Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2
Introduction and Objectives: The development of hepatocellular carcinoma (HCC) is a multi-step process that accumulates genetic and epigenetic alterations, including changes in circular RNA (circRNA). This study aimed to understand the alterations in circRNA expression in HCC development and metasta...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Annals of Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1665268123002284 |
| _version_ | 1797733038934720512 |
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| author | Ping Gao Yuan Yang Xiaowei Li Qi Zhao Yujin Liu Chunnan Dong Yanan Zhang Dianwu Liu |
| author_facet | Ping Gao Yuan Yang Xiaowei Li Qi Zhao Yujin Liu Chunnan Dong Yanan Zhang Dianwu Liu |
| author_sort | Ping Gao |
| collection | DOAJ |
| description | Introduction and Objectives: The development of hepatocellular carcinoma (HCC) is a multi-step process that accumulates genetic and epigenetic alterations, including changes in circular RNA (circRNA). This study aimed to understand the alterations in circRNA expression in HCC development and metastasis and to explore the biological functions of circRNA. Materials and Methods: Ten pairs of adjacent chronic hepatitis tissues and HCC tissues from patients without venous metastases, and ten HCC tissues from patients with venous metastases were analyzed using human circRNA microarrays. Differentially expressed circRNAs were then validated by quantitative real-time PCR. In vitro and in vivo assays were performed to assess the roles of the circRNA in HCC progression. RNA pull-down assay, mass spectrometry analysis, and RNA-binding protein immunoprecipitation were conducted to explore the protein partners of the circRNA. Results: CircRNA microarrays revealed that the expression patterns of circRNAs across the three groups were significantly different. Among these, hsa_circ_0098181 was validated to be lowly expressed and associated with poor prognosis in HCC patients. Ectopic expression of hsa_circ_0098181 delayed HCC metastasis in vitro and in vivo. Mechanistically, hsa_circ_0098181 sequestered eukaryotic translation elongation factor 2 (eEF2) and dissociated eEF2 from filamentous actin (F-actin) to prevent F-actin formation, which blocked activation of the Hippo signaling pathway. In addition, the RNA binding protein Quaking-5 bound directly to hsa_circ_0098181 and induced its biogenesis. Conclusions: Our study reveals changes in circRNA expression from chronic hepatitis, primary HCC, to metastatic HCC. Further, the QKI5-hsa_circ_0098181-eEF2-Hippo signaling pathway exerts a regulatory role in HCC. |
| first_indexed | 2024-03-12T12:23:16Z |
| format | Article |
| id | doaj.art-0200d43b83f64d4dacd1901c6fb9c86e |
| institution | Directory Open Access Journal |
| issn | 1665-2681 |
| language | English |
| last_indexed | 2024-03-12T12:23:16Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Annals of Hepatology |
| spelling | doaj.art-0200d43b83f64d4dacd1901c6fb9c86e2023-08-30T05:50:17ZengElsevierAnnals of Hepatology1665-26812023-09-01285101124Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2Ping Gao0Yuan Yang1Xiaowei Li2Qi Zhao3Yujin Liu4Chunnan Dong5Yanan Zhang6Dianwu Liu7Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, ChinaEastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, ChinaChangping District Center for Disease Control and Prevention of Beijing Municipality, Beijing, ChinaDepartment of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, ChinaDepartment of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, ChinaDepartment of Pathogenic Biology, Hebei Medical University, Shijiazhuang, ChinaExperimental Center for Teaching, Hebei Medical University, Shijiazhuang, ChinaDepartment of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China; Corresponding author.Introduction and Objectives: The development of hepatocellular carcinoma (HCC) is a multi-step process that accumulates genetic and epigenetic alterations, including changes in circular RNA (circRNA). This study aimed to understand the alterations in circRNA expression in HCC development and metastasis and to explore the biological functions of circRNA. Materials and Methods: Ten pairs of adjacent chronic hepatitis tissues and HCC tissues from patients without venous metastases, and ten HCC tissues from patients with venous metastases were analyzed using human circRNA microarrays. Differentially expressed circRNAs were then validated by quantitative real-time PCR. In vitro and in vivo assays were performed to assess the roles of the circRNA in HCC progression. RNA pull-down assay, mass spectrometry analysis, and RNA-binding protein immunoprecipitation were conducted to explore the protein partners of the circRNA. Results: CircRNA microarrays revealed that the expression patterns of circRNAs across the three groups were significantly different. Among these, hsa_circ_0098181 was validated to be lowly expressed and associated with poor prognosis in HCC patients. Ectopic expression of hsa_circ_0098181 delayed HCC metastasis in vitro and in vivo. Mechanistically, hsa_circ_0098181 sequestered eukaryotic translation elongation factor 2 (eEF2) and dissociated eEF2 from filamentous actin (F-actin) to prevent F-actin formation, which blocked activation of the Hippo signaling pathway. In addition, the RNA binding protein Quaking-5 bound directly to hsa_circ_0098181 and induced its biogenesis. Conclusions: Our study reveals changes in circRNA expression from chronic hepatitis, primary HCC, to metastatic HCC. Further, the QKI5-hsa_circ_0098181-eEF2-Hippo signaling pathway exerts a regulatory role in HCC.http://www.sciencedirect.com/science/article/pii/S1665268123002284Hepatocellular carcinomaCircular RNA expression profilehsa_circ_0098181eEF2Hippo signaling pathway |
| spellingShingle | Ping Gao Yuan Yang Xiaowei Li Qi Zhao Yujin Liu Chunnan Dong Yanan Zhang Dianwu Liu Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 Annals of Hepatology Hepatocellular carcinoma Circular RNA expression profile hsa_circ_0098181 eEF2 Hippo signaling pathway |
| title | Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 |
| title_full | Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 |
| title_fullStr | Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 |
| title_full_unstemmed | Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 |
| title_short | Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2 |
| title_sort | circular rna hsa circ 0098181 inhibits metastasis in hepatocellular carcinoma by activating the hippo signaling pathway via interaction with eef2 |
| topic | Hepatocellular carcinoma Circular RNA expression profile hsa_circ_0098181 eEF2 Hippo signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S1665268123002284 |
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