Cao Qingfei, Ma Jiaji, Li Weitao, Hong Peng, Shen Tong, Tong Ming
Department of Medicine, Soochow University, Jiangsu, China.
Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
Genes Genomics. 2023 Jan;45(1):1-11. doi: 10.1007/s13258-022-01334-w. Epub 2022 Nov 8.
Guanine nucleotide-binding protein 2 (GNBP2) is a GTPase that has critical roles in host immunity and some types of cancer, but its function in clear cell renal cell carcinoma (ccRCC) is not fully understood.
This work explored the role of GNBP2 in ccRCC progression and the underlying molecular mechanism.
Two public human cancer databases TNMplot and TISIDB were employed to analyze the expression pattern of GNBP2 during ccRCC progression and the correlation between GNBP2 expression and clinical features of ccRCC patients. GNBP2 functions in ccRCC cells were determined by EdU staining, flow cytometry, scratch wound assay, transwell assay, and xenograft model. Gene expression was evaluated using qPCR, Western blot, immunofluorescence staining, and immunohistochemical staining.
GNBP2 expression was significantly elevated in ccRCC tissues and increased gradually with the increasing tumor grades. Patients with higher GNBP2 expression had shorter overall survival times. Knockdown of GNBP2 suppressed tumor cell proliferation and cell cycle progression and reduced the capability of migration and invasion, while GNBP2 overexpression exhibited protumor effects. GNBP2 silencing by RNA interference significantly inhibited the tumor growth of tumor-bearing nude mice and decreased the proliferation marker Ki67. Mechanistically, GNBP2 downregulation suppressed the STAT3 signaling transduction, as it reduced the phosphorylation of STAT3 and modulated the expression of the target genes, including c-Myc, MMP2, N-cadherin, and E-cadherin.
These findings reveal that GNBP2 promotes ccRCC progression by regulating STAT3 signaling transduction, indicating that GNBP2 might be a promising molecular target for ccRCC therapy.
鸟嘌呤核苷酸结合蛋白2（GNBP2）是一种GTP酶，在宿主免疫和某些类型的癌症中起关键作用，但其在肾透明细胞癌（ccRCC）中的功能尚未完全明确。
本研究探讨GNBP2在ccRCC进展中的作用及其潜在的分子机制。
利用两个公开的人类癌症数据库TNMplot和TISIDB分析GNBP2在ccRCC进展过程中的表达模式，以及GNBP2表达与ccRCC患者临床特征之间的相关性。通过EdU染色、流式细胞术、划痕实验、Transwell实验和异种移植模型确定GNBP2在ccRCC细胞中的功能。使用qPCR、蛋白质免疫印迹、免疫荧光染色和免疫组织化学染色评估基因表达。
GNBP2在ccRCC组织中的表达显著升高，并随着肿瘤分级的增加而逐渐升高。GNBP2表达较高的患者总生存时间较短。敲低GNBP2可抑制肿瘤细胞增殖和细胞周期进程，并降低迁移和侵袭能力，而GNBP2过表达则表现出促肿瘤作用。RNA干扰沉默GNBP2可显著抑制荷瘤裸鼠的肿瘤生长，并降低增殖标志物Ki67的表达。机制上，GNBP2下调抑制了STAT3信号转导，因为它降低了STAT3的磷酸化水平，并调节了包括c-Myc、MMP2、N-钙黏蛋白和E-钙黏蛋白在内的靶基因的表达。
这些发现表明，GNBP2通过调节STAT3信号转导促进ccRCC进展，提示GNBP2可能是ccRCC治疗的一个有前景的分子靶点。
