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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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1382-x) contains supplementary material, which is available to authorized users.

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BackgroundPapillary thyroid carcinoma (PTC) is characterized by frequent metastases to cervical lymph nodes (CLNs), and the presence of lymph node metastasis at diagnosis has a significant impact on the surgical approach. Therefore, we established a radiomic signature to predict the CLN status of PTC patients using preoperative thyroid ultrasound, and investigated the association between the radiomic features and underlying molecular characteristics of PTC tumors.MethodsIn total, 270 patients were enrolled in this prospective study, and radiomic features were extracted according to multiple guidelines. A radiomic signature was built with selected features in the training cohort and validated in the validation cohort. The total protein extracted from tumor samples was analyzed with LC/MS and iTRAQ technology. Gene modules acquired by clustering were chosen for their diagnostic significance. A radiogenomic map linking radiomic features to gene modules was constructed with the Spearman correlation matrix. Genes in modules related to metastasis were extracted for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and a protein-protein interaction (PPI) network was built to identify the hub genes in the modules. Finally, the screened hub genes were validated by immunohistochemistry analysis.ResultsThe radiomic signature showed good performance for predicting CLN status in training and validation cohorts, with area under curve of 0.873 and 0.831 respectively. A radiogenomic map was created with nine significant correlations between radiomic features and gene modules, and two of them had higher correlation coefficient. Among these, MEmeganta representing the upregulation of telomere maintenance via telomerase and cell-cell adhesion was correlated with ‘Rectlike’ and ‘deviation ratio of tumor tissue and normal thyroid gland’ which reflect the margin and the internal echogenicity of the tumor, respectively. MEblue capturing cell-cell adhesion and glycolysis was associated with feature ‘minimum calcification area’ which measures the punctate calcification. The hub genes of the two modules were identified by protein-protein interaction network. Immunohistochemistry validated that LAMC1 and THBS1 were differently expressed in metastatic and non-metastatic tissues (p=0.003; p=0.002). And LAMC1 was associated with feature ‘Rectlike’ and ‘deviation ratio of tumor and normal thyroid gland’ (p<0.001; p<0.001); THBS1 was correlated with ‘minimum calcification area’ (p<0.001).ConclusionsThe radiomic signature proposed here has the potential to noninvasively predict the CLN status in PTC patients. Merging imaging phenotypes with genomic data could allow noninvasive identification of the molecular properties of PTC tumors, which might support clinical decision making and personalized management.