JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.

The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. Ó2016 AACR.

BackgroundLiver cancer is one of the main causes of cancer-related death in human. HOXA7 has been proved to be related with several cancers.MethodThe expression levels of HOXA7 were examined by Western blot, qRT-PCR or ICH. MTT was used to detect the proliferative rate of liver cancer cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of liver cancer cells were revealed in BALB/c nude mice.ResultsIn this report, we revealed that HOXA7 promoted metastasis of HCC patients. First, increased levels of HOXA7 were examined in liver cancer especially in metastatic liver cancer. Moreover, higher expression level of HOXA7 was associated with poorer prognosis of liver cancer patients. Overexpression of HOXA7 significantly enhanced proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo meanwhile silencing HOXA7 significantly inhibited the aboves abilities of liver cancer cells. In this research, we identified that HOXA7 performed its oncogenic characteristics through activating Snail.ConclusionCollectively, we identify the critical role and possible mechanism of HOXA7 in metastasis of liver cancer which suggest that HOXA7 may be a potential therapeutic target of liver cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0540-4) contains supplementary material, which is available to authorized users.

SummaryLiver ischemia-reperfusion injury (IRI) is a major cause of morbidity and mortality after resection surgery, liver transplantation, and hemorrhagic and septic shock. Mir-155 is upregulated by a broad range of inflammatory mediators, and it has been demonstrated to be involved in both innate and adaptive immune responses. However, the role of mir-155 in liver IRI has never been investigated. In this study, mir-155 deficiency protected mice from liver IRI, as shown by lower serum alanine aminotransferase (ALT) levels and Suzuki scores. Mir-155 deficiency results in the development of M2 macrophages, which respond to IR-induced innate immune stimulation by producing a regulatory inflammatory response with higher level of IL-10, but lower levels of TNF-a, IL-6, and IL12p40. Mir-155 deficiency suppresses IL-17 expression, which contributes to the liver IRI development. In our further in vitro study, the results show that the Th17 differentiation is inhibited by SOCS1 overexpression and the promoted M2 macrophage development induced by mir-155 deficiency is abolished by SOCS1 knockdown. In conclusion, mir-155 deficiency attenuates liver IRI through upregulation of SOCS1, and this was associated with promoted M2 macrophage and inhibited Th17 differentiation.

Recent studies have shown that deubiquitination plays a key role in tumor progression, metastasis, resistance to chemotherapy drugs, and prognosis. In this study, we investigated the effects of the deubiquitinating enzyme USP22 on the expression of the drug-resistance genes BMI1 and EZH2 in hepatocellular carcinoma (HCC) and on prognosis. Downregulation of USP22 expression with interference ribonucleic acid in resistant HCC cell lines with high USP22 expression resulted in decreased BMI1 expression, but had no effect on EZH2 expression. USP22, BMI1, and EZH2 were highly expressed in HCC tissue, and the expression levels were positively correlated with tumor grade and clinical stage. Correlation analysis showed that USP22 expression was positively correlated with that of BMI1. Kaplan–Meier analysis showed that high levels of USP22 and BMI1 expression were associated with poor overall survival and relapse-free survival in all of the cases and in patients treated with transcatheter arterial chemoembolization. These results suggested that high levels of USP22 expression played an important role in drug resistance to chemotherapeutic drugs in HCC patients by upregulating the expression of BMI1; therefore, coexpression of USP22 and BMI1 may become a new predictor for HCC prognosis and may help guide clinical treatment.