Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China; Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
J Hepatol. 2022 Jan;76(1):135-147. doi: 10.1016/j.jhep.2021.08.027. Epub 2021 Sep 9.
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.
CircRNA microarray was performed to screen significantly 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.
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 β-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively.
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.
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.
肝内胆管癌（ICC）是一种原发性肝癌，侵袭性强，预后极差。环状 RNA（circRNA）在 ICC 发生和进展中的作用仍有待确定。
通过对配对的 ICC 和非肿瘤组织进行 circRNA 微阵列筛选，筛选出显著上调的 circRNAs。采用集落形成、Transwell 侵袭和异种移植模型来研究 circRNAs 在 ICC 增殖和转移中的作用。利用 RNA 下拉、质谱、染色质免疫沉淀、RNA 结合蛋白免疫沉淀、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，来探索 circRNA（通过 miRNA 结合）的分子海绵作用，以及 circRNA 与 RNA 结合蛋白之间的相互作用。
Hsa_circ_0050898 来源于 ACTN4 基因外显子 1 到外显子 20（命名为 circACTN4），在 ICC 中显著上调。circACTN4 高表达与体外和体内肿瘤增殖和转移增强相关，以及 ICC 切除后的预后较差相关。此外，circACTN4 通过海绵吸附 miR-424-5p 而上调 Yes 相关蛋白 1（YAP1）的表达。更重要的是，circACTN4 还募集 Y 盒结合蛋白 1（YBX1）来刺激卷曲受体 7（FZD7）转录。此外，ICC 细胞中 circACTN4 的过表达增强了 Hippo 和 Wnt 信号通路的核心成分 YAP1 和 β-连环蛋白之间的相互作用。
circACTN4 在 ICC 中上调，并通过作为 miR-424-5p 的分子海绵，以及与 YBX1 相互作用转录激活 FZD7，促进 ICC 的增殖和转移。这些结果表明 circACTN4 是 ICC 的一个潜在的预后标志物和治疗靶点。
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