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首页> 外文期刊>Cell cycle >MAD2, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors
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MAD2, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors

机译：MAD2是一种新型的MAD2亚型，可减少有丝分裂阻滞并与睾丸生殖细胞肿瘤的耐药性相关

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Background: Prolonged mitotic arrest in response to anti-cancer chemotherapeutics, such as DNA-damaging agents, induces apoptosis, mitotic catastrophe, and senescence. Disruptions in mitotic checkpoints contribute resistance to DNA-damaging agents in cancer. MAD2 has been associated with checkpoint failure and chemotherapy response. In this study, a novel splice variant of MAD2, designated MAD2, was identified, and its association with the DNA damage response was investigated.Methods: Endogenous expression of MAD2 and full-length MAD2 (MAD2) was measured using RT-PCR in cancer cell lines, normal foreskin fibroblasts, and tumor samples collected from patients with testicular germ cell tumors (TGCTs). A plasmid expressing MAD2 was transfected into HCT116 cells, and its intracellular localization and checkpoint function were evaluated according to immunofluorescence and mitotic index.Results: MAD2 was expressed in several cancer cell lines and non-cancerous fibroblasts. Ectopically expressed MAD2 localized to the nucleus and reduced the mitotic index, suggesting checkpoint impairment. In patients with TGCTs, the overexpression of endogenous MAD2, but not MAD2, was associated with resistance to cisplatin-based chemotherapy. Likewise, cisplatin induced the overexpression of endogenous MAD2, but not MAD2, in HCT116 cells.Conclusions: Overexpression of MAD2 may play a role in checkpoint disruption and is associated with resistance to cisplatin-based chemotherapy in TGCTs.
机译：背景：响应抗癌化学疗法（例如DNA损伤剂）而延长的有丝分裂阻滞可诱导细胞凋亡，有丝分裂灾难和衰老。有丝分裂检查点的破坏会增强癌症中对DNA破坏剂的抵抗力。 MAD2与检查点失败和化疗反应有关。本研究确定了一种新的MAD2剪接变体MAD2，并研究了其与DNA损伤反应的关系。方法：使用RT-PCR检测MAD2和全长MAD2的内源表达睾丸生殖细胞肿瘤（TGCT）患者收集的细胞系，正常的包皮成纤维细胞和肿瘤样品。将表达MAD2的质粒转染到HCT116细胞中，根据免疫荧光和有丝分裂指数评估其在细胞内的定位和检查点功能。结果：MAD2在几种癌细胞和非癌性成纤维细胞中表达。异位表达的MAD2定位于细胞核并降低了有丝分裂指数，提示检查点受损。在TGCT患者中，内源性MAD2而不是MAD2的过表达与对基于顺铂的化学疗法的耐药有关。同样，顺铂诱导了HCT116细胞中内源性MAD2的过度表达，但未诱导MAD2的表达。结论：MAD2的过度表达可能在检查点中断中起作用，并且与TGCT中基于顺铂的化疗耐药有关。

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