Lee Juwon, Wang Amy, Hu Qiande, Lu Shan, Dong Zhongyun
Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Int J Oncol. 2006 Dec;29(6):1405-12.
Interferon (IFN)-beta is a multifunctional cytokine. Our previous studies revealed that intratumoral transfer of the murine interferon (IFN)-beta gene inhibited the growth of human and mouse prostate cancer cells in mice. Since IFN-beta activity is species-restricted, we investigated the efficacy and mechanisms of forced expression of human IFN-beta in suppressing the growth of human prostate cancer cells in mice. Orthotopic tumors of PC-3MM2 human prostate cancer cells were forced to express human IFN-beta by intratumoral injection of an adenoviral vector (AdhIFN-beta). Tumor growth and survival of tumor-bearing mice were determined. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Angiogenesis and angiogenic molecule expression were evaluated by IHC and quantitative real-time reverse-transcriptional PCR (qRT-PCR). We found that forced expression of human IFN-beta inhibited tumor growth in a dose-dependent manner. An injection of 2 x 10(9) PFU (plaque-forming units) of AdhIFN-beta retarded tumor growth by 90% and prolonged the survival of tumor-bearing mice. Control tumors contained more proliferating cells (PCNA(+)) and fewer apoptotic cells (TUNEL(+)) than did AdhIFN-beta treated-tumors. Treatment with AdhIFN-beta downregulated the expression of interleukin-8 and vascular endothelial cell growth factor-A. Taken together, our data indicated that forced expression of human IFN-beta in human prostate cancer cells significantly inhibited their prostatic growth, which correlated with downregulation of angiogenic molecules and suggested that adenoviral vector-mediated IFN-beta gene therapy could be an effective approach for the management of human prostate cancer.
干扰素（IFN）-β是一种多功能细胞因子。我们之前的研究表明，小鼠干扰素（IFN）-β基因的瘤内转移可抑制小鼠体内人源和鼠源前列腺癌细胞的生长。由于IFN-β的活性具有种属限制性，我们研究了人IFN-β强制表达在抑制小鼠体内人前列腺癌细胞生长方面的疗效和机制。通过瘤内注射腺病毒载体（AdhIFN-β），使PC-3MM2人前列腺癌细胞的原位肿瘤强制表达人IFN-β。测定荷瘤小鼠的肿瘤生长和存活情况。通过免疫组织化学（IHC）和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）评估细胞增殖和凋亡。通过IHC和定量实时逆转录PCR（qRT-PCR）评估血管生成和血管生成分子表达。我们发现人IFN-β的强制表达以剂量依赖的方式抑制肿瘤生长。注射2×10⁹ PFU（噬斑形成单位）的AdhIFN-β可使肿瘤生长延缓90%，并延长荷瘤小鼠的存活时间。与AdhIFN-β处理的肿瘤相比，对照肿瘤含有更多的增殖细胞（PCNA⁺）和更少的凋亡细胞（TUNEL⁺）。AdhIFN-β处理下调了白细胞介素-8和血管内皮细胞生长因子-A的表达。综上所述，我们的数据表明人前列腺癌细胞中人IFN-β的强制表达显著抑制其前列腺生长，这与血管生成分子的下调相关，并提示腺病毒载体介导的IFN-β基因治疗可能是治疗人前列腺癌的有效方法。
