Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours
Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours
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DOI：
10.1186/s12885-019-6496-1
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发表时间：
2020-01-06
期刊：
影响因子：
3.8
通讯作者：
Chovanec, Miroslav
中科院分区：
文献类型：
--
作者：
Cierna, Zuzana;Miskovska, Vera;Chovanec, Miroslav
背景生殖细胞肿瘤（GCTs）代表了一种高度可治愈的恶性肿瘤，因为它们对顺铂（CDDP）为基础的化疗反应良好。然而，一小部分GCT患者复发或对治疗无反应。由于这可能是由CDDP诱导的DNA损伤的修复能力增加引起的，因此鉴定DNA修复生物标志物预测对CDDP的反应不足或异常，从而预测GCT患者的预后不良，这是一个挑战。本研究的目的是研究的关键核苷酸切除修复（NER）因子，XPA，ERCC 1和XPF，在GCT患者和细胞株的表达水平。MethodsTwo百7 GCT患者的标本有足够的后续临床病理数据和成对组合的CDDP耐药和敏感的GCT细胞系。采用免疫组化法检测GCT患者标本中ERCC 1、XPF和XPA蛋白的表达水平，Western blot和qRT-PCR检测GCT细胞系中ERCC 1、XPF和XPA蛋白及mRNA的表达水平。结果XPA低表达的GCT患者的总生存率显著高于高表达的患者（hazard ratio=0.38，95%confidence interval：0.12-1.23，p=0.0228）。此外，XPA表达在非肿瘤性组织学亚型、IGCCCG预后不良组、S分期增加以及存在肺、肝和非肺内脏转移中增加。重要的是，在GCT患者中发现的CDDP反应不足或异常和XPA表达之间的相关性也被认为是在GCT celllines.ConclusionsXPA表达是一个额外的独立的预后生物标志物分层GCT患者，允许改善那些在高风险的难治性或复发的治疗决策。此外，它可能代表GCT中的新治疗靶点。
BackgroundGerm cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines.MethodsTwo hundred seven GCT patients' specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients' specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines.ResultsGCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio=0.38, 95% confidence interval: 0.12-1.23, p=0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines.ConclusionsXPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.