Abstract
Backgroundp53 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.MethodsTo 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.ResultsWe 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.ConclusionThese 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.
Highlights
Endometrial cancer (EC) is the commonest gynecologic malignancy in the US and other Western nations [1]
Forced over-expression of p53-R175H by cDNA transfection promoted cell invasion and migration To evaluate whether p53-R175H expression associated with the invasive potential in EC, we chose human EC KLE cells to test the effects of forced over-expression of p53 GOF mutation R175H because this cell line expresses endogenous mutant p53-R175H
EsFixoigpnurearnsesdi1omnigorfapti5o3n-Rin17K5LHE ciseallssociated with enhanced invaExpression of p53-R175H is associated with enhanced invasion and migration in KLE cells. (A) Western blot analysis showing p53 expression of p53-R175H in KLE cells after they had been transfected with a vector containing p53R175H construct (R175H)
Summary
Endometrial cancer (EC) is the commonest gynecologic malignancy in the US and other Western nations [1]. Asian nations such as China and Japan have an incidence that is 4-5 times lower than in Western nations [2]. The incidence of EC in Asian countries has markedly increased in recent years [3]. Patients with advanced-stage EC frequently exhibit a poor prognosis, even after radical (page number not for citation purposes). Molecular Cancer 2009, 8:103 http://www.molecular-cancer.com/content/8/1/103 resection combined with radiotherapy or chemotherapy. These poor outcomes are closely associated with the progression and metastasis of the disease. A better understanding of the molecular mechanisms underlying the aggressive behavior of EC is necessary to identify potential targets for efficient therapy
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