Therapeutic SHPRH-146aa encoded by circ-SHPRH dynamically upregulates P21 to inhibit CDKs in neuroblastoma

• Published in: Cancer letters Vol. 598; p. 217120
• Main Authors: Chang, Saishuo, Ren, Dong, Zhang, Li, Liu, Shan, Yang, Wei, Cheng, Haiyan, Zhang, Xuexi, Hong, Enyu, Geng, Di, Wang, Yadi, Chen, Chenghao, Zhang, Jie, Shi, Tieliu, Guo, Yongli, Ni, Xin, Wang, Huanmin, Jin, Yaqiong
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 28.08.2024
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.217120

Recent research has underscored the significance of circular RNAs (circRNAs) in various cancers, including neuroblastoma (NB). Specifically, circ-SHPRH, a unique circRNA, has been revealed to inhibit tumor growth by sequestering miRNAs or producing the SHPRH-146aa protein. To explore circ-SHPRH's involvement in NB and its potential application in gene therapy, this study examined circ-SHPRH expression in 94 NB tissues and cell lines (SK–N-BE(2), SH-SY5Y) using real-time PCR and fluorescence in situ hybridization (FISH). Functional assays encompassing both overexpression and knockdown experiments in NB cell lines, as well as in vivo investigations, were conducted. RNA-seq analysis revealed a correlation between circ-SHPRH and the pathway of P21 (CDKN1A), a pivotal cell cycle regulator. Validation through PCR and other techniques confirmed that circ-SHPRH upregulated P21 expression. Furthermore, the regulatory role of circ-SHPRH in the P21-CDK pathway was corroborated through SHPRH-146aa expression analysis. Notably, adenovirus-mediated circ-SHPRH overexpression effectively curbed NB tumor growth in NSG mice, while combining circ-SHPRH with everolimus exhibited potential for NB treatment. This study elucidates the remarkable significance of circ-SHPRH in NB and its prospective utility in gene therapy, thereby paving the way for innovative therapeutic approaches. •Downregulation of Circ-SHPRH in NB Cells and High-Risk NB Patients (INRG).•Circ-SHPRH significantly inhibited the proliferation and migration of NB cells.•Regulation of the P21-CDK Pathway by Circ-SHPRH via SHPRH-146aa Expression.•The cell cycle progression of NB could be arrested by circ-SHPRH through P21-CDK Pathway.•Potential of Circ-SHPRH as a Critical Gene Therapy Drug for NB treatment.