Kobatake Kohei, Ikeda Kenichiro, Nakata Yuichiro, Yamasaki Norimasa, Kanai Akinori, Sekino Yohei, Takemoto Kenshiro, Fukushima Takafumi, Babasaki Takashi, Kitano Hiroyuki, Goto Keisuke, Hayashi Tetsutaro, Sentani Kazuhiro, Teishima Jun, Kaminuima Osamu, Hinata Nobuyuki
Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
Urol Oncol. 2022 Oct;40(10):456.e9-456.e18. doi: 10.1016/j.urolonc.2022.07.001. Epub 2022 Jul 30.
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.
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.
The presence of TN was significantly associated with the upregulation of mRNA and protein expression of DDX41 in the 2different 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 common features in ccRCC, was shown to play an extremely important role in increasing the expression of the CXCL family in DDX41-expressing ccRCC, leading to the acquisition of a worse malignant phenotype.
DDX41 expression is associated with TN in ccRCC and leads to a worse prognosis in cooperation with VHL loss.
组织学肿瘤坏死（TN）是接受手术治疗的透明细胞肾细胞癌（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盒蛋白DDX41是解旋酶大家族的成员之一，已被鉴定为一种模式识别受体，可识别由细菌、双链DNA病毒产生的一系列双链（ds）DNA，以及通过坏死释放dsDNA片段的邻近细胞产生的dsDNA。我们假设，在伴有TN的ccRCC中，DDX41表达可能上调，导致预后更差。
利用癌症基因组图谱数据集或我们机构的ccRCC样本，研究TN的存在与DDX41表达之间的关系。此外，用人ccRCC细胞研究DDX41的分子功能。
在两个不同的ccRCC患者队列中，TN的存在与DDX41的mRNA和蛋白表达上调显著相关。此外，DDX41的mRNA和蛋白表达水平显示预后较差。对ccRCC细胞的体外分析表明，DDX41表达促进肿瘤促进活性。此外，VHL缺失是ccRCC最常见的特征之一，在增加表达DDX41的ccRCC中CXCL家族的表达方面发挥了极其重要的作用，导致获得更差的恶性表型。
在ccRCC中，DDX41表达与TN相关，并与VHL缺失共同导致预后更差。
