Department of Pathology and Immunology and Michael E. DeBakey Department of Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Clin Cancer Res. 2012 Dec 15;18(24):6648-57. doi: 10.1158/1078-0432.CCR-12-2715. Epub 2012 Oct 10.
The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer.
We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms.
The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed.
Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer.
TMPRSS2/ERG（T/E）融合基因存在于一半的前列腺癌肿瘤中。致癌 ERG 基因与雄激素调节的 TMPRSS2 基因启动子融合，导致前列腺癌细胞中融合 mRNA 的表达。融合 mRNA 的 TMPRSS2 和 ERG 衍生部分的连接处构成了含有 T/E 融合基因的细胞中的癌症特异性靶标。使用脂质体纳米载体中的 siRNA 靶向体内最常见的选择性剪接融合基因 mRNA 连接体异构体，可能是一种新的、低毒性的前列腺癌治疗方法。
我们设计并优化了靶向两种最常见的 T/E 融合基因 mRNA 连接体异构体（III 型或 VI 型）的 siRNAs。通过瞬时共转染在体外评估 siRNA 的特异性。为了测试它们在体内抑制表达这些融合基因异构体的前列腺癌细胞生长的能力，使用脂质体纳米载体中的特异性 siRNA 治疗表达靶向融合异构体的原位或皮下异种移植肿瘤的小鼠。
靶向 siRNA 在体外既有效又高度特异。在体内，它们显著抑制肿瘤生长。生长抑制的程度是可变的，与融合基因敲低的程度相关。生长抑制与血管生成的显著抑制相关，在较小程度上与增殖和肿瘤细胞凋亡的显著增加相关。未观察到毒性。
使用脂质体纳米载体体内靶向特定的 siRNA 针对 T/E 融合连接体是治疗前列腺癌男性患者的一种很有前途的疗法。
