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Cancer Lett. 2014 Mar 28;344(2):223-31. doi: 10.1016/j.canlet.2013.10.028. Epub 2013 Nov 1.

Efficient targeting and tumor retardation effect of pancreatic adenocarcinoma up-regulated factor (PAUF)-specific RNA replacement in pancreatic cancer mouse model.

Author information

  • 1Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: sensia37@ncc.re.kr.
  • 2Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
  • 3Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Suji-Gu, Yongin, Republic of Korea.
  • 4Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • 5Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: inhookim@gmail.com.

Abstract

The soluble protein pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in pancreatic tumor progression and has begun to attract attention as a therapeutic target for pancreatic cancer. We herein present PAUF RNA-targeting gene therapy strategies with both targeting and therapeutic function using trans-splicing ribozyme (TSR) in pancreatic cancer. We developed adenoviral PAUF-targeting TSR (Rz) containing a PAUF-specific internal guide sequence (IGS) determined by library screening. This Rz harbors suicide gene, herpes simplex virus thymidine kinase (HSV-tk) or firefly luciferase (Luc) as a transgene for 3' exon replacement of PAUF RNAs. Ad-Rz-TK, Rz harboring the HSV-tk, showed significant inhibition of tumor growth in vivo as well as PAUF-dependent cell death in vitro via a successful trans-splicing reaction. Selective induction of Rz-controlled transgene in PAUF-expressing pancreatic cancer was confirmed through noninvasive in vivo imaging; a luminescence signal from Rz harboring Luc (Ad-Rz-Luc) was detectable only in pancreatic tumor sites, not in normal mice. In addition, a [(125)I] FIAU signal reflecting thymidine kinase expression through SPECT and ex vivo biodistribution was co-localized with the tumor sites when we treated with Ad-Rz-TK in orthotopic xenograft model. Taken together, these results imply that PAUF-targeting TSR can contribute to successful targeted gene therapy for pancreatic cancer.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Gene therapy; PAUF; Pancreatic cancer; RNA replacement

PMID:
24189457
[PubMed - indexed for MEDLINE]
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