Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis

• Published in: Cancer letters 2021-12, Vol.523, p.121-134
• Main Authors: Huang, Kang-Bo, Pan, Yi-Hui, Shu, Guan-Nan, Yao, Hao-Hua, Liu, Xi, Zhou, Mi, Wei, Jin-Huan, Chen, Zhen-Hua, Lu, Jun, Feng, Zi-Hao, Chen, Wei, Han, Hui, Zheng, Zhou-San, Luo, Jun-Hang, Zhang, Jia-Xing
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - mortality; Cell Line, Tumor; circSNX6; Circular RNA; Drug Resistance, Neoplasm; Female; Flow cytometry; Glycerophosphocholine phosphodiesterase; GPCPD1; Humans; Inhibitor drugs; Intracellular; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - mortality; Kinases; Lysophosphatidic acid; Lysophospholipids - physiology; Male; Medical prognosis; Mice; Mice, Inbred BALB C; MicroRNAs; MicroRNAs - physiology; Middle Aged; miR-1184; miRNA; Patients; Phosphodiesterase; Phospholipases - physiology; Renal cell carcinoma; RNA, Circular - physiology; Sunitinib - pharmacology; Sunitinib resistance; Targeted cancer therapy; Tumors; Vascular endothelial growth factor
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.10.003

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular “sponge” to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets. •circSNX6 is upregulated in sunitinib-resistant RCC cells.•The expression of circSNX6 is correlated with sunitinib resistance and poorer survival.•circSNX6 promotes sunitinib resistance of RCC cells in vitro and in vivo.•circSNX6 exerts its function via miR-1184/GPCPD1/intracellular LPA axis.•circSNX6 may be a promising therapeutic target and biomarker for sunitinib resistance.