Fhit loss-associated initiation and progression of neoplasia in vitro.
Fhit loss-associated initiation and progression of neoplasia in vitro.
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DOI：
10.1111/cas.13032
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发表时间：
2016-11
期刊：
影响因子：
5.7
通讯作者：
Huebner K
中科院分区：
文献类型：
--
作者：
Karras JR;Schrock MS;Batar B;Zhang J;La Perle K;Druck T;Huebner K
FHIT基因，包括一个活跃的共同脆性位点，FRA 3B，经常沉默在癌前病变和癌症，通过基因重排或甲基化的调控序列。Fhit蛋白表达的沉默导致胸苷激酶1下调，导致dNTP失衡和自发复制应激，导致染色体畸变、等位基因拷贝数变异、插入/缺失和单碱基取代。因此，在大多数人类癌症中表达降低的Fhit是基因组“看护者”，其缺失引发肿瘤前病变中的基因组不稳定性。为了跟踪Fhit缺失诱导的早期遗传改变和功能变化（可能重演体外肿瘤过程），我们从断奶后早期的Fhit−/−和+/+小鼠幼仔的肾组织中建立了上皮细胞系，并将细胞培养物置于营养和致癌物应激下，其中+/+细胞无法存活。通过转录组分析和蛋白质表达分析，我们观察到了−/−细胞中Trp 53/p21和生存素凋亡途径的变化，以及参与上皮-间充质转化的蛋白质表达的变化。一些Fhit缺陷细胞系显示出锚定非依赖性集落形成和体外侵袭能力增加。此外，应激的Fhit-/-细胞系的细胞形成s.c.和转移性肿瘤。总的来说，我们表明，Fhit损失和随后的胸苷激酶1失活，结合选择性压力，导致肿瘤相关的基因和基因表达模式在体外和体内的变化。
The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single‐base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome “caretaker” whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit−/− and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in −/− cells, and in expression of proteins involved in epithelial–mesenchymal transition. Some Fhit‐deficient cell lines showed anchorage‐independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit−/− cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia‐associated alterations in genes and gene expression patterns in vitro and in vivo.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
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Bao, Bin;Wang, Zhiwei;Ali, Shadan;Kong, Dejuan;Banerjee, Sanjeev;Ahmad, Aamir;Li, Yiwei;Azmi, Asfar S.;Miele, Lucio;Sarkar, Fazlul H.
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Sarkar, Fazlul H.
影响因子：
11.2
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通讯作者：
Brabletz, Thomas
影响因子：
5.2
作者：
Joannes, Audrey;Grelet, Simon;Nawrocki-Raby, Beatrice
通讯作者：
Nawrocki-Raby, Beatrice