Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth
Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth
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DOI：
10.1093/jnci/djn024
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发表时间：
2008-03-05
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影响因子：
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通讯作者：
Sood, Anil K.
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文献类型：
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作者：
Merritt, William M.;Lin, Yvonne G.;Sood, Anil K.
背景白细胞介素-8（IL-8）是一种促血管生成的细胞因子，在许多人类癌症中过度表达。我们研究了IL-8在卵巢癌中的临床和生物学意义，使用人类样本和原位小鼠models.Methods卵巢癌患者（n = 102）的临床和生存数据，通过免疫组织化学的肿瘤表达IL-8进行了评估。我们研究了IL-8基因沉默与小干扰RNA掺入中性脂质体（siRNA-DOPC），单独和与多西他赛联合，对体内肿瘤生长，血管生成（微血管密度），和肿瘤细胞增殖的影响（n = 10/治疗组）携带原位紫杉烷敏感（HeyA 8和SKOV 3 ip 1）和紫杉烷耐药（SKOV 3 ip 2）的小鼠。TR）卵巢肿瘤。结果在102例乳腺癌组织中，43例（42%）IL-8高表达，59例（58%）IL-8低表达或不表达，IL-8高表达与肿瘤分期有关（P = 0.019）、高肿瘤分级（P = 0.031）和更差的生存率（IL-8高表达与低表达患者的中位生存期：1.62年与3.79年; P <0.001）。与空脂质体相比，IL-8 siRNA-DOPC在HeyA 8和SKOV 3 ip 1小鼠模型中分别使平均肿瘤重量降低32%（95%置信区间[CI] = 14%至50%; P = 0.03）和52%（95% CI = 27%至78%; P = 0.03）。在所有三种小鼠模型中，与空脂质体相比，用IL-8 siRNA-DOPC加紫杉烷多西他赛治疗使肿瘤生长减少最多（肿瘤生长减少77%至98%;所有P <0.01）。在HeyA 8和SKOV 3 ip 1模型中，来自单独用IL-8 siRNA-DOPC处理的小鼠的肿瘤具有比来自用空脂质体处理的小鼠的肿瘤更低的微血管密度（HeyA 8：低34%，95%CI =低32%至36%[P = .002]; SKOV 3 ip 1：低39%，95%CI =低34%至44%[P = .007]）。与空脂质体相比，IL-8 siRNA-DOPC联合多西他赛可使肿瘤细胞增殖减少35%（95% CI = 25%至44%; P < .001）和38%（95% CI = 28%至48%;结论IL-8表达的增加与卵巢癌的不良临床预后有关，IL-8基因沉默通过抗血管生成机制降低肿瘤生长。
Background Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models.Methods Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2. TR) ovarian tumors. All statistical tests were two-sided.Results Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively.Conclusions Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.