He Changjing, Qin Huatao, Tang Haizhou, Yang Di, Li Yufeng, Huang Zhenwen, Zhang Donghu, Lv Changheng
Department of Pediatric Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
Department of Nursing, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
Ann Transl Med. 2020 Oct;8(19):1228. doi: 10.21037/atm-20-6047.
Differential expression of tumor protein 53 (TP53, or p53) has been observed in multiple cancers. However, the expression levels and prognostic role of TP53 signaling pathway genes in Wilms' tumor (WT) have yet to be fully explored.
The expression levels of TP53 signaling pathway genes including TP53, mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), cyclin-dependent kinase 2A (CDKN2A), cyclin-dependent kinase 2B (CDKN2B), and tumor suppressor p53-binding protein 1 (TP53BP1) in WT were analyzed using the Oncomine database. Aberration types, co-mutations, mutation locations, signaling pathways, and the prognostic role of TP53 in WT were investigated using cBioPortal. MicroRNA (miRNA) and transcription factor (TF) targets were identified with miRTarBase, miWalk, and ChIP-X Enrichment Analysis 3 (CheA3), respectively. A protein-protein network was constructed using GeneMANIA. The expression of TP53 signaling genes were confirmed in WT samples and normal kidney tissues using the Human Protein Atlas (HPA). Cancer Therapeutics Response Portal (CTRP) was used to analyze the small molecules potentially targeting TP53.
TP53 was significantly expressed in the Cutcliffe Renal (P=0.010), but not in the Yusenko Renal (P=0.094). Meanwhile, MDM2 was significantly overexpressed in the Yusenko Renal (P=0.058), but not in the Cutcliffe Renal (P=0.058). The expression levels of MDM4 no significant difference between the tumor and normal tissue samples. The most common TP53 alteration was missense and the proportion of TP53 pathway-related mutations was 2.3%. Co-expressed genes included ZNF609 (zinc finger protein 609), WRAP53 (WD40-encoding RNA antisense to p53), CNOT2 (CC chemokine receptor 4-negative regulator of transcription 2), and CDH13 (cadherin 13). TP53 alterations indicated poor prognosis of WT (P=1.051e-4). The regulators of the TP53 pathway included miR-485-5p and TFs NR2F2 and KDM5B. The functions of TP53 signaling pathway were signal transduction in response to DNA damage and regulate the cell cycle. The small molecules targeting TP53 included PRIMA-1, RITA, SJ-172550, and SCH-529074.
TP53 was found to be differentially expressed in WT tissues. TP53 mutations indicated poor outcomes of WT. Therefore, pifithrin-mu, PRIMA-1, RITA, SJ-172550, and SCH-529074 could be used in combination with traditional chemotherapy to treat WT.
肿瘤蛋白53（TP53，即p53）在多种癌症中存在差异表达。然而，TP53信号通路基因在肾母细胞瘤（WT）中的表达水平及预后作用尚未得到充分研究。
利用Oncomine数据库分析WT中TP53信号通路基因包括TP53、小鼠双微体2（MDM2）、小鼠双微体4（MDM4）、细胞周期蛋白依赖性激酶2A（CDKN2A）、细胞周期蛋白依赖性激酶2B（CDKN2B）以及肿瘤抑制因子p53结合蛋白1（TP53BP1）的表达水平。使用cBioPortal研究WT中TP53的畸变类型、共突变、突变位置、信号通路及预后作用。分别通过miRTarBase、miWalk和ChIP-X富集分析3（CheA3）鉴定微小RNA（miRNA）和转录因子（TF）靶点。利用GeneMANIA构建蛋白质-蛋白质网络。使用人类蛋白质图谱（HPA）在WT样本和正常肾组织中确认TP53信号基因的表达。利用癌症治疗反应门户（CTRP）分析可能靶向TP53的小分子。
TP53在Cutcliffe肾组织中显著表达（P = 0.010），而在Yusenko肾组织中不显著（P = 0.094）。同时，MDM2在Yusenko肾组织中显著过表达（P = 0.058），而在Cutcliffe肾组织中不显著（P = 0.058）。MDM4在肿瘤组织和正常组织样本中的表达水平无显著差异。TP53最常见的改变是错义突变，TP53通路相关突变的比例为2.3%。共表达基因包括ZNF609（锌指蛋白609）、WRAP53（p53的WD40编码RNA反义物）、CNOT2（CC趋化因子受体4转录负调节因子2）和CDH13（钙黏蛋白13）。TP53改变表明WT预后不良（P = 1.051e - 4）。TP53通路的调节因子包括miR - 485 - 5p以及转录因子NR2F2和KDM5B。TP信号通路的功能是响应DNA损伤进行信号转导并调节细胞周期。靶向TP53的小分子包括PRIMA - 1、RITA、SJ - 172550和SCH - 529074。
发现TP53在WT组织中存在差异表达。TP53突变表明WT预后不良。因此，pifithrin - mu、PRIMA - 1、RITA、SJ - 172550和SCH - 529074可与传统化疗联合用于治疗WT。
