Zhu Hongbo, Zhu Yuping, Hu Jingzi, Hu Wenxian, Liao Yongqiang, Zhang Jun, Wang Da, Huang Xuefeng, Fang Bingliang, He Chao
Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Zhejiang, China.
Int J Cancer. 2007 Sep 15;121(6):1366-72. doi: 10.1002/ijc.22856.
Bcl-XL, an anti-apoptotic protein of Bcl-2 family, is overexpressed in colon cancers. To determine Bcl-XL's potential feasibility as a therapeutic target, we constructed a recombinant adenovirus that expressed a U6 promoter-driven small hairpin RNA (shRNA) targeting Bcl-XL (Ad/Bcl-XL shRNA) and evaluated the vector's ability to induce RNA interference in vivo and alter apoptosis induction in colon cancer cells and tumours. Ad/Bcl-XL shRNA effectively knocked down Bcl-XL expression in colon cancer cells and decreased their viability. Treatment with Ad/Bcl-XL shRNA but not control vectors led to dramatically increased cleavage of cellular apoptosis-related enzymes caspase-9, caspase-3 and poly(ADP-ribose) polymerase. Ad/Bcl-XL shRNA also significantly suppressed the growth of subcutaneous tumours derived from DLD1 cells in a nude mouse model and did so without causing any obvious damage to normal tissues or normal human fibroblasts. Together, our results support the feasibility of using adenovirus-mediated RNA interference therapy targeting Bcl-XL against colon cancers and warrant further studies of its safety and efficacy.
Bcl-XL是Bcl-2家族的一种抗凋亡蛋白，在结肠癌中过表达。为了确定Bcl-XL作为治疗靶点的潜在可行性，我们构建了一种重组腺病毒，该病毒表达靶向Bcl-XL的U6启动子驱动的小发夹RNA（shRNA）（Ad/Bcl-XL shRNA），并评估了该载体在体内诱导RNA干扰以及改变结肠癌细胞和肿瘤中细胞凋亡诱导的能力。Ad/Bcl-XL shRNA有效敲低了结肠癌细胞中Bcl-XL的表达并降低了它们的活力。用Ad/Bcl-XL shRNA而非对照载体处理导致细胞凋亡相关酶caspase-9、caspase-3和聚（ADP-核糖）聚合酶的切割显著增加。Ad/Bcl-XL shRNA在裸鼠模型中也显著抑制了源自DLD1细胞的皮下肿瘤的生长，并且在不对正常组织或正常人成纤维细胞造成任何明显损伤的情况下做到了这一点。总之，我们的结果支持使用腺病毒介导的靶向Bcl-XL的RNA干扰疗法治疗结肠癌的可行性，并值得对其安全性和疗效进行进一步研究。
