ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma

Molecular Cancer

Hui Zhang¹  Chunhui Liu²  Si Sun²  Lei Zhang²  Shuqiu Chen²  Jianping Wu²  Qiang Hu²  Bin Xu³  Ming Chen³  Weipu Mao³  Bo Peng⁴  Keyi Wang⁴  Wei Li⁴ 

[1]Department of Anesthesiology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, 200072, Shanghai, China

[2]Department of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, 210009, Nanjing, China

[3]Department of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, 210009, Nanjing, China

[4]Surgical Research Center, Institute of Urology, Southeast University Medical School, 210009, Nanjing, China

[5]Department of Urology, Nanjing Lishui District People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, 211200, Nanjing, China

[6]Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, No. 301, Yanchang Road, Jing’an District, 200072, Shanghai, China

关键词: Renal cell carcinoma;    ciRS-7;    PBAE/si-ciRS-7 nanocomplexes;    Metastasis;    Gene therapeutic;   

DOI  :  10.1186/s12943-021-01443-2

来源: Springer

【 摘 要 】

Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

【 授权许可】

CC BY