An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
Abstract Background Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers,...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1382-x |
| _version_ | 1818498733863600128 |
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| author | Lei Zhang Jiewei Chen Juanjuan Yong Liang Qiao Leibo Xu Chao Liu |
| author_facet | Lei Zhang Jiewei Chen Juanjuan Yong Liang Qiao Leibo Xu Chao Liu |
| author_sort | Lei Zhang |
| collection | DOAJ |
| description | Abstract Background Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown. Methods The expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression. Results By RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC. Conclusions For the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis. |
| first_indexed | 2024-12-10T20:19:34Z |
| format | Article |
| id | doaj.art-bab6e12b19df4889b0de17f3c00fe10c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T20:19:34Z |
| publishDate | 2019-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-bab6e12b19df4889b0de17f3c00fe10c2022-12-22T01:35:06ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-09-0138111510.1186/s13046-019-1382-xAn essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinomaLei Zhang0Jiewei Chen1Juanjuan Yong2Liang Qiao3Leibo Xu4Chao Liu5Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineDepartment of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityStorr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead HospitalGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityAbstract Background Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown. Methods The expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression. Results By RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC. Conclusions For the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis.http://link.springer.com/article/10.1186/s13046-019-1382-xHepatocellular carcinomaRNF187Notch signalingMetastasis |
| spellingShingle | Lei Zhang Jiewei Chen Juanjuan Yong Liang Qiao Leibo Xu Chao Liu An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research Hepatocellular carcinoma RNF187 Notch signaling Metastasis |
| title | An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma |
| title_full | An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma |
| title_fullStr | An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma |
| title_full_unstemmed | An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma |
| title_short | An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma |
| title_sort | essential role of rnf187 in notch1 mediated metastasis of hepatocellular carcinoma |
| topic | Hepatocellular carcinoma RNF187 Notch signaling Metastasis |
| url | http://link.springer.com/article/10.1186/s13046-019-1382-x |
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