Abstract
JARID2 is crucial for maintenance of pluripotency and differentiation of embryonic stem cells. However, little is known about the role of JARID2 in metastasis of hepatocellular carcinoma (HCC). This study found that JARID2 expression was significantly higher in HCC tissues than that in adjacent non-tumor liver tissues (ANLTs), and its expression level correlated with HCC metastasis. High JARID2 expression was significantly correlated with multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05) and indicated poor prognosis of HCC in training and validation cohorts (all P < 0.05) totaling 182 patients. High JARID2 expression was an independent and significant risk factor for disease-free survival (DFS; P = 0.017) and overall survival (OS; P = 0.041) after curative liver resection in training cohort, and also validated as an independent and significant risk factor for DFS (P = 0.033) and OS (P = 0.031) in validation cohort. Moreover, down-regulation of JARID2 dramatically inhibited HCC cell migration, invasion, proliferation in vitro and metastasis in vivo, whereas overexpression of JARID2 significantly increased migration, invasion, proliferation in vitro and metastasis in vivo. Mechanistically, the data showed that JARID2 exerted its function by repressing PTEN expression through increasing H3K27 trimethylation (H3K27me3) at PTEN promoter region, which subsequently resulted in activation of protein kinase B (AKT) and enhanced epithelial-mesenchymal transition (EMT). In conclusion, this study revealed that JARID2 promotes invasion and metastasis of HCC by facilitating EMT through PTEN/AKT signaling.
Highlights
JARID2 is crucial for maintenance of pluripotency and differentiation of embryonic stem cells
Tissues was significantly higher than those in adjacent non-tumor liver tissues (ANLTs). (C) Western blot results showed that JARID2 protein in hepatocellular carcinoma (HCC) tissues was significantly higher than those in ANLTs. (D) JARID2 mRNA expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in nodular hepatocellular carcinoma (NHCC), solitary large hepatocellular carcinoma (SLHCC) and small hepatocellular carcinoma (SHCC)
In training cohort (Supplementary Figure 1 and Supplementary Table 1), the results showed that, in addition to tumor numbers, capsular formation, microvascular invasion, tumor node metastasis (TNM) stage and Barcelona Clinic Liver Cancer (BCLC) stage, high JARID2 expression in HCC tissues was found to be a significant independent prognosis factor for disease-free survival (DFS) (HR 1.641; 95% CI: 1.294 to 3.102; P = 0.017; Table 2) and overall survival (OS) (HR 1.873; 95% CI: 1.108 to 3.845; P = 0.041; Table 3)
Summary
JARID2 is crucial for maintenance of pluripotency and differentiation of embryonic stem cells. This study found that JARID2 expression was significantly higher in HCC tissues than that in adjacent non-tumor liver tissues (ANLTs), and its expression level correlated with HCC metastasis. High JARID2 expression was significantly correlated with multiple tumor nodules, high EdmondsonSteiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05) and indicated poor prognosis of HCC in training and validation cohorts (all P < 0.05) totaling 182 patients. HCC cell migration, invasion, proliferation in vitro and metastasis in vivo, whereas overexpression of JARID2 significantly increased migration, invasion, proliferation in vitro and metastasis in vivo. This study revealed that JARID2 promotes invasion and metastasis of HCC by facilitating EMT through PTEN/AKT signaling. Though several molecules associated with metastasis of HCC had been found by our research group and others,
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