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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

p53 inactivation and lamin A/C suppression lead to malignant tumors. Primary p53 knockout MOSE cells were transfected with control or siRNA (si-Lam A) and cultured for about 2 months. When the lamin A/C-suppressed and p53 (-/-) MOSE cells were implanted in nude mice subcutaneously, invasive tumors developed in 4 weeks (a). Two areas of the tumor are shown in higher magnification (b, c). Three examples of tumors formed from lamin A/C-suppressed p53 (-/-) MOSE cells were stained with lamin A/C, as shown in (d), (e), and (f). g Tumors formed from p53 (-/-) MOSE cells (not treated with lamin A/C-siRNA)) were compared, and a higher magnification (h) is shown. i An example of lamin A/C immunostaining is shown for a tumor derived for p53 (-/-) MOSE cells
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Fig4: p53 inactivation and lamin A/C suppression lead to malignant tumors. Primary p53 knockout MOSE cells were transfected with control or siRNA (si-Lam A) and cultured for about 2 months. When the lamin A/C-suppressed and p53 (-/-) MOSE cells were implanted in nude mice subcutaneously, invasive tumors developed in 4 weeks (a). Two areas of the tumor are shown in higher magnification (b, c). Three examples of tumors formed from lamin A/C-suppressed p53 (-/-) MOSE cells were stained with lamin A/C, as shown in (d), (e), and (f). g Tumors formed from p53 (-/-) MOSE cells (not treated with lamin A/C-siRNA)) were compared, and a higher magnification (h) is shown. i An example of lamin A/C immunostaining is shown for a tumor derived for p53 (-/-) MOSE cells

Mentions: When the MOSE cells were implanted into nude mice, both p53 (-/-) and lamin A/C-suppressed p53 (-/-) MOSE cells were tumorigenic (Fig. 4). Tumors formed in 5 of 6 nude mice when p53 (-/-) MOSE cells were implanted; and lamin A/C-suppressed p53 (-/-) MOSE cells formed tumors in 6 out of 6 mice tested. The tumors derived from the lamin A/C-suppressed p53 (-/-) MOSE cells had unique malignant features (Fig. 4a): the tumor cells often presented as small nodules invaded into muscle fibers (Fig. 4b, c). The tumor cells also exhibited a higher variation in nuclear sizes. In contrast, tumors derived from p53 (-/-) MOSE cells grew as a single mass with a more uniform nuclear morphology and size (Fig. 4g, h). Thus, a transient suppression of lamin A/C and generation of aneuploidy enable the growth of tumors with an increased degree of malignancy. Nevertheless, when implanted into immune competent female littermates from which the MOSE cells were prepared, neither p53 (-/-) nor lamin A/C-suppressed p53 (-/-) MOSE cells were able to produce significant or persistent tumors, indicating these MOSE cells were unable to escape the host immune surveillance in the development of tumors.Fig. 4


Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis
p53 inactivation and lamin A/C suppression lead to malignant tumors. Primary p53 knockout MOSE cells were transfected with control or siRNA (si-Lam A) and cultured for about 2 months. When the lamin A/C-suppressed and p53 (-/-) MOSE cells were implanted in nude mice subcutaneously, invasive tumors developed in 4 weeks (a). Two areas of the tumor are shown in higher magnification (b, c). Three examples of tumors formed from lamin A/C-suppressed p53 (-/-) MOSE cells were stained with lamin A/C, as shown in (d), (e), and (f). g Tumors formed from p53 (-/-) MOSE cells (not treated with lamin A/C-siRNA)) were compared, and a higher magnification (h) is shown. i An example of lamin A/C immunostaining is shown for a tumor derived for p53 (-/-) MOSE cells
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Related In: Results  -  Collection

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Show All Figures
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Fig4: p53 inactivation and lamin A/C suppression lead to malignant tumors. Primary p53 knockout MOSE cells were transfected with control or siRNA (si-Lam A) and cultured for about 2 months. When the lamin A/C-suppressed and p53 (-/-) MOSE cells were implanted in nude mice subcutaneously, invasive tumors developed in 4 weeks (a). Two areas of the tumor are shown in higher magnification (b, c). Three examples of tumors formed from lamin A/C-suppressed p53 (-/-) MOSE cells were stained with lamin A/C, as shown in (d), (e), and (f). g Tumors formed from p53 (-/-) MOSE cells (not treated with lamin A/C-siRNA)) were compared, and a higher magnification (h) is shown. i An example of lamin A/C immunostaining is shown for a tumor derived for p53 (-/-) MOSE cells
Mentions: When the MOSE cells were implanted into nude mice, both p53 (-/-) and lamin A/C-suppressed p53 (-/-) MOSE cells were tumorigenic (Fig. 4). Tumors formed in 5 of 6 nude mice when p53 (-/-) MOSE cells were implanted; and lamin A/C-suppressed p53 (-/-) MOSE cells formed tumors in 6 out of 6 mice tested. The tumors derived from the lamin A/C-suppressed p53 (-/-) MOSE cells had unique malignant features (Fig. 4a): the tumor cells often presented as small nodules invaded into muscle fibers (Fig. 4b, c). The tumor cells also exhibited a higher variation in nuclear sizes. In contrast, tumors derived from p53 (-/-) MOSE cells grew as a single mass with a more uniform nuclear morphology and size (Fig. 4g, h). Thus, a transient suppression of lamin A/C and generation of aneuploidy enable the growth of tumors with an increased degree of malignancy. Nevertheless, when implanted into immune competent female littermates from which the MOSE cells were prepared, neither p53 (-/-) nor lamin A/C-suppressed p53 (-/-) MOSE cells were able to produce significant or persistent tumors, indicating these MOSE cells were unable to escape the host immune surveillance in the development of tumors.Fig. 4

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