10月13-16日，第14届国际妇科肿瘤学会双年会（IGCS 2012）在加拿大温哥华举行。IGCS 2012一如既往地为参会者奉上妇科肿瘤学领域最新研究进展，提供发布、讨论和争辩最新科学信息的良机。金宝搏网站登录技巧 对本届年会进行了专题报道（http://zt.cmt.com.cn/zt/igcs2012/index.html）。 

研究摘要：

Wild-Type TRP53 (53) Promotes Ovarian Cancer Cell
Survival
L Mullany1, Z Liu1, K-KWong2, ER King2, JS Richards1
1Department of Molecular and Cellular Biology, Baylor College
of Medicine; 2The University of Texas MD Anderson Cancer
Center, Houston, TX.
Background: Ovarian cancers have been divided into 2 categories:
low-grade type 1 and high-grade type 2. One distinguishing
and relevant feature of type 1 and type 2 ovarian
cancer is the expression of the tumor repressor protein 53
(Trp53; or p53): almost all high-grade serous adenocarcinomas
(96%) have Trp53 mutations, whereas low-grade tumors express
elevated levels of wild-type Trp53. We have recently
shown that Pten/Kras (Ptenfl/fl;KrasG12D fl/fl;Amhr2-Cre)
mice exhibit many features similar to human low-grade invasive
serous ovarian carcinomas, including elevated levels of
wild-type Trp53. To investigate the functions of TRP53 in the
mutant mouse OSE cells, Trp53 was conditionally deleted in
Pten/Kras mice.
Methods: Purified OSE cells were isolated from mutant and
control mouse ovaries, and RNA was prepared for gene
profiling and quantitative polymerase chain reaction analyses.
Purified mutant and control cells were also grown in culture
and matrigel to characterize the transformed phenotype of the
TRP53-positive (Pten/Kras [Trp53+]) and TRP53-negative
(Pten/Kras [Trp53-negative]) OSE cells.
Results: In the TRP53-positive cells, wild-type TRP53 controls
or enhances the expression of genes regulating proliferation,
DNA repair, and mitotic activity and markedly decreases genes
with tumor suppressor functions. Rather than activating cell
cycle arrest or apoptosis, wild-type TRP53 in the Pten/Kras
(Trp53+) OSE cells promotes the formation of papillarylike
structures, cell migration, adhesion, and invasion. By contrast,
cells lacking Trp53 exhibit a less aggressive phenotype and gene
expression profiles more like control OSE cells. Thus, we have
unveiled a novel role for wild-type TRP53 as a major promoter
of ovarian cancer cell survival, differentiation, and migration.
These results provide a new paradigm:Wild-type TRP53 at low
levels of activity does not preferentially induce apoptotic or
senescent related genes in the Pten/Kras (Trp53-positive) cells.
To test this paradigm, purified TPR53-positive and TRP53-
negative OSE cells were exposed to the p53 activator nutlin-3a.
In TRP53-positive OSE cells, nutlin-3a stimulated TRP53 activity
as indicated by the rapid induction of cell cycle arrest and
apoptotic genes.
Conclusion: In the Pten/Kras mutant mouse OSE cells and
likely in human low-grade ovarian cancer cells, TRP53 controls
global molecular changes that are dependent not only on the
level of wild-type TRP53 expression but also on its activation
status. Low levels of TRP53 activity promote tumor survival and
growth, whereas higher TRP53 activity induces cell cycle arrest
and apoptosis. Thus, nutlin-3a provides a promising therapeutic
for managing type 1 ovarian cancer and other cancers where
wild-type TRP53 is expressed.