Cancer-type organic anion transporting polypeptide 1B3 is a target for cancer suicide gene therapy using RNA trans-splicing technology

Y. Sun, J. Piñón Hofbauer, M. Harada, K. Wöss, U. Koller, H. Morio, A. Stierschneider, K. Kitamura, M. Hashimoto, K. Chiba, H. Akita, N. Anzai, J. Reichelt, J.W. Bauer, C. Guttmann-Gruber, T. Furihata

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) has been identified as a cancer-specific transcript in various solid cancers, including colorectal cancer. Given its excellent cancer-specific expression profile, we hypothesized that Ct-OATP1B3 could represent a promising target for cancer-specific expression of the suicide gene, herpes simplex virus 1 thymidine kinase (HSV-tk), via a spliceosome-mediated RNA trans-splicing (SMaRT) approach. SMaRT technology is used to recombine two RNA molecules to generate a chimeric transcript. In this study, we engineered an RNA trans-splicing molecule carrying a translation-defective HSV-tk sequence (RTM44), which was capable of inducing its own trans-splicing to the desired Ct-OATP1B3 pre-mRNA target. RTM44 expression in LS180 cells resulted in generation of Ct-OATP1B3/HSV-tk fusion mRNA. A functional translation start site contributed by the target pre-mRNA restored HSV-tk protein expression, rendering LS180 cells sensitive to ganciclovir treatment in vitro and in xenografted mice. The observed effects are ascribed to accurate and efficient trans-splicing, as they were absent in cells carrying a splicing-deficient mutant of RTM44. Collectively, our data highlights Ct-OATP1B3 as an ideal target for the HSV-tk SMaRT suicide system, which opens up new translational avenues for Ct-OATP1B3-targeted cancer therapy.

Original languageEnglish
Pages (from-to)107-116
Number of pages10
JournalCancer Letters
Volume433
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Colorectal cancer
  • Herpes simplex virus 1 thymidine kinase
  • Organic anion transporting polypeptide 1B3
  • Spliceosome-mediated RNA trans-splicing
  • Suicide gene therapy

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