Center for Radiological Research, College of Physicians and Surgeons, Columbia University Medical Center, New York 10032, USA.
Int J Cancer. 2013 Jan 1;132(1):19-28. doi: 10.1002/ijc.27656. Epub 2012 Jul 3.
Human small airway epithelial cells (SAECs) immortalized with human telomerase reverse transcriptase were exposed to either a single or multiple doses of α-particles. Irradiated cells showed a dose-dependent cytotoxicity and progressive neoplastic transformation phenotype. These included an increase in saturation density of growth, a greater resistance to N-phosphonoacetyl-L-aspartate, faster anchorage-independent growth, reinforced cell invasion and c-Myc expression. In addition, the transformed cells formed progressively growing tumors upon inoculation into athymic nude mice. Specifically, α-irradiation induced damage to both mitochondrial DNA (mtDNA) and mitochondrial functions in transformed cells as evidenced by increased mtDNA copy number and common deletion, decreased oxidative phosphorylation activity as measured by cytochrome C oxidase (COX) activity and oxygen consumption. There was a linear correlation between mtDNA copy number, common deletion, COX activity and cellular transformation represented by soft agar colony formation and c-Myc expression. These results suggest that mitochondria are associated with neoplastic transformation of SAEC cells induced by α-particles, and that the oncogenesis process may depend not only on the genomes inside the nucleus, but also on the mitochondrial DNA outside the nucleus.
人端粒酶逆转录酶永生化的人小气道上皮细胞（SAECs）暴露于单次或多次α-粒子照射下。受照射的细胞表现出剂量依赖性细胞毒性和进行性肿瘤转化表型。这些包括生长饱和密度增加、对 N-膦酰基乙酰-L-天冬氨酸的抗性增强、锚定独立生长更快、细胞侵袭增强和 c-Myc 表达增强。此外，转化细胞在接种到无胸腺裸鼠中后形成进行性生长的肿瘤。具体而言，α-照射诱导转化细胞中线粒体 DNA（mtDNA）和线粒体功能的损伤，表现为 mtDNA 拷贝数增加和常见缺失，氧化磷酸化活性降低，如细胞色素 C 氧化酶（COX）活性和耗氧量所示。mtDNA 拷贝数、常见缺失、COX 活性和细胞转化之间存在线性相关性，以软琼脂集落形成和 c-Myc 表达来表示。这些结果表明，线粒体与α-粒子诱导的 SAEC 细胞肿瘤转化有关，致癌过程可能不仅取决于核内基因组，还取决于核外线粒体 DNA。
