Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment.
Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment.
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DOI：
10.1002/pros.20854
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发表时间：
2009-01-01
期刊：
影响因子：
2.8
通讯作者：
Petros, John A.
中科院分区：
文献类型：
--
作者：
Arnold, Rebecca S.;Sun, Carrie Q.;Richards, Jendai C.;Grigoriev, Galina;Coleman, Ilsa M.;Nelson, Peter S.;Hsieh, Chia-Ling;Lee, Jae K.;Xu, Zhiheng;Rogatko, Andre;Osunkoya, Adeboye O.;Zayzafoon, Majd;Chung, Leland;Petros, John A.
遗传性和体细胞获得性的线粒体DNA（mtDNA）突变在临床前列腺癌中很常见。我们已经开发出了设计用于在受控实验中研究特定mtDNA突变的模型系统。由于前列腺癌经常转移到骨，我们测试了mtDNA突变增强前列腺癌在骨微环境中生长和存活的假设。通过形成胞质杂交体将致病性核苷酸位置（np）8993 mDNA突变引入PC 3前列腺癌细胞。野生型和突变体胞质杂交体在有或没有骨基质细胞共接种的情况下作为裸鼠皮下异种移植物生长。胞质杂种也生长在胫骨内空间。通过直接肿瘤测量和荧光素酶化学发光测定肿瘤生长。采用cDNA微阵列技术检测基因表达，并通过真实的时间PCR、蛋白质印迹分析和免疫组化进行验证。具有8993 mtDNA突变的胞质杂种比野生型胞质杂种生长得更快。在骨微环境中证实了进一步的生长加速。一个37个基因的分子标记特征的生长优势所赋予的mtDNA突变和骨微环境。在临床前列腺癌，FGF1和FAK，两个已知的重要基因，被发现只有当mtDNA突变和骨基质细胞都存在时才显著上调。ATP6 np 8993 mtDNA突变赋予人前列腺癌生长优势，在骨微环境中最充分地表现出来。识别与线粒体DNA突变和骨生长相关的特定分子改变可能会让人们对前列腺癌骨转移有新的认识。
Mitochondrial DNA (mtDNA) mutations, inherited and somatically acquired, are common in clinical prostate cancer. We have developed model systems designed to study specific mtDNA mutations in controlled experiments. Because prostate cancer frequently metastasizes to bone we tested the hypothesis that mtDNA mutations enhance prostate cancer growth and survival in the bone microenvironment. The pathogenic nucleotide position (np) 8993 mDNA mutation was introduced into PC3 prostate cancer cells by cybrid formation. Wildtype and mutant cybrids were grown as nude mouse subcutaneous xenografts with or without bone stromal cell co-inoculation. Cybrids were also grown in the intratibial space. Tumor growth was assayed by direct tumor measurement and luciferase chemiluminescence. Gene expression was assayed using cDNA microarrays confirmed by real time PCR, western blot analysis and immunohistochemistry. Cybrids with the 8993 mtDNA mutation grew faster than wildtype cybrids. Further growth acceleration was demonstrated in the bone microenvironment. A thirty-seven gene molecular signature characterized the growth advantage conferred by the mtDNA mutation and bone microenvironment. Two genes of known importance in clinical prostate cancer, FGF1 and FAK, were found to be substantially upregulated only when both mtDNA mutation and bone stromal cell were present. The ATP6 np 8993 mtDNA mutation confers a growth advantage to human prostate cancer that is most fully manifest in the bone microenvironment. The identification of specific molecular alterations associated with mtDNA mutation and growth in bone may allow new understanding of prostate cancer bone metastasis.
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