Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang, Wuhan, Hubei 430071, P.R. China.
Oncol Rep. 2013 Dec;30(6):3006-12. doi: 10.3892/or.2013.2783. Epub 2013 Oct 3.
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Mitochondrial dysfunction has been postulated to render cancer cells resistant to apoptosis based on the Warburg hypothesis. However, few studies have investigated the prognostic value of mitochondrial DNA (mtDNA) content and G10398A polymorphism in NSCLC patients. mtDNA copy number and G10398A polymorphism in 128 NSCLC tissue samples were assessed by real-time PCR (RT-PCR) and PCR-RFLP respectively, and their relationship to prognosis were analyzed by survival analysis and Cox proportional hazards model. In vitro, an mtDNA deletion A549 ρ(0) cell model was utilized to assess the function of mtDNA on radiosensitivity. Cell cycle distribution and reactive oxygen species (ROS) were analyzed to elucidate the potential mechanisms. For the whole group, the median follow-up time and overall survival time were 22.5 and 23.4 months, respectively. Patients with high mtDNA content had a marginally longer survival time than patients with low mtDNA content (P=0.053). Moreover, patients with high mtDNA content plus 10398G had a significantly longer overall survival time compared with those having low mtDNA content plus 10398A (47 vs. 27 months, P<0.05). In addition, multivariate analysis showed that stage and low mtDNA content plus 10398A were the two most independent prognostic factors. In vitro, the A549 ρ(0) cells showed more resistance to radiation than ρ(+) cells. Following radiation, ρ(0) cells showed delayed G2 arrest and lower ROS level as compared to ρ(+) cells. In conclusion, the present study suggests that in patients with NSCLC, low mtDNA content plus 10398A could be a marker of poor prognosis which is associated with resistance to anticancer treatment caused by low mtDNA content plus 10398A polymorphism resulting in mitochondrial dysfunction.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因之一。基于沃伯格假说，线粒体功能障碍被认为使癌细胞对细胞凋亡产生抗性。然而，很少有研究调查线粒体 DNA（mtDNA）含量和 G10398A 多态性在 NSCLC 患者中的预后价值。通过实时 PCR（RT-PCR）和 PCR-RFLP 分别评估了 128 例 NSCLC 组织样本中的 mtDNA 拷贝数和 G10398A 多态性，并通过生存分析和 Cox 比例风险模型分析了它们与预后的关系。在体外，利用 mtDNA 缺失 A549 ρ(0)细胞模型评估 mtDNA 对放射敏感性的功能。分析细胞周期分布和活性氧（ROS）以阐明潜在的机制。对于整个组，中位随访时间和总生存时间分别为 22.5 和 23.4 个月。mtDNA 含量高的患者的生存时间略长于 mtDNA 含量低的患者（P=0.053）。此外，mtDNA 含量高加 10398G 的患者的总生存时间明显长于 mtDNA 含量低加 10398A 的患者（47 与 27 个月，P<0.05）。此外，多变量分析表明，分期和低 mtDNA 含量加 10398A 是两个最独立的预后因素。在体外，A549 ρ(0)细胞对辐射的抵抗力强于 ρ(+)细胞。与 ρ(+)细胞相比，辐射后 ρ(0)细胞的 G2 期阻滞延迟，ROS 水平较低。总之，本研究表明，在 NSCLC 患者中，低 mtDNA 含量加 10398A 可能是预后不良的标志物，与低 mtDNA 含量加 10398A 多态性导致的线粒体功能障碍引起的抗癌治疗耐药性相关。
