Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
J Gastroenterol Hepatol. 2014 May;29(5):973-83. doi: 10.1111/jgh.12501.
The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.
抑癌基因 REIC/ Dickkopf-3（Dkk-3）在永生化细胞中的表达减少，其在多种恶性肿瘤中下调。在一项前列腺癌研究中，携带 REIC/Dkk-3 基因的腺病毒载体（Ad-REIC）可诱导细胞凋亡。在本研究中，我们检测了 REIC/Dkk-3 基因治疗对胰腺癌的影响。
采用免疫印迹和免疫组化法检测胰腺癌细胞系（ASPC1、MIAPaCa2、Panc1、BxPC3、SUIT-2、KLM1 和 T3M4）和胰腺癌组织中 REIC/Dkk-3 基因的表达。采用 Ad-REIC 试剂检测体外的凋亡效应及体内的抗肿瘤效应。我们还评估了与吉西他滨联合应用 Ad-REIC 治疗的疗效。
REIC/Dkk-3 的表达在胰腺癌细胞系中缺失，并在胰腺癌组织中减少。Ad-REIC 在体外诱导 ASPC1 和 MIAPaCa2 细胞系发生凋亡和抑制细胞生长，并且在使用 ASPC1 细胞的小鼠异种移植模型中抑制肿瘤生长。与吉西他滨联合应用可增强抗肿瘤作用。这种协同作用可能是通过增强雷帕霉素靶蛋白信号转导来抑制自噬所致。
Ad-REIC 诱导胰腺癌细胞系发生凋亡并抑制肿瘤生长。REIC/Dkk-3 基因治疗是一种有吸引力的胰腺癌治疗工具。
