circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis.
circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis.
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circCHST15是一种新型预后生物标志物，通过miR-125a-5p/EIF4EBP1轴促进透明细胞肾细胞癌细胞增殖和转移
DOI：
10.1186/s12943-021-01449-w
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发表时间：
2021-12-18
期刊：
影响因子：
37.3
通讯作者：
Wei JH
中科院分区：
文献类型：
--
作者：
Gui CP;Liao B;Luo CG;Chen YH;Tan L;Tang YM;Li JY;Hou Y;Song HD;Lin HS;Xu QH;Yao GS;Yao HH;Xi-Liu;Luo JH;Cao JZ;Wei JH
研究背景环状RNA（CircRNA）在多种肿瘤的发生、发展过程中起着重要的介导作用，通常作为microRNA（miRNA）海绵调控下游基因的表达。然而，circRNA在人肾透明细胞癌（ccRCC）中的异常表达和功能障碍尚需进一步研究。方法从Gene Expression Omnibus数据库中提取两个circRNA微阵列，通过比较肿瘤组织与癌旁正常组织、原发肿瘤组织与转移肿瘤组织，筛选出circCHST 15（hsa_circ_0020303）。这些结果通过实时定量聚合酶链反应和琼脂糖凝胶电泳进行了验证。我们证明了circCHST 15在体外和体内的ccRCC中的生物学效应。为了测试circCHST 15和miRNAs之间的相互作用，我们进行了一些实验，包括RNA下拉分析，双荧光素酶报告基因分析和荧光原位杂交。ResultsThe circCHST 15的表达是较高的ccRCC组织相比，健康的邻近肾组织和较高的RCC细胞系相比，正常肾细胞系。circCHST 15的水平与侵袭性临床病理特征呈正相关，circCHST 15可作为ccRCC患者手术切除后总生存期和无进展生存期的独立预后指标。我们的体内和体外数据表明，circCHST 15促进ccRCC细胞的增殖、迁移和侵袭。机制上，我们发现circCHST 15直接与miR-125 a-5 p相互作用，并作为microRNA海绵调控EIF 4 EBP 1的表达。结论我们发现，海绵状的miR-125 a-5 p促进EIF 4 EBP 1的表达是hsa_circ_0020303诱导ccRCC进展的潜在机制。这促使进一步研究circCHST 15作为ccRCC的潜在预后生物标志物和治疗靶点。
BackgroundCircular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC.MethodscircCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization.ResultsThe expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression.ConclusionsWe found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.
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