Hsa_circ_0057105 modulates a balance of epithelial‐mesenchymal transition and ferroptosis vulnerability in renal cell carcinoma

• Published in: Clinical and translational medicine 2023-08, Vol.13 (8), p.e1339-n/a
• Main Authors: Cen, Junjie, Liang, Yanping, Feng, Zihao, Chen, Xu, Chen, Jinlong, Wang, Yinghan, Zhu, Jiangquan, Xu, Quanhui, Shu, Guannan, Zheng, Wenbin, Liang, Hui, Wang, Zhu, Deng, Qiong, Cao, Jiazheng, Luo, Junhang, Jin, Xiaohan, Huang, Yong
• Format: Article
• Language: English
• Subjects: Animal research; Animals; Carcinoma, Renal Cell - metabolism; Cells; Chi-square test; circRNA; Clinical medicine; EMT pathway; Epithelial-Mesenchymal Transition - genetics; Ferroptosis; Ferroptosis - genetics; In Situ Hybridization, Fluorescence; Kidney cancer; Kidney Neoplasms - metabolism; Metastasis; MicroRNAs - genetics; renal cell carcinoma; RNA, Circular - genetics; RNA, Circular - metabolism; Surgery; Survival analysis
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1339

Background The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood. Methods High‐throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK‐8 assays were used to assess the function of hsa_circ_0057105 in RCC cells. The clinical relevance of hsa_circ_0057105 was evaluated in a cohort of RCC patients. The hsa_circ_0057105 regulatory axis was defined using RNA pull‐down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa_circ_0057105 was validated using animal experiments. Results Single‐sample gene set enrichment analysis and correlation analysis of RNA‐seq data showed that hsa_circ_0057105 was potentially oncogenic and may serve to regulate epithelial‐mesenchymal transition (EMT) activation in RCC. Hsa_circ_0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa_circ_0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa_circ_0057105 was shown to inhibit the expression of miR‐577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa_circ_0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa_circ_0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo. Conclusions In RCC, hsa_circ_0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR‐577, acting like a ‘double‐edged sword’. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment. In renal cell carcinoma (RCC), hsa_circ_0057105 acts like a 'double‐edged sword’. On one hand, it promotes the metastasis of RCC cells through activation of epithelial‐mesenchymal transition. On the other hand, it also increases the ferroptosis sensitivity of RCC cells. This suggests that under the modulation of hsa_circ_0057105, R