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Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis

View Article: PubMed Central - PubMed

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 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.

No MeSH data available.


Related in: MedlinePlus

Working model: nuclear envelope defect is the main cause of aneuploidy in carcinogenesis. a Depiction of normal cytokinesis: at the start of M phase, the nuclear envelope dissolves, chromatin undergoes condensation, chromosomes pair and then separate, two new nuclear envelopes form, and cytokinesis is completed. b Chromosomal Disjunction: during chromosomal separation, one or more chromosomes are not attached. As a result, the two daughter cells have unequal distribution of chromosomes following cytokinesis. This mechanism is generally thought to be the main cause of aneuploidy. c Nuclear envelope defect causes aneuploidy: We reason that loss of a nuclear envelope structural component such as lamin A/C results in a misshapen nucleus. Additionally, the lamin A/C-deficient cells frequently fail to complete cytokinesis. Thus, tetraploid cells and subsequently aneuploid cells are generated. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes. Thus, we propose that the nuclear envelope defect is the main cause of aneuploidy in ovarian cancer development
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Fig5: Working model: nuclear envelope defect is the main cause of aneuploidy in carcinogenesis. a Depiction of normal cytokinesis: at the start of M phase, the nuclear envelope dissolves, chromatin undergoes condensation, chromosomes pair and then separate, two new nuclear envelopes form, and cytokinesis is completed. b Chromosomal Disjunction: during chromosomal separation, one or more chromosomes are not attached. As a result, the two daughter cells have unequal distribution of chromosomes following cytokinesis. This mechanism is generally thought to be the main cause of aneuploidy. c Nuclear envelope defect causes aneuploidy: We reason that loss of a nuclear envelope structural component such as lamin A/C results in a misshapen nucleus. Additionally, the lamin A/C-deficient cells frequently fail to complete cytokinesis. Thus, tetraploid cells and subsequently aneuploid cells are generated. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes. Thus, we propose that the nuclear envelope defect is the main cause of aneuploidy in ovarian cancer development

Mentions: The experimental results described here support a hypothesis that nuclear envelope defects (loss of lamin A/C proteins) may be the common cause of chromosomal numerical instability and aneuploidy in ovarian cancer (Fig. 5a-c). The idea explains both nuclear morphological deformation and aneuploidy, two prominent hallmarks of ovarian cancer. Generally, chromosomal disjunction is thought to be the cause of aneuploidy [7, 9, 10]. However, the results reported here leads us to a provocative hypothesis that nuclear envelope defect, such as loss of lamin A/C, rather than chromosomal disjunction (Fig. 5a), may be the main cause of aneuploidy in ovarian cancer (Fig. 5c). We reason that lamin A/C-deficient cells frequently fail to complete cytokinesis. We speculate that this is cause by the failure to properly form new nuclear envelope to encase the two new daughter nuclei, and the dividing nucleus undergoes furrow regression to produce tetraploid intermediates. Subsequently, aneuploid cells are generated by tripolar division. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes [61–64].Fig. 5


Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis
Working model: nuclear envelope defect is the main cause of aneuploidy in carcinogenesis. a Depiction of normal cytokinesis: at the start of M phase, the nuclear envelope dissolves, chromatin undergoes condensation, chromosomes pair and then separate, two new nuclear envelopes form, and cytokinesis is completed. b Chromosomal Disjunction: during chromosomal separation, one or more chromosomes are not attached. As a result, the two daughter cells have unequal distribution of chromosomes following cytokinesis. This mechanism is generally thought to be the main cause of aneuploidy. c Nuclear envelope defect causes aneuploidy: We reason that loss of a nuclear envelope structural component such as lamin A/C results in a misshapen nucleus. Additionally, the lamin A/C-deficient cells frequently fail to complete cytokinesis. Thus, tetraploid cells and subsequently aneuploid cells are generated. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes. Thus, we propose that the nuclear envelope defect is the main cause of aneuploidy in ovarian cancer development
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5120486&req=5

Fig5: Working model: nuclear envelope defect is the main cause of aneuploidy in carcinogenesis. a Depiction of normal cytokinesis: at the start of M phase, the nuclear envelope dissolves, chromatin undergoes condensation, chromosomes pair and then separate, two new nuclear envelopes form, and cytokinesis is completed. b Chromosomal Disjunction: during chromosomal separation, one or more chromosomes are not attached. As a result, the two daughter cells have unequal distribution of chromosomes following cytokinesis. This mechanism is generally thought to be the main cause of aneuploidy. c Nuclear envelope defect causes aneuploidy: We reason that loss of a nuclear envelope structural component such as lamin A/C results in a misshapen nucleus. Additionally, the lamin A/C-deficient cells frequently fail to complete cytokinesis. Thus, tetraploid cells and subsequently aneuploid cells are generated. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes. Thus, we propose that the nuclear envelope defect is the main cause of aneuploidy in ovarian cancer development
Mentions: The experimental results described here support a hypothesis that nuclear envelope defects (loss of lamin A/C proteins) may be the common cause of chromosomal numerical instability and aneuploidy in ovarian cancer (Fig. 5a-c). The idea explains both nuclear morphological deformation and aneuploidy, two prominent hallmarks of ovarian cancer. Generally, chromosomal disjunction is thought to be the cause of aneuploidy [7, 9, 10]. However, the results reported here leads us to a provocative hypothesis that nuclear envelope defect, such as loss of lamin A/C, rather than chromosomal disjunction (Fig. 5a), may be the main cause of aneuploidy in ovarian cancer (Fig. 5c). We reason that lamin A/C-deficient cells frequently fail to complete cytokinesis. We speculate that this is cause by the failure to properly form new nuclear envelope to encase the two new daughter nuclei, and the dividing nucleus undergoes furrow regression to produce tetraploid intermediates. Subsequently, aneuploid cells are generated by tripolar division. Formation of micronuclei at G-phases is another mechanism for the loss of individual chromosomes [61–64].Fig. 5

View Article: PubMed Central - PubMed

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 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.

No MeSH data available.


Related in: MedlinePlus