Ge Minghuan, Zhu Hengcheng, Song Huajie, Schmeusser Benjamin N, Ng Keng Lim, Zeng Yan, Liu Ting, Yang Kang
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
Transl Androl Urol. 2023 Aug 31;12(8):1308-1320. doi: 10.21037/tau-23-355. Epub 2023 Aug 22.
Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), is insensitive to radiotherapy and chemotherapy after surgery. Deoxyribonuclease 1-like 3 (DNASE1L3), an endonuclease that cleaves both membrane-encapsulated single- and double-stranded DNA, suppresses cell cycle progression, proliferation and metabolism in hepatocellular carcinoma cells. There is currently no established link between DNASE1L3 and RCC inhibition. We are gonging to explored the mechanism underlying the relationship between DNASEL1L3 and RCC.
RNA sequencing data for RCC tissue and peritumoral tissue were downloaded from The Cancer Genome Atlas database and analyzed. The expression levels of DNASE1L3 in RCC and normal samples were verified using the Gene Expression Omnibus (GEO) database, Human Protein Atlas database and western blotting. The role and potential mechanism of DNASE1L3 were investigated by analysis of immune-related databases and wound healing, invasion, cell counting kit 8 and immunofluorescence assays.
We revealed that DNASE1L3 expression was downregulated in RCC group compared with control group [The Cancer Genome Atlas (TCGA): 7.98 10.87, P<0.001]. Meanwhile, DNASE1L3 expression correlated with the clinical characteristics of patients. Patients with low DNASE1L3 expression had worse survival (P<0.001) and larger (r=-0.32, P<0.001) and heavier tumors (r=-0.17, P<0.001). DNASE1L3 overexpression inhibited the proliferation (786-O: 0.135±0.014 0.322±0.027, P<0.001) and invasion (786-O: 1,479±134 832±67, P<0.05) of RCC cells. The expression of DNASE1L3 was significantly correlated with the tumor immune microenvironment and drug sensitivity in ccRCC. Moreover, the level of the key phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway protein P-AKT was decreased in the group of cells transfected with DNASE1L3.
This study strongly suggest that DNASE1L3 may be a promising potential biomarker for the diagnosis and treatment of ccRCC patients.
透明细胞肾细胞癌（ccRCC）是肾细胞癌（RCC）最常见的亚型，术后对放疗和化疗不敏感。脱氧核糖核酸酶1样3（DNASE1L3）是一种可切割膜包裹的单链和双链DNA的核酸内切酶，可抑制肝癌细胞的细胞周期进程、增殖和代谢。目前DNASE1L3与RCC抑制之间尚无明确联系。我们将探讨DNASEL1L3与RCC之间关系的潜在机制。
从癌症基因组图谱数据库下载RCC组织和瘤旁组织的RNA测序数据并进行分析。使用基因表达综合数据库（GEO）、人类蛋白质图谱数据库和蛋白质免疫印迹法验证RCC和正常样本中DNASE1L3的表达水平。通过分析免疫相关数据库以及伤口愈合、侵袭、细胞计数试剂盒8和免疫荧光试验，研究DNASE1L3的作用和潜在机制。
我们发现，与对照组相比，RCC组中DNASE1L3表达下调[癌症基因组图谱（TCGA）：7.98对10.87，P<0.001]。同时，DNASE1L3表达与患者的临床特征相关。DNASE1L3表达低的患者生存率较差（P<0.001），肿瘤更大（r=-0.32，P<0.001）且更重（r=-0.17，P<0.001）。DNASE1L3过表达抑制了RCC细胞的增殖（786-O：0.135±0.014对0.322±0.027，P<0.001）和侵袭（786-O：1479±134对832±67，P<0.05）。在ccRCC中，DNASE1L3的表达与肿瘤免疫微环境和药物敏感性显著相关。此外，在转染了DNASE1L3的细胞组中，关键的磷酸肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路蛋白P-AKT的水平降低。
本研究强烈表明，DNASE1L3可能是ccRCC患者诊断和治疗的一个有前景的潜在生物标志物。
