title: Efficient targeting and tumor retardation effect of pancreatic adenocarcinoma up-regulated factor (PAUF)-specific RNA replacement in pancreatic cancer mouse model.
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.
authors.affiliation: Research 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.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Kim
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Se Hun
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyun
authors.initials: K
authors.lastname: Heo
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Yusun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Kim
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Daehong
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Suji-Gu, Yongin, Republic of Korea.
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Song
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Suji-Gu, Yongin, Republic of Korea.
authors.forename: Seoung-Wook
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Yangsoon
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: Research Institute & Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: inhookim@gmail.com.
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D037102:Lectins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D012313:RNA / Q000235:genetics*; D016337:RNA, Catalytic / Q000235:genetics; D011897:Random Allocation; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D037102:Lectins; D016337:RNA, Catalytic; C517340:ZG16B protein, human; D001086:Arabinofuranosyluracil; C043457:fialuridine; D012313:RNA; D013937:Thymidine Kinase
keywords: Gene therapy; PAUF; Pancreatic cancer; RNA replacement