The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC

Junwei Tong; Xiangui Meng; Qingyang Lv; Hongwei Yuan; Weiquan Li; Wen Xiao; Xiaoping Zhang

doi:10.2147/IJGM.S335713

The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC

Int J Gen Med. 2021 Oct 11:14:6587-6599. doi: 10.2147/IJGM.S335713. eCollection 2021.

Authors

Junwei Tong^#^{1

2

3}, Xiangui Meng^#^{1

2

3}, Qingyang Lv^#^{1

2

3}, Hongwei Yuan^{1

2

3}, Weiquan Li^{1

2

3}, Wen Xiao^{1

2

3}, Xiaoping Zhang^{1

2

3}

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
² Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, People's Republic of China.
³ Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.

^# Contributed equally.

Abstract

Background: Increasing evidence indicated that the aberrant expression of the cytoplasmic FMR1-interacting protein (CYFIP) family might possess critical role and potential functions in cancer. But the role of CYFIP2 in clear cell renal cell carcinoma (ccRCC) is still uncharacteristic.

Methods: We investigated the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for the expression profile, clinicopathological variables, clinical prognosis information, and promoter methylation levels of CYFIPs in ccRCC. The aberrant CYFIP2 protein expression was validated by the Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to uncover CYFIP2 mRNA levels in 28 pairs of ccRCC cancer tissues. Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard regression were performed to assess CYFIPs' prognosis value. Gene set enrichment analysis (GSEA) was used to determined hallmark functions, gene ontology of CYFIP2. TIMER database was utilized to assess the correlation with immune infiltration in ccRCC.

Results: Results showed CYFIP2 was downregulated in ccRCC, relative to paired normal tissues in TCGA-KIRC database and 28 pairs of clinical samples (P < 0.0001). Similarly, a decreased CYFIP2 protein expression was confirmed by ccRCC tissues. The results showed CYFIP2 was negatively regulated by promoter DNA methylation. Survival analysis results showed CYFIP2 could be an independent biomarker for ccRCC and its reduction predicted a poor overall survival (OS) and disease-free survival (DFS). GSEA showed CYFIP2 was involved in metabolic pathways and epithelial-mesenchymal transition (EMT). Immune infiltration analysis revealed that a list of immune markers was significantly correlated with CYFIP2 expression especially with CD4+ cells and CD8+ cells in ccRCC.

Conclusion: These results show that CYFIP2 was downregulated in ccRCC patients and predicted an unfavorable prognosis. CYFIP2 might be a potential novel prognostic molecule, and related to immune infiltration, the metabolism, as well as EMT process in ccRCC. CYFIP2 could act as tumor suppressor gene in ccRCC and positive modulation of CYFIP2 might lead to development of a novel strategy for ccRCC treatment.

Keywords: CYFIP2; ccRCC; immune infiltration; methylation; prognosis.

Grants and funding

We thank for the supporting of grants from the National Natural Science Foundation of China (81902588), the National Key Scientific Instrument Development Project (81927807), National Key R&D Program of China (2017YFB1303100), Wuhan Science and Technology Plan Application Foundation Frontier Project (2020020601012247), and from Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20190809102415054).