| Resume |
Abstract
Background: The Cancer Atlas project has shown that p53 is the only commonly (96 %) mutated gene found in
high-grade serous epithelial ovarian cancer, the major histological subtype. Another general genetic change is
extensive aneuploidy caused by chromosomal numerical instability, which is thought to promote malignant
transformation. Conventionally, aneuploidy is thought to be the result of mitotic errors and chromosomal
nondisjunction during mitosis. Previously, we found that ovarian cancer cells often lost or reduced nuclear lamina
proteins lamin A/C, and suppression of lamin A/C in cultured ovarian epithelial cells leads to aneuploidy. Following
up, we investigated the mechanisms of lamin A/C-suppression in promoting aneuploidy and synergy with p53
inactivation.
Results: We found that suppression of lamin A/C by siRNA in human ovarian surface epithelial cells led to frequent
nuclear protrusions and formation of micronuclei. Lamin A/C-suppressed cells also often underwent mitotic failure
and furrow regression to form tetraploid cells, which frequently underwent aberrant multiple polar mitosis to form
aneuploid cells. In ovarian surface epithelial cells isolated from p53 null mice, transient suppression of lamin A/C
produced massive aneuploidy with complex karyotypes, and the cells formed malignant tumors when implanted in
mice.
Conclusions: Based on the results, we conclude that a nuclear envelope structural defect, such as the loss or
reduction of lamin A/C proteins, leads to aneuploidy by both the formation of tetraploid intermediates following
mitotic failure, and the reduction of chromosome (s) following nuclear budding and subsequent loss of
micronuclei. We suggest that the nuclear envelope defect, rather than chromosomal unequal distribution during
cytokinesis, is the main cause of aneuploidy in ovarian cancer development. |