环状 RNA circZFR 通过调控 miR-375/HMGA2 轴促进肝癌进展。
Circular RNA circZFR Promotes Hepatocellular Carcinoma Progression by Regulating miR-375/HMGA2 Axis.
机构信息
Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 1 Swan Lake Road, New District of Political Affairs and Culture, Hefei, 230036, Anhui, China.
Department of Interventional Radiology, The Second People's Hospital of Hefei, Hefei, 230000, Anhui, China.
出版信息
Dig Dis Sci. 2021 Dec;66(12):4361-4373. doi: 10.1007/s10620-020-06805-2. Epub 2021 Jan 12.
BACKGROUND
Mounting evidence indicates that circular RNAs (circRNAs) have vital roles in human diseases, especially in cancers.
AIMS
The aim of this study was to explore the biological functions and underlying mechanism of circRNA zinc finger RNA binding (circZFR) in hepatocellular carcinoma (HCC).
METHODS
The expression levels of circZFR, microRNA-375 (miR-375) and high mobility group A2 (HMGA2) were detected by qRT-PCR or western blot assay. Glycolytic metabolism was examined via the measurement of extracellular acidification rate, oxygen consumption rate, glucose uptake, lactate production, and ATP level. MTT assay and flow cytometry were used to assess cell proliferation and cell apoptosis, respectively. The interaction between miR-375 and circZFR or HMGA2 was verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The mice xenograft model was established to investigate the role of circZFR in vivo.
RESULTS
CircZFR and HMGA2 were upregulated while miR-375 was downregulated in HCC tissues and cells. CircZFR silence inhibited HCC progression by inhibiting cell proliferation, glycolysis and tumor growth and promoting apoptosis. MiR-375 was a direct target of circZFR and its knockdown reversed the inhibitory effect of circZFR silence on the progression of HCC cells. Moreover, HMGA2 was a downstream target of miR-375, and miR-375 suppressed proliferation and glycolysis and induced apoptosis by targeting HMGA2 in HCC cells. Besides, circZFR acted as a molecular sponge of miR-375 to regulate HMGA2 expression.
CONCLUSION
Knockdown of circZFR suppressed the progression of HCC by upregulating miR-375 and downregulating HMGA2, providing new insight into the pathogenesis of HCC.
背景
越来越多的证据表明，环状 RNA（circRNA）在人类疾病中，尤其是癌症中具有重要作用。
目的
本研究旨在探讨 circRNA 锌指 RNA 结合蛋白（circZFR）在肝细胞癌（HCC）中的生物学功能和潜在机制。
方法
通过 qRT-PCR 或 Western blot 检测 circZFR、微小 RNA-375（miR-375）和高迁移率族蛋白 A2（HMGA2）的表达水平。通过测量细胞外酸化率、耗氧量、葡萄糖摄取、乳酸生成和 ATP 水平来检测糖酵解代谢。MTT assay 和流式细胞术分别用于评估细胞增殖和细胞凋亡。通过双荧光素酶报告和 RNA 免疫沉淀（RIP）assay 验证 miR-375 与 circZFR 或 HMGA2 的相互作用。建立小鼠异种移植模型来研究 circZFR 在体内的作用。
结果
在 HCC 组织和细胞中，circZFR 和 HMGA2 上调，而 miR-375 下调。circZFR 沉默通过抑制细胞增殖、糖酵解和肿瘤生长，促进细胞凋亡来抑制 HCC 的进展。miR-375 是 circZFR 的直接靶标，其下调逆转了 circZFR 沉默对 HCC 细胞进展的抑制作用。此外，HMGA2 是 miR-375 的下游靶标，miR-375 通过靶向 HMGA2 抑制 HCC 细胞的增殖和糖酵解并诱导凋亡。此外，circZFR 作为 miR-375 的分子海绵调节 HMGA2 的表达。
结论
下调 circZFR 通过上调 miR-375 和下调 HMGA2 抑制 HCC 的进展，为 HCC 的发病机制提供了新的见解。
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