Overexpression of Progerin Results in Impaired Proliferation and Invasion of Non-Small Cell Lung Cancer Cells
Overexpression of Progerin Results in Impaired Proliferation and Invasion of Non-Small Cell Lung Cancer Cells
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早老蛋白的过度表达导致非小细胞肺癌细胞的增殖和侵袭受损
DOI：
10.2147/ott.s237016
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Chen, Wei-Chun
中科院分区：
文献类型：
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作者：
Hu, Xiao-Ting;Song, Hao-Chang;Chen, Wei-Chun
目的：患者体内progerin （PG）的积累是导致Hutchinson-Gilford Progeria Syndrome （HGPS）发病的原因，因为它触发细胞加速老化。然而，关于progerin对肿瘤细胞作用的研究很少。肺癌是最常见的恶性癌症之一，全球发病率和死亡率都很高；非小细胞肺癌占大多数病例。本研究旨在探讨progerin对A549细胞增殖、细胞周期、侵袭、迁移、对DNA损伤剂敏感性、衰老和凋亡的影响，以期为肺癌治疗探索新的思路。方法：采用慢病毒感染法构建过表达progerin （A549- pg）的A549细胞和相应的空白对照（A549- gfp）。核染色法检测异常核形态。分别通过EdU、流式细胞术、集落形成实验和Matrigel侵袭和迁移实验比较A549-PG与A549-GFP的增殖、细胞周期、集落形成、侵袭和迁移能力。采用sa - β -gal染色法测定细胞的衰老情况。结果：A549-PG中progerin的表达明显高于A549-GFP。约20%的A549-PG具有异常细胞核。A549细胞过表达progerin抑制细胞增殖、迁移和侵袭，相关蛋白（CDK4、pRB、ANLN、MMP7和MMP9）下调。DNA损伤修复也受损。Progerin未引起细胞衰老，细胞凋亡无差异。结论：A549-PG产生了一些细胞变化，包括核骨架、细胞周期、DNA损伤修复、迁移和侵袭能力等。我们的数据表明，progerin可能导致A549细胞稳态失衡，增加其对化疗药物的敏感性。
Purpose: The accumulation of progerin (PG) in patients is responsible for the pathogenesis of Hutchinson-Gilford Progeria Syndrome (HGPS) because it triggers accelerated aging of cells. However, there are few studies on the effects of progerin on tumor cells. Lung cancer is one of the most common malignant cancers with high global morbidity and mortality rates; non-small cell lung cancer accounts for the majority of cases. The purpose of this study was to determine the effects of progerin on A549 cell proliferation, cell cycle, invasion, migration, sensitivity to DNA damaging agents, senescence and apoptosis with a goal of exploring new ideas for lung cancer treatment.Methods: A549 cells overexpressing progerin (A549-PG) and a corresponding blank control (A549-GFP) were constructed by lentiviral infection. A nuclear staining assay was utilized to detect abnormal nuclear morphology. The proliferation, cell cycle, colony formation, invasion and migration abilities of A549-PG were compared with those of A549-GFP via EdU assays, flow cytometry, colony formation experiments, and Matrigel invasion and migration assays, respectively. SA-beta-gal staining was used to measure senescence in cells.Results: The expression of progerin was significantly higher in A549-PG than A549-GFP. About 20% of A549-PG possessed abnormal nuclei. Overexpression of progerin in A549 cells inhibited cell proliferation, migration and invasion, and associated proteins (CDK4, pRB, ANLN, MMP7 and MMP9) were downregulated. DNA damage repair was also impaired. Progerin did not cause cells to senesce, and there was no difference in apoptosis.Conclusion: A549-PG generated some cellular changes, including the nuclear skeleton, the cell cycle, DNA damage repair, and migration and invasion abilities. Our data indicate that progerin could cause an imbalance in the steady state in A549 cells and increase their sensitivity to chemotherapeutic drugs.