Circular RNA Sequencing Identifies CircASAP1 as a Key Regulator in Hepatocellular Carcinoma Metastasis
Circular RNA Sequencing Identifies CircASAP1 as a Key Regulator in Hepatocellular Carcinoma Metastasis
复制标题
环状 RNA 测序确定 CircASAP1 是肝细胞癌转移的关键调节因子。
DOI：
10.1002/hep.31068
复制
发表时间：
2020-09-01
期刊：
影响因子：
13.5
通讯作者：
Zhou, Jian
中科院分区：
文献类型：
--
作者：
Hu, Zhi-Qiang;Zhou, Shao-Lai;Zhou, Jian
越来越多的证据表明，单链环状RNA（circRNA）在某些癌症（包括肝细胞癌（HCC））的发展中起关键作用。然而，circRNA在HCC转移中的作用尚不清楚。方法和结果在这项研究中，通过circRNA测序，我们鉴定了一种circRNA：circASAP 1（一种来自ASAP 1基因外显子2和3的circRNA，hsa_circ_0085616），它与HCC患者根治性切除术后的肺转移相关。CircASAP 1在具有高转移潜力的肝癌细胞系和转移性肝癌中过表达，在体外促进细胞增殖、集落形成、迁移和侵袭，在体内促进肿瘤生长和肺转移。机制研究表明，circASAP 1作为竞争性内源性RNA与microRNA 326（miR-326）和microRNA 532- 5 p（miR-532- 5 p）竞争，这两种RNA都是HCC中的肿瘤抑制因子。我们发现，丝裂原活化蛋白激酶（MAPK）1和集落刺激因子（CSF）-1是microRNA 326（miR-326）和microRNA 532- 5 p（miR-532- 5 p）的直接共同靶点，它们受circASAP 1调控。CircASAP 1通过调节miR-326/miR-532- 5 p-MAPK 1信号通路促进HCC细胞增殖和侵袭，此外，通过调节miR-326/miR-532- 5 p-CSF-1通路介导肿瘤相关巨噬细胞浸润。临床HCC样本显示circASAP 1表达与CSF-1、MAPK 1和CD 68+肿瘤相关巨噬细胞水平呈正相关，所有这些都可预测患者结局。结论我们鉴定了circASAP 1作为HCC转移的关键调节因子，其作用于miR-326/miR-532- 5 p-MAPK 1/CSF-1信号传导，并作为HCC患者的预后预测因子。
Background and Aims There is growing evidence that single-stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less clear, however, what role circRNA plays in HCC metastasis. Approach and Results In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs.In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, andin vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), both of which are tumor suppressors in HCC. We found that mitogen-activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)-1 were direct common targets for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR-326/miR-532-5p-MAPK1 signaling and, furthermore, mediates tumor-associated macrophage infiltration by regulating the miR-326/miR-532-5p-CSF-1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF-1, MAPK1, and CD68+ tumor-associated macrophages, all of which were predictive of patient outcomes. Conclusion We identified circASAP1 as a key regulator of HCC metastasis that acts on miR-326/miR-532-5p-MAPK1/CSF-1 signaling and serves as a prognostic predictor in patients with HCC.