Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma
Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma
复制标题
DOI：
10.3390/cancers12020472
复制
发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Terai, Shuji
中科院分区：
文献类型：
--
作者：
Kamimura, Kenya;Yokoo, Takeshi;Terai, Shuji
肝细胞癌（HCC）是全球主要的恶性肿瘤，占原发性肝癌的90%以上。由于肿瘤细胞的高度异质性，目前可用的治疗选择性能较差;复发的可能性很高，并且一些患者对治疗产生耐药性。因此，开发一种新的治疗方法至关重要。我们评估了肝癌的基因治疗使用白喉毒素片段A（DTA）基因表达质粒，利用非病毒流体力学为基础的程序。通过检查HCC细胞生长在体外评估HCC细胞系中DTA表达的抗肿瘤作用（和甲胎蛋白（AFP）启动子选择性）。此外，AFP启动子选择性DTA表达的效果和安全性进行了检查，在体内使用HCC小鼠模型建立的流体动力学基因传递的是相关蛋白（雅普）表达质粒。在DTA质粒递送后，共转染的tdTomato和GFP表达的消失抑制了DTA转染细胞中的蛋白质合成; HCC细胞生长以AFP启动子选择性方式被HCC细胞中DTA的表达抑制。在雅普基因递送后0个月和2个月，在用DTA的流体动力学基因递送处理的小鼠组中可以看到HCC发生的显著抑制和AFP和脱-γ-羧基凝血酶原的肿瘤标志物的抑制。提示DTA基因治疗肝癌是有效的。
Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC.