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

  • Cancer Lett. 2021 Dec 28;523:121-134. doi: 10.1016/j.canlet.2021.10.003.
Kang-Bo Huang  1 ,  Yi-Hui Pan  1 ,  Guan-Nan Shu  1 ,  Hao-Hua Yao  1 ,  Xi Liu  1 ,  Mi Zhou  2 ,  Jin-Huan Wei  1 ,  Zhen-Hua Chen  1 ,  Jun Lu  1 ,  Zi-Hao Feng  1 ,  Wei Chen  1 ,  Hui Han  3 ,  Zhou-San Zheng  4 ,  Jun-Hang Luo  5 ,  Jia-Xing Zhang  6
Affiliations
  • 1. Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4. Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 5. Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 6. Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 34626691 DOI: 10.1016/j.canlet.2021.10.003
Abstract

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.

Keywords
GPCPD1; Renal cell carcinoma; Sunitinib resistance; circSNX6; miR-1184.
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