Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis
Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis
复制标题
环状RNA circSNX6通过miR-1184/GPCPD1/溶血磷脂酸轴促进肾细胞癌舒尼替尼耐药
DOI：
10.1016/j.canlet.2021.10.003
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发表时间：
2021-10-11
期刊：
影响因子：
9.7
通讯作者：
Zhang, Jia-Xing
中科院分区：
文献类型：
--
作者：
Huang, Kang-Bo;Pan, Yi-Hui;Zhang, Jia-Xing
舒尼替尼耐药性是肾细胞癌（RCC）全身治疗的主要挑战。环状rna （circRNAs）在调节RCC舒尼替尼耐药性中的作用在很大程度上是未知的。我们在体内建立了抗舒尼替的RCC细胞系。通过rna测序，我们鉴定出circSNX6，其在舒尼替尼耐药细胞中的表达与亲本细胞相比上调。在81例RCC患者中，高circSNX6表达与舒尼替尼耐药性和更差的肿瘤预后相关。体外和体内实验证实circSNX6可促进RCC对舒尼替尼的耐药。circSNX6作为分子“海绵”，缓解microRNA (miR)-1184对其靶基因甘油磷胆碱磷酸二酯酶1 （GPCPD1）的抑制作用，从而增加细胞内溶血磷脂酸（LPA）水平，最终促进RCC细胞对舒尼替尼的耐药。我们的研究结果表明，circSNX6/miR-1184/GPCPD1轴在RCC细胞内LPA水平和舒尼替尼耐药性的调节中起关键作用；它们还提供了一种新的预后指标和有希望的治疗靶点。
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.