Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.
Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.
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DOI：
10.1371/journal.pone.0018677
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发表时间：
2011-04-20
期刊：
影响因子：
3.7
通讯作者：
Beeser A
中科院分区：
文献类型：
--
作者：
Cain EL;Braun SE;Beeser A
对原发肿瘤内染色体重排的分析在识别新的癌基因方面具有重要作用。然而，由于大多数扩增片段都含有许多基因产物，这一事实阻碍了对癌症来源扩增片段中“驱动”基因(S)的识别。1q21-1q23的扩增与脂肪肉瘤密切相关，基于微阵列的比较基因组杂交将可能的候选癌基因缩小到两个：激活转录因子6(ATF6)和双特异性磷酸酶12(Dusp12)。虽然ATF6是一个已建立的未折叠蛋白反应的转录调节因子，但dusp12在癌症中的潜在作用仍未确定。为了评估dusp12的致癌潜力，我们建立了稳定的细胞系，在分离的情况下异位过表达dusp12，并确定该细胞系是否具有经常与转化细胞相关的特性。在这里，我们证明了过度表达dusp12的细胞表现出更强的细胞活力和对凋亡的抵抗力。此外，dusp12的过度表达促进了原癌基因c-met和与转移有关的胶原和层粘连蛋白受体α1(Itga1)的表达增加。总体而言，这些结果表明dusp12与肿瘤相关，并揭示了dusp12与已建立的可作为治疗靶点的癌基因之间的潜在关联。
Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the “driver” gene(s) within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21–1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6) and the dual specificity phosphatase 12 (dusp12). While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized. To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1) which is implicated in metastasis. Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.
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