Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion.
Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion.
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DOI：
10.4161/cbt.7.11.6729
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发表时间：
2008-11
影响因子：
3.6
通讯作者：
Singh KK
中科院分区：
文献类型：
--
作者：
Kulawiec M;Safina A;Desouki MM;Still I;Matsui S;Bakin A;Singh KK
人类线粒体DNA （mtDNA）编码13种参与氧化磷酸化（OXPHOS）的蛋白质。为了研究线粒体OXPHOS基因在乳腺肿瘤发生中的作用，我们建立了一个缺乏线粒体dna的乳腺上皮细胞系（ρ0细胞）。我们的分析表明，乳腺上皮细胞中mtDNA的缺失导致体外致瘤表型以及异种移植模型中的乳腺肿瘤发生。我们确定了亲本和ρ0上皮细胞之间的两个主要基因网络的差异调节。这些网络中的局灶蛋白包括(i) FN1（纤维连接蛋白）和（ii） p53。FN1网络的生物信息学分析发现层粘连蛋白、整合素和过氧化物还氧蛋白6个成员中的3个在ρ0上皮细胞中表达改变。在p53网络中，我们发现SMC4和WRN的表达变化表明该网络可能影响染色体稳定性。与上述发现一致，我们的研究显示在ρ0乳腺上皮细胞中DNA双链断裂和独特的染色体重排增加。此外，我们在p53网络中发现了紧密连接蛋白claudin-1和claudin-7。为了确定基因表达改变的功能相关性，我们重点分析了claudin-1和-7蛋白在乳腺肿瘤发生中的作用。我们的研究确定(1)claudin-1和-7在ρ0乳腺上皮细胞中确实下调，(2)claudin-1或-7的下调导致乳腺上皮细胞的肿瘤转化，(3)claudin-1和-7在原发性乳腺肿瘤中也下调。综上所述，我们的研究表明，mtDNA编码的OXPHOS基因在乳腺上皮细胞的转化中发挥了关键作用，线粒体到细胞核逆行调控的多种途径参与了乳腺上皮细胞的转化。
Human mitochondrial DNA (mtDNA) encodes 13 proteins involved in oxidative phosphorylation (OXPHOS). In order to investigate the role of mitochondrial OXPHOS genes in breast tumorigenesis, we have developed a breast epithelial cell line devoid of mtDNA (ρ0 cells). Our analysis revealed that depletion of mtDNA in breast epithelial cells results in in vitro tumorigenic phenotype as well as breast tumorigenesis in a xenograft model. We identified two major gene networks which were differentially regulated between parental and ρ0 epithelial cells. The focal proteins in these networks include (i) FN1 (fibronectin) and (ii) p53. Bioinformatic analyses of FN1 network identified laminin, integrin and 3 of 6 members of peroxiredoxin whose expression were altered in ρ0 epithelial cells. In the p53 network, we identified SMC4 and WRN whose changes in expression suggest that this network may affect chromosomal stability. Consistent with above finding our study revealed an increase in DNA double strand breaks and unique chromosomal rearrangements in ρ0 breast epithelial cells. Additionally, we identified tight junction proteins claudin-1 and claudin-7 in p53 network. To determine the functional relevance of altered gene expression, we focused on detailed analyses of claudin-1 and -7 proteins in breast tumorigenesis. Our study determined that (i) claudin-1 and 7 were indeed downregulated in ρ0 breast epithelial cells, (ii) downregulation of claudin-1 or -7 led to neoplastic transformation of breast epithelial cells, and (iii) claudin-1 and -7 were also downregulated in primary breast tumors. Together, our study suggest that mtDNA encoded OXPHOS genes play a key role in transformation of breast epithelial cells and that multiple pathway involved in mitochondria-to-nucleus retrograde regulation contribute to transformation of breast epithelial cells.
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影响因子：
3.6
作者：
Desouki, MM;Kulawiec, M;Singh, KK
通讯作者：
Singh, KK
影响因子：
5.3
作者：
Krämer, F;White, K;Weber, BHF
通讯作者：
Weber, BHF
影响因子：
3.7
作者：
Knutsen, T;Gobu, V;Ried, T
通讯作者：
Ried, T
影响因子：
3.5
作者：
Clark, KM;Brown, TA;Clayton, DA
通讯作者：
Clayton, DA
影响因子：
4.8
作者：
Inoue, K;Ito, S;Hayashi, JI
通讯作者：
Hayashi, JI