Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition.
Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition.
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DOI：
10.1158/1535-7163.679.3.6
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发表时间：
2004-06
影响因子：
5.7
通讯作者：
Dong Wang;M. Luo;M. Kelley
中科院分区：
文献类型：
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作者：
Dong Wang;M. Luo;M. Kelley
骨肉瘤是最常见的高度恶性骨肿瘤，主要表现在第二和第三个十年的生活。它与复发的高风险相关，可能是由于对化疗药物产生耐药性。作为克服骨肉瘤肿瘤细胞耐药性和/或使肿瘤细胞对目前使用的化疗治疗敏感的手段，我们研究了人脱嘌呤核酸内切酶1（APE 1）在骨肉瘤肿瘤细胞耐药性和预后中的作用。对60例存档的常规（髓内）骨肉瘤样本进行了分析。在这些组织中，72%的组织中APE 1蛋白升高，并且在具有已知临床结果的组织中，高APE 1表达水平与生存时间缩短之间存在显著相关性。其余28%的样本显示APE 1的低表达。鉴于APE 1在骨肉瘤中过表达，我们使用沉默RNA（siRNA）靶向技术在骨肉瘤细胞系人成骨肉瘤（HOS）中降低APE 1水平，以增强化疗和放射敏感性。使用针对APE 1的siRNA靶向技术，蛋白水平在24小时内降低90%以上，72小时保持低水平，并在96小时恢复正常水平。在APE 1-siRNA处理后，APE 1核酸内切酶活性也明显丧失。在siRNA处理的人成骨肉瘤细胞中，APE 1水平的降低导致细胞对DNA损伤剂的敏感性增强：甲磺酸甲酯、H（2）O（2）、电离辐射和化疗剂。本研究结果对骨肉瘤的治疗具有预后和治疗意义。APE 1-siRNA结果证明了使用各种分子和方法治疗性调节APE 1的可行性。
Osteosarcoma is the most common highly malignant bone tumor with primary appearance during the second and third decade of life. It is associated with a high risk of relapse, possibly resulting from a developed resistance to chemotherapy agents. As a means to overcome osteosarcoma tumor cell resistance and/or to sensitize tumor cells to currently used chemotherapeutic treatments, we examined the role of human apurinic endonuclease 1 (APE1) in osteosarcoma tumor cell resistance and prognosis. Sixty human samples of archived conventional (intramedullary) osteosarcoma were analyzed. APE1 protein was elevated in 72% of these tissues and among those with a known clinical outcome, there was a significant correlation between high APE1 expression levels and reduced survival times. The remaining 28% of samples showed low expression of APE1. Given that APE1 was overexpressed in osteosarcoma, we decreased APE1 levels using silencing RNA (siRNA) targeting technology in the osteosarcoma cell line, human osteogenic sarcoma (HOS), to enhance chemo- and radiation sensitivity. Using siRNA targeted technology of APE1, protein levels were reduced by more than 90% within 24 hours, remained low for 72 hours, and returned to normal levels at 96 hours. There was also a clear loss of APE1 endonuclease activity following APE1-siRNA treatment. A decrease in APE1 levels in siRNA-treated human osteogenic sarcoma cells led to enhanced cell sensitization to the DNA damaging agents: methyl methanesulfonate, H(2)O(2), ionizing radiation, and chemotherapeutic agents. The findings presented here have both prognostic and therapeutic implications for treating osteosarcoma. The APE1-siRNA results demonstrate the feasibility for the therapeutic modulation of APE1 using a variety of molecules and approaches.