Sawahara H, Shiraha H, Uchida D, Kato H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Sakaguchi M, Takaki A, Nouso K, Nasu Y, Kumon H, Okada H
Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Departments of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Cancer Gene Ther. 2016 Aug;23(8):278-83. doi: 10.1038/cgt.2016.31. Epub 2016 Jul 29.
Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3), a tumor suppressor gene, is downregulated in various cancers. We previously reported the tumor-inhibitory effects of the REIC/Dkk-3 gene, delivered by a conventional adenoviral vector (Ad-CAG-REIC) in pancreatic cancer. Here, we developed an Ad-REIC vector with a novel gene expression system, termed the super gene expression (SGE) system, and assessed its therapeutic effects relative to those of Ad-CAG-REIC in pancreatic cancer cells. Human pancreatic cancer cell lines ASPC1 and MIAPaCa2 were used. REIC/Dkk-3 expression was assessed by western blot analysis. Relative cell viability and apoptotic effects were examined in vitro. The anti-tumor effects of Ad-REIC treatment were assessed in the mouse xenograft model. Compared with Ad-CAG-REIC, Ad-SGE-REIC elicited a significant increase in REIC protein expression in the cells studied. Relative to Ad-CAG-REIC, Ad-SGE-REIC reduced cell viability and induced apoptosis in the ASPC1 and MIAPaCa2 cell lines in vitro, and achieved superior tumor growth inhibition in the mouse xenograft model. Compared with conventional Ad-REIC agents, Ad-SGE-REIC provided enhanced inhibitory effects against tumor growth. Our results indicate that Ad-SGE-REIC is an innovative therapeutic tool for pancreatic cancer.
抑癌基因永生细胞系中表达降低因子（REIC）/dickkopf-3（Dkk-3）在多种癌症中表达下调。我们之前报道了由传统腺病毒载体（Ad-CAG-REIC）递送的REIC/Dkk-3基因在胰腺癌中的抑癌作用。在此，我们开发了一种具有新型基因表达系统（称为超级基因表达（SGE）系统）的Ad-REIC载体，并评估了其相对于Ad-CAG-REIC在胰腺癌细胞中的治疗效果。使用了人胰腺癌细胞系ASPC1和MIAPaCa2。通过蛋白质免疫印迹分析评估REIC/Dkk-3的表达。在体外检测相对细胞活力和凋亡作用。在小鼠异种移植模型中评估Ad-REIC治疗的抗肿瘤效果。与Ad-CAG-REIC相比，Ad-SGE-REIC在所研究的细胞中引起REIC蛋白表达显著增加。相对于Ad-CAG-REIC，Ad-SGE-REIC在体外降低了ASPC1和MIAPaCa2细胞系的细胞活力并诱导了凋亡，并且在小鼠异种移植模型中实现了更好的肿瘤生长抑制。与传统的Ad-REIC制剂相比，Ad-SGE-REIC对肿瘤生长具有更强的抑制作用。我们的结果表明，Ad-SGE-REIC是一种用于胰腺癌的创新治疗工具。
