p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells
p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells
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DOI：
10.1007/s10585-007-9084-8
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发表时间：
2007-10-01
影响因子：
4
通讯作者：
Sakuragi, Noriaki
中科院分区：
文献类型：
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作者：
Dong, Peixin;Tada, Mitsuhiro;Sakuragi, Noriaki
肿瘤抑制基因p53（TP 53）显性阴性（DN）突变在临床上与子宫内膜恶性肿瘤的进展和转移相关。为了研究DN对肿瘤迁移和侵袭的影响，我们通过转染表达wt p53的子宫内膜癌细胞HHUA来产生稳定共表达野生型（wt）和R273 H DN突变体TP 53（273 H细胞）以及wt和R213 Q隐性突变体TP 53（213 Q细胞）的细胞。R273 H，而不是R213 Q，抑制野生型p53刺激的p21，Bax和MDM 2的转录。与213 Q和wt细胞相比，273 H细胞也显示出显著增加的体外侵袭和迁移能力，并且显示出Maspin、派-1和KAI 1 mRNA表达降低。通过使用阿霉素诱导wt p53功能导致与p53靶基因的上调相关的侵袭/迁移能力的抑制，在213 Q和wt细胞中比在273 H细胞中的抑制程度大得多。在p53缺失的癌细胞SK-OV-3和Saos-2中，R273 H表达不显著影响细胞侵袭和迁移活性。综上所述，这些结果表明，R273 H突变体的转显性超过野生型p53，而不是一个功能获得性通过增加侵袭和迁移在HHUA细胞促进肿瘤转移。
Dominant negative (DN) mutations of tumor suppressor p53 (TP53) are clinically associated with cancer progression and metastasis of endometrial malignancy. To investigate the DN effect on tumor migration and invasion, we generated cells that stably co-expressed wild-type (wt) and R273H DN mutant TP53 (273H cells), and wt and R213Q recessive mutant TP53 (213Q cells), by transfection in endometrial cancer cells HHUA that expressed wt p53. R273H, but not R213Q, repressed wt p53-stimulated transcription of p21, Bax, and MDM2. 273H cells also showed markedly increased in vitro invasion and migration potentials, and displayed reduced Maspin, PAI-1, and KAI1 mRNA expressions as compared with 213Q and wt cells. The induction of wt p53 function by use of Adriamycin resulted in the inhibition of the invasion/migration capacity in association with the up-regulation of p53 target genes to a far greater degree in 213Q and wt cells than in 273H cells. R273H expression in p53-null cancer cell SK-OV-3 and Saos-2 did not significantly affect cell invasion and migration activities. Taken together, these results suggest that transdominance of R273H mutant over wt p53 rather than a gain-of-function promotes tumor metastasis by increasing invasion and migration in HHUA cells.