DDX41 expression is associated with tumor necrosis in clear cell renal cell carcinoma and in cooperation with VHL loss leads to worse prognosis
DDX41 expression is associated with tumor necrosis in clear cell renal cell carcinoma and in cooperation with VHL loss leads to worse prognosis
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DOI：
10.1016/j.urolonc.2022.07.001
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发表时间：
2022-09-23
影响因子：
2.7
通讯作者：
Hinata, Nobuyuki
中科院分区：
文献类型：
--
作者：
Kobatake, Kohei;Ikeda, Kenichiro;Hinata, Nobuyuki
背景：组织学肿瘤坏死(TN)是手术治疗肾透明细胞癌(CcRCC)患者公认的独立预后指标。然而，TN改变疾病进展的确切机制仍不清楚。DEAD-box蛋白DDX41是一个解旋酶大家族的成员，它是一种模式识别受体，可以对抗细菌、双链DNA病毒和附近通过坏死释放双链DNA片段的细胞产生的双链DNA。我们推测DDX41可能在伴有TN的肾细胞癌中表达上调，从而导致更差的预后。方法：使用癌症基因组图谱数据集或本研究所的肾细胞癌样本，研究TN的存在与DDX41表达之间的关系。在此基础上，进一步研究了DDX41在人肾癌细胞中的分子功能。结果：在2个不同的肾细胞癌患者队列中，TN的存在与DDX41基因和蛋白的表达上调显著相关。此外，DDX41的mRNA和蛋白表达水平提示预后较差。体外ccRCC细胞分析表明，DDX41的表达促进了肿瘤的促进活性。此外，作为ccRCC最常见的特征之一，VHL缺失在DDX41表达的ccRCC中CXCL家族的表达增加，导致获得更差的恶性表型方面起着极其重要的作用。结论：CCRCC中DDX41的表达与TN有关，与VHL缺失共同导致预后较差。(C)2022由Elsevier Inc.发表。
Background: Histologic tumor necrosis (TN) is a well-established independent prognostic indicator in patients treated surgically for clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms by which TN alters disease progression remain unknown. The DEAD-box protein DDX41, a member of a large family of helicases, has been characterized as a pattern recognition receptor against an array of double-stranded (ds)DNA produced from bacteria, dsDNA viruses, and nearby cells that have released dsDNA fragments through necrosis. We hypothesized that DDX41 expression may be upregulated in ccRCC with TN, leading to worse prognosis. Methods: Relationship between the presence of TN and DDX41 expression were examined using The Cancer Genome Atlas data sets or using ccRCC samples in our institution. Further, the molecular functions of DDX41 were investigated with human ccRCC cells. Results: The presence of TN was significantly associated with the upregulation of mRNA and protein expression of DDX41 in the 2dif-ferent patient cohorts with ccRCC. In addition, the mRNA and protein expression levels of DDX41 revealed a worse prognosis. In vitro analyses with ccRCC cells revealed that DDX41 expression promotes tumor-promoting activity. Furthermore, VHL loss, 1of the most com-mon features in ccRCC, was shown to play an extremely important role in increasing the expression of the CXCL family in DDX41-express-ing ccRCC, leading to the acquisition of a worse malignant phenotype. Conclusions: DDX41 expression is associated with TN in ccRCC and leads to a worse prognosis in cooperation with VHL loss.(c) 2022 Published by Elsevier Inc.