F-box蛋白FBXO21的过表达抑制透明细胞肾细胞癌的增殖和转移，并与CREB通路及肿瘤免疫细胞浸润密切相关。

F-box protein FBXO21 overexpression inhibits the proliferation and metastasis of clear cell renal cell carcinoma and is closely related to the CREB pathway and tumor immune cell infiltration.

作者信息

Yang Wuping, Jing Taile, Wu Cunjin, Lu Minghao, Yao Xiaolin, Xia Dan, Peng Ding

机构信息

Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.

出版信息

J Transl Med. 2025 Mar 15;23(1):335. doi: 10.1186/s12967-025-06356-y.

DOI:10.1186/s12967-025-06356-y

PMID:40089779

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11909812/

Abstract

BACKGROUND

Many studies have shown that F-box proteins regulate epithelial-mesenchymal transition, which is closely related to tumor metastasis. However, there is still limited research on the role of F-box proteins in renal cell carcinoma (RCC).

METHODS

Public databases were used to screen differentially expressed genes among 37 F-box proteins in clear cell RCC (ccRCC). The expression of the differential gene FBXO21 and its prognostic value were verified by RT-qPCR and immunohistochemistry. Pyrosequencing was used to detect the regulatory effect of DNA methylation on FBXO21 expression. The effects of FBXO21 expression on cell proliferation and metastasis were clarified through cell phenotype experiments and animal models. The relationship between FBXO21 expression and the infiltration levels of tumor immune cells was also analyzed. GSEA and Western blot were used to identify the downstream molecular pathways associated with FBXO21 expression.

RESULTS

Our results revealed that FBXO21 was significantly underexpressed in ccRCC and that increased FBXO21 expression predicted a better patient prognosis. The promoter region of FBXO21 exhibited DNA hypermethylation, and FBXO21 expression was significantly restored after demethylation. In addition, FBXO21 overexpression significantly inhibited the proliferation and metastasis of ccRCC cells both in vitro and in vivo. Mechanistically, FBXO21 expression was related to the stroma score and the infiltration levels of immune infiltrating cells associated with prognosis. Moreover, FBXO21 overexpression increased the expression of key molecules in the CREB pathway.

CONCLUSIONS

These results suggest that FBXO21 is a novel prognostic biomarker for ccRCC patients and functions as a tumor suppressor gene. Moreover, FBXO21 may regulate the CREB pathway and is closely related to tumor immune cell infiltration in ccRCC.

摘要

背景

许多研究表明，F-box蛋白调节上皮-间质转化，这与肿瘤转移密切相关。然而，关于F-box蛋白在肾细胞癌（RCC）中的作用仍研究有限。

方法

利用公共数据库筛选透明细胞肾细胞癌（ccRCC）中37种F-box蛋白的差异表达基因。通过RT-qPCR和免疫组化验证差异基因FBXO21的表达及其预后价值。采用焦磷酸测序检测DNA甲基化对FBXO21表达的调控作用。通过细胞表型实验和动物模型阐明FBXO21表达对细胞增殖和转移的影响。还分析了FBXO21表达与肿瘤免疫细胞浸润水平之间的关系。使用基因集富集分析（GSEA）和蛋白质免疫印迹法确定与FBXO21表达相关的下游分子途径。

结果

我们的结果显示，FBXO21在ccRCC中显著低表达，且FBXO21表达增加预示着患者预后较好。FBXO21的启动子区域表现出DNA高甲基化，去甲基化后FBXO21表达显著恢复。此外，FBXO21过表达在体外和体内均显著抑制ccRCC细胞的增殖和转移。机制上，FBXO21表达与基质评分以及与预后相关的免疫浸润细胞浸润水平有关。此外，FBXO21过表达增加了CREB通路关键分子的表达。