PARKIN Inactivation Links Parkinson's Disease to Melanoma
PARKIN Inactivation Links Parkinson's Disease to Melanoma
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DOI：
10.1093/jnci/djv340
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发表时间：
2016-03-01
影响因子：
10.3
通讯作者：
Soufir, Nadem
中科院分区：
文献类型：
--
作者：
Hu, Hui-Han;Kannengiesser, Caroline;Soufir, Nadem
背景：帕金森病 (PD) 患者的黑色素瘤发病率较高，反之亦然，但这两种疾病的遗传联系尚不清楚。由于 PARK2 既是一种肿瘤抑制基因，并且在年轻发病的 PD 中经常发生突变，我们评估了 PARK2 在黑色素瘤易感性和进展中的作用。方法：对 512 名法国病例患者和 562 名健康对照患者以及散发性肿瘤和黑色素瘤细胞系进行了深入的 PARK2 基因剂量分析和测序。使用双边费舍尔精确检验和比值比 (OR) 计算，比较病例患者和对照患者之间的基因改变频率。我们使用蛋白质印迹法测定黑色素细胞和黑色素瘤细胞系中的 PARKIN 表达，并使用转染和克隆形成分析来评估 PARKIN 表达对细胞增殖的影响。所有统计检验都是双向的。 结果：25 名病例患者中存在种系 PARK2 突变（包括拷贝数变异、剪接和假定的有害错义突变），但只有 4 名对照患者存在（OR = 3.95，95% 置信区间 = 1.34 至 15.75）。原发性肿瘤中分别有 60% 和 74% 存在拷贝数变异 (CNV) 和杂合性缺失。 PARKIN 蛋白在黑素细胞中表达，但在大多数黑素瘤细胞系中不表达，并且其表达在致癌 NRAS 转化黑素细胞后下降。黑色素瘤细胞系中 PARKIN 的重新表达导致细胞增殖急剧减少，黑色素细胞中 PARKIN 的抑制刺激了其增殖。结论：我们的结果表明 PARK2 作为肿瘤抑制因子在黑色素瘤易感性和进展中发挥着重要作用，这可以解释这些疾病的流行病学关联。
Background: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.Methods: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.Results: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.Conclusion: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.