Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway
Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway
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DOI：
10.1186/1476-4598-8-103
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发表时间：
2009-11-16
期刊：
影响因子：
37.3
通讯作者：
Feng, Youji
中科院分区：
文献类型：
--
作者：
Dong, Peixin;Xu, Zhujie;Feng, Youji
背景：p53是人类肿瘤中最常见的突变肿瘤抑制基因。除了肿瘤抑制功能的丧失和对剩余野生型蛋白的显性负作用外，一些p53突变体可以获得新的致癌功能（功能获得，GOF），积极调节癌症的发生和进展。在人类子宫内膜癌中，p53突变更常与侵袭性非子宫内膜癌相关。然而，目前尚不清楚p53突变是否通过GOF特性导致子宫内膜癌的进展。方法：为明确p53 GOF突变（p53- r175h）的表达与人子宫内膜癌KLE细胞侵袭潜能的关系，我们通过诱导p53- r175h表达载体或用短发夹RNA抑制p53基因，检测KLE细胞中p53- r175h上调和下调的后果。结果：我们发现强迫过表达p53-R175H显著促进细胞迁移和侵袭，诱导表皮生长因子受体(EGFR)/磷脂酰肌醇3-激酶(PI3K)/AKT通路的激活。相反，短发夹RNA抑制p53-R175H显著抑制细胞迁移和侵袭，导致EGFR/PI3K/AKT通路衰减。结论：这些发现首次表明p53-R175H突变体的表达升高可能发挥功能获得活性，激活EGFR/PI3K/AKT通路，从而可能参与子宫内膜癌的侵袭性表型。
Background: p53 is the most commonly mutated tumor suppressor gene in human cancers. In addition to the loss of tumor suppression function and exertion of dominant-negative effects over the remaining wild-type protein, several p53 mutants can gain novel oncogenic functions (gain-of-function, GOF) that actively regulate cancer development and progression. In human endometrial cancer, p53 mutation is more often associated with aggressive nonendometrioid cancer. However, it was unknown if p53 mutants contributed to endometrial cancer progression through the GOF properties.Methods: To clarify the relationship between expression of p53 GOF mutation (p53-R175H) and invasive potential of human endometrial cancer KLE cells, we tested the consequences of up-regulation and down-regulation of p53-R175H in KLE cells by inducing p53-R175H expression vector or suppressing the p53 gene with short hairpin RNA.Results: We found that forced over-expression of p53-R175H significantly promoted cell migration and invasion, and induced activation of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Conversely, suppression of p53-R175H with short hairpin RNA significantly inhibited cell migration and invasion, and resulted in attenuation of EGFR/PI3K/AKT pathway.Conclusion: These findings show for the first time that elevated expression of p53-R175H mutant may exert gain-of-function activity to activate the EGFR/PI3K/AKT pathway and thus may contribute to the invasive phenotype in endometrial cancer.