe leading cancer-related causes. Many evidences have shown that tumornecrosis factor-related apoptosis-inducing ligand (TRAIL) potentlyinduces apoptosis in cancer cells, and thus, is a promising biologic agentfor prostate carcinoma therapy. However, TRAIL expression mediated bythe current vectors lacks tumor specificity, thereby exerting cytotoxicityto normal cells. To solve this problem, we inserted miRNA responseelements (MRE), miR-143and miR-145, expression levels of which werereduced in prostate carcinoma, as well as that of miR-122, which isspecifically expressed in hepatic cells, into adenoviral vectors to controlTRAIL expression (Ad-TRAIL-M3). qPCR data confirmed that miR-143,miR-145, and miR-122levels were all decreased in prostate carcinomacell lines and prostate cancer samples from patients. Luciferase assaysshowed that MRE-regulated luciferase expression was potentlysuppressed in normal cells, but not in prostate cancer cells.Ad-TRAIL-M3, which expresses TRAIL in a MRE-regulated manner,produced high level of TRAIL and suppressed the survival of prostatecancer cells by inducing apoptosis, while Ad-TRAIL-M3had no TRAILexpression in normal cells and thus exerted no cytotoxicity to them. Thestudies on PC-3tumor xenograft in mice further confirmed thatAd-TRAIL-M3was able to inhibit the growth of tumors and possessed high biosafety. In conclusion, we successfully generated an adenoviralvector that expresses TRAIL in miRNA-regulated mechanism. ThismiRNA-based gene therapy may be promising for prostate carcinomatreatment.Objective:To investigate the miRNA regulation of TRAIL expression exertsselective cytotoxicity to prostate carcinoma cells， looking for newtreatment strategies to prostate carcinoma.Method:Inserted MRE of miR-143and miR-145into adenoviral vectors torestrict TRAIL expression within prostate cancer cells. In addition, MREof liver-specific miR-122was also applied to further reduce theunexpected expression of TRAIL in liver tissue. The recombinantadenoviral vector was designated as Ad-TRAIL-M3. The antitumorefficacy and specificity of this vector to prostate carcinoma were alsoexamined in the subsequent experiments.Result:The expressions of miR-143, miR-145and miR-122was reduced inprostate carcinoma cells; MRE of miR-143, miR-145, and miR-122wereable to restrict adenovirus-mediated TRAIL expression within prostatecancer cells; Ad-TRAIL-M3exhibited prostate cancer specificity and hadno significant cytotoxicity to normal cells; MRE-regulated TRAIL expression was able to induce selective apoptosis in prostate cancer cells;Ad-TRAIL-M3induced apoptosis in tumors rather than in normal livertissues. These data suggested that Ad-TRAIL-M3leads to no cytotoxicityto liver tissues in vivo.Conclusion:We generated a TRAIL-expressing ad-enviral vector, where MRE ofmiR-143, miR-145, and miR-122were applied for prostate cancerselectivity. In vitro and in vivo data showed that this strategy suppressedthe growth of prostate cancers without hepatotoxicity, and may bepromising candidate agents for prostate cancer treatment.