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Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA
Replacement through MicroRNA Regulation
#MMPMID26189916
Kim J
; Won R
; Ban G
; Ju MH
; Cho KS
; Young Han S
; Jeong JS
; Lee SW
Sci Rep
2015[Jul]; 5
(?): 12315
PMID26189916
show ga
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.
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