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Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.

Kim J, Won R, Ban G, Ju MH, Cho KS, Young Han S, Jeong JS, Lee SW - Sci Rep (2015)

Bottom Line: To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC.Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC.The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin 448-701, Republic of Korea.

ABSTRACT
Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

No MeSH data available.


Related in: MedlinePlus

Scheme for the TERT-targeting trans-splicing ribozyme-induced selective expression of therapeutic RNA in cancer cells through microRNA regulation.Trans-splicing ribozymes with target sites to liver-specific miR-122a at the 3′-UTR of the 3′exon recognize TERT RNA at the targeted uridine residue by selective base-pairing through their internal guide sequence in cancer cells lacking the miRNA. The ribozymes then remove the sequence downstream of the target site and replace it with the 3′ exon exerting anti-cancer activity.
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f1: Scheme for the TERT-targeting trans-splicing ribozyme-induced selective expression of therapeutic RNA in cancer cells through microRNA regulation.Trans-splicing ribozymes with target sites to liver-specific miR-122a at the 3′-UTR of the 3′exon recognize TERT RNA at the targeted uridine residue by selective base-pairing through their internal guide sequence in cancer cells lacking the miRNA. The ribozymes then remove the sequence downstream of the target site and replace it with the 3′ exon exerting anti-cancer activity.

Mentions: In this study, we combined post-transcriptional regulation with an RNA replacement strategy by developing TERT-targeting trans-splicing ribozymes regulated by liver-specific miR-122a (Fig. 1) and evaluated the cellular and in vivo specificity and efficacy as a tool for targeted HCC gene therapy to address the cancer-selectivity challenge raised by the TERT-targeting approach. Viral vectors encoding the ribozymes were constructed herein, and their target RNA specificity, transgene controllability, tissue selectivity, liver toxicity, and anti-cancer efficacy were analyzed in mouse models orthotopically implanted with not only xenografts but also syngeneic HCC.


Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.

Kim J, Won R, Ban G, Ju MH, Cho KS, Young Han S, Jeong JS, Lee SW - Sci Rep (2015)

Scheme for the TERT-targeting trans-splicing ribozyme-induced selective expression of therapeutic RNA in cancer cells through microRNA regulation.Trans-splicing ribozymes with target sites to liver-specific miR-122a at the 3′-UTR of the 3′exon recognize TERT RNA at the targeted uridine residue by selective base-pairing through their internal guide sequence in cancer cells lacking the miRNA. The ribozymes then remove the sequence downstream of the target site and replace it with the 3′ exon exerting anti-cancer activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507181&req=5

f1: Scheme for the TERT-targeting trans-splicing ribozyme-induced selective expression of therapeutic RNA in cancer cells through microRNA regulation.Trans-splicing ribozymes with target sites to liver-specific miR-122a at the 3′-UTR of the 3′exon recognize TERT RNA at the targeted uridine residue by selective base-pairing through their internal guide sequence in cancer cells lacking the miRNA. The ribozymes then remove the sequence downstream of the target site and replace it with the 3′ exon exerting anti-cancer activity.
Mentions: In this study, we combined post-transcriptional regulation with an RNA replacement strategy by developing TERT-targeting trans-splicing ribozymes regulated by liver-specific miR-122a (Fig. 1) and evaluated the cellular and in vivo specificity and efficacy as a tool for targeted HCC gene therapy to address the cancer-selectivity challenge raised by the TERT-targeting approach. Viral vectors encoding the ribozymes were constructed herein, and their target RNA specificity, transgene controllability, tissue selectivity, liver toxicity, and anti-cancer efficacy were analyzed in mouse models orthotopically implanted with not only xenografts but also syngeneic HCC.

Bottom Line: To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC.Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC.The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin 448-701, Republic of Korea.

ABSTRACT
Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

No MeSH data available.


Related in: MedlinePlus