Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription,Journal of Hepatology

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Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription
Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-09-09 , DOI: 10.1016/j.jhep.2021.08.027
Qinjunjie Chen ₁ , Haibo Wang ₁ , Zheng Li ₁ , Fengwei Li ₂ , Leilei Liang ₃ , Yiran Zou ₁ , Hao Shen ₄ , Jun Li ₁ , Yong Xia ₁ , Zhangjun Cheng ₅ , Tian Yang ₄ , Kui Wang ₆ , Feng Shen ₁

Affiliation

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 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.

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 β-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.

中文翻译：

环状 RNA ACTN4 通过募集 YBX1 启动 FZD7 转录促进肝内胆管癌进展

背景与目标

肝内胆管癌（ICC）是一种原发性肝癌，具有高侵袭性和极差的预后。环状 RNA (circRNA) 在 ICC 癌变和进展中的作用仍有待确定。

方法

进行 CircRNA 微阵列以筛选成对的 ICC 和非肿瘤组织中显着上调的 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 纯化分离染色质、电泳迁移率变化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）和相互作用circRNA 和 RNA 结合蛋白之间的关系。

结果

Hsa_circ_0050898 起源于ACTN4基因（称为 circACTN4）的外显子 1 至外显子 20，在 ICC 中显着上调。circACTN4 高表达与体外和体内肿瘤增殖和转移增强以及 ICC 切除后预后较差有关。此外，circACTN4 通过海绵化 miR-424-5p 上调 Yes 相关蛋白 1 (YAP1) 的表达。更重要的是，circACTN4 还招募了 Y-box 结合蛋白 1 (YBX1) 来刺激 Frizzled-7 (FZD7) 转录。此外，ICC 细胞中的 circACTN4 过表达增强了 YAP1 和 β-catenin 之间的相互作用，这分别是 Hippo 和 Wnt 信号通路的核心成分。