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Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells.

ABSTRACT: Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model.At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p?

SUBMITTER: Urzua U

PROVIDER: S-EPMC5088517 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells.

Urzúa Ulises U Ampuero Sandra S Roby Katherine F KF Owens Garrison A GA Munroe David J DJ

BMC genomics 20161025 Suppl 8

<h4>Background</h4>Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA co ...[more]

PMID: 27801298

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Project description:Tp53 mutation is frequent and associates with malignant, high-grade ovarian cancer. However, the details about the progression of Tp53 mutation from heterozygous to homozygous, and association between genotypes and morphological transformation are not clear. We further investigated the expression and mutation of Tp53 and associated markers such as p21 and HDM2 in ovarian cancer.Areas of contiguous ovarian surface epithelia linking morphological normal monolayer to multilayer neoplastic cells were analyzed for the correlation of Tp53 pathway alteration in relation to morphological transformation, by immunostaining and sequencing of Tp53 gene in cells from laser captured microdissection.Consistent with previous reports, Tp53 staining is positive in 78% of the tumors. The staining of p21 is positive in about 12%, and HMD2 is positive in only 1% of the tumors. In 9 out of 10 cases of p21-positive tumors, p53 is also positive. In the majority of cases of epithelial histological transitions, overexpression of Tp53 correlates with morphological transformation: Tp53 is negative in monolayered cells and positive in neoplastic lesions. Morphological transformation also closely correlates with cell proliferation as indicated by Ki-67 staining and loss of p21 expression. We detected heterozygous mutation of Tp53 in the monolayers adjacent to neoplastic cells.p21 expression is an indicator of a wild type Tp53 and lack of p21 in the presence of Tp53 expression predicts an inactivated Tp53. Tp53 inactivation immediately precedes morphological transformation of the ovarian surface epithelium in most cases, and the histological transitional epithelia containing a heterozygous Tp53 mutation are thus pre-neoplastic lesions. We propose that the loss of a second allele of Tp53 leading to the loss of p21 expression, and subsequent cell proliferation, compose a sequence of events that lead to morphological transformation and instigation of ovarian epithelial tumor development.

Dataset Information

Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells.

Publications

Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells.

Similar Datasets

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