Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription
Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription
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DOI：
10.1016/j.jhep.2021.08.027
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发表时间：
2021-12-15
影响因子：
25.7
通讯作者：
Shen, Feng
中科院分区：
文献类型：
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作者：
Chen, Qinjunjie;Wang, Haibo;Shen, Feng
背景与目的：肝内胆管细胞癌（Intrahepatic cholangiocarcinoma，ICC）是一种侵袭性强、预后极差的原发性肝癌。方法：应用CircRNA微阵列技术，在配对的ICC和非肿瘤组织中筛选表达显著上调的circRNA。使用集落形成、transwell和异种移植模型来检查circRNA在ICC增殖和转移中的作用。RNA pulldown、质谱、染色质免疫沉淀、RNA结合蛋白免疫沉淀、通过RNA纯化的染色质分离、电泳迁移率变动分析和荧光素酶报告基因分析用于探索circRNA的分子海绵作用。（通过miRNA结合），以及circRNA和RNA结合蛋白之间的相互作用。Hsa_circ_0050898，其起源于ACTN 4基因的外显子1至外显子20（命名为circACTN 4），在ICC中显著上调。circACTN 4高表达与体外和体内肿瘤增殖和转移的增强以及ICC切除后预后不良相关。此外，circACTN 4通过海绵状miR-424- 5 p上调YAP 1表达。更重要的是，circACTN 4还招募Y盒结合蛋白1（YBX 1）来刺激Frizzled-7（FZD 7）转录。结论：CircACTN 4在ICC细胞中表达上调，并通过与YBX 1相互作用激活FZD 7，促进ICC细胞增殖和转移，同时作为miR-424- 5 p的分子海绵发挥作用。这些结果表明，circACTN 4是一个潜在的预后标志物和治疗ICC.Lay总结：肝内胆管细胞癌是一种原发性肝癌与侵略性和极差的预后。我们发现相关的致病途径对治疗发展至关重要。在此，我们发现环状RNA（circACTN 4）在肝内胆管癌中高度表达，并通过关键的发育信号通路与肿瘤生长和转移呈正相关。因此，circACTN 4可能是肝内胆管癌的预后生物标志物和治疗靶点。(C)2021作者由Elsevier B. V.代表欧洲肝脏研究协会出版。
Background & Aims: Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with high aggressiveness and extremely poor prognosis. The role of circular RNAs (circRNAs) in ICC carcinogenesis and progression remains to be determined.Methods: CircRNA microarray was performed to screen signifi- cantly upregulated circRNAs in paired ICC and non-tumor tissues. Colony formation, transwell, and xenograft models were used to examine the role of circRNAs in ICC proliferation and metastasis. RNA pulldown, mass spectrometry, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, chromatin isolation by RNA purification, electrophoretic mobility shift assay, and luciferase reporter assays were used to explore the molecular sponge role of the circRNA (via miRNA binding), and the interaction between circRNA and RNA-binding proteins.Results: Hsa_circ_0050898, which originated from exon 1 to exon 20 of the ACTN4 gene (named circACTN4), was significantly upregulated in ICC. High circACTN4 expression was associated with enhanced tumor proliferation and metastasis in vitro and in vivo, as well as a worse prognosis following ICC resection. In addition, circACTN4 upregulated Yes-associated protein 1 (YAP1) expression by sponging miR-424-5p. More importantly, circACTN4 also recruited Y-box binding protein 1 (YBX1) to stimulate Frizzled-7 (FZD7) transcription. Furthermore, circACTN4 overexpression in ICC cells enhanced the interaction between YAP1 and b-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively.Conclusions: CircACTN4 was upregulated in ICC and promoted ICC proliferation and metastasis by acting as a molecular sponge of miR-424-5p, as well as by interacting with YBX1 to transcriptionally activate FZD7. These results suggest that circACTN4 is a potential prognostic marker and therapeutic target for ICC.Lay summary: Intrahepatic cholangiocarcinoma is a primary liver cancer associated with aggressiveness and extremely poor prognosis. It is essential for therapeutic development that we uncover relevant pathogenic pathways. Herein, we showed that a circular RNA (circACTN4) was highly expressed in intrahepatic cholangiocarcinoma and was positively associated with tumor growth and metastasis through key developmental signaling pathways. Thus, circACTN4 could be a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.