세포융합에 따른 유전체 불안정성

Alternative Title
Chromosomal instability induced by cell-to-cell fusion using HeLa cells
Author(s)
도미향
Alternative Author(s)
Mihyang Do
Advisor
이재호
Department
일반대학원 의생명과학과
Publisher
The Graduate School, Ajou University
Publication Year
2017-08
Language
eng
Keyword
cell fusionapoptosissurvivinasymmetric divisionchromosomal instability
Alternative Abstract
Tetraploidy, a potential precursor of cancer-associated aneuploidy, is produced either by cell fusion or cytokinesis failure. These cells undergo cell-cycle arrest or apoptosis in a p53-dependent manner. Here, I used low p53-expressing HeLa cells as a model system to address the fate of cancer cells after fusion in the context of decreased influence of p53. I found that massive apoptotic cell death or growth arrest occurred a few days after fusion and was accompanied by an increase in p53. In addition, cells with larger nuclei preferentially died after fusion, suggesting that a larger deviation from normal DNA content is a strong inducer of apoptosis. Closer observation of the cells revealed that the division of fused cells immediately after cell fusion showed the formation of multipolar spindles due to increased number of centrosomes, resulting in various mitotic defects (DNA bridges, lagging chromosome, micronucleus, etc.) and asymmetric division with subsequent cytokinesis failure. After a series of unstable cell division processes, the surviving cells showed depolyploidization to have a little bit more chromosomes comparing to parental cells. The CIN (chromosomal instability) assay measuring the centromere of chromosomes 8 and 18 confirmed that chromosomal instability was increased in fused cells, and even in stable fused cell lines. Notably, a fraction of cells escaped from cell death and proliferated. These surviving fused cells were characterized by upregulation of survivin, reflecting increased survivin protein stability. Moreover, in fused cells, survivin became preferentially localized to the cytosol, where it is known to exert its anti-apoptotic function. Knockdown of survivin decreased survival to a greater extent in fused cells than in unfused cells, suggesting that fused cells became more dependent on survivin. Therefore, above findings indicate that, after cancer cell fusion, a subpopulation of fused cells with a higher level of cytosolic survivin are able to avoid apoptotic crisis and survive to proliferate continuously, a process that might contribute to human cancer progression. Regarding cancer progression, fused cells were superior to unfused cells in their overall cell migration ability, and their abilities varied according to each cell line. In addition, when the cells were grown under low concentration of cisplatin, fused cells got resistance more readily than unfused cells. Collectively, the fusion of cancer cells leads to chromosomal instability that induce p53-dependent cell death; however, a fraction of cells such as the cells having more cytosolic survivin survive and get genetic diversity, which probably confers the cancer cells more progressed characteristics such as acquisition of chemoresistance as well as migration ability.
URI
https://dspace.ajou.ac.kr/handle/2018.oak/19048
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Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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