Prognostic value of increased expression of RACO-1 in patients with hepatitis B-related hepatocellular carcinoma.

RING domain AP-1 coactivator-1 (RACO-1) is a coactivator that links c-Jun to growth factor signaling and is essential for AP-1 function. This study aimed to investigate the expression and clinical significance of RACO-1 protein in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in China. A total of 136 tissue samples of HBV-related HCC were detected by immunohistochemistry (including 76 patients in training cohort and 60 patients in validation cohort). Correlation between RACO-1 expression and clinicopathologic features of HBV-related HCC was analyzed in both the cohorts. RACO-1 expression was significantly higher in HBV-related HCC tissues than in adjacent non-tumor liver tissues. All the patients were divided into two groups: the low expression group and the high expression group. RACO-1 expression was significantly related to vascular invasion (P=0.021), tumor numbers (P=0.046), International Union for Cancer Control/American Joint Committee on Cancer stage (P=0.006), cirrhosis (P=0.046), capsular (P=0.039), and Barcelona Clinic Liver Cancer stage (P=0.041) in training cohort. The validation cohort showed the same results. The high RACO-1 expression was the independent prognostic factor for HBV-related HCC patients in both training cohort and validation cohort. Our data implicate RACO-1 as a novel prognostic marker and a potential therapeutic target for HBV-related HCC.

Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy.

RNA-binding motif 4 (RBM4) has been reported to play an important role in many human tumors such as lung cancer, breast cancer, ovarian cancer and gastric cancer by regulating alternative splicing and messenger RNA (mRNA) translation. However, little is known about the role of RBM4 in the development of hepatocellular carcinoma (HCC). This study aimed to investigate the expression of RBM4 in HCC tissues. Expression of RBM4 was detected by immunohistochemistry in 95 cases of HCC. Correlations of RBM4 expression with the overall survival and disease-free survival of HCC were also studied. Patients with high RBM4 expression had better overall survival rate and disease-free survival rate than those with low RBM4 expression (P<0.001, P=0.007, respectively). RBM4 expression, together with tumor numbers, capsular formation, vascular invasion and Barcelona clinic liver cancer (BCLC) stage, was an independent prognostic factor for overall survival rate and disease-free survival rate of HCC. Our data implicate RBM4 as a novel prognostic marker and a potential therapeutic target for HCC.

YMO1 suppresses invasion and metastasis by inhibiting RhoC signaling and predicts favorable prognosis in hepatocellular carcinoma.

Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity.

JARID2 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition through PTEN/AKT signaling.

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.

MicroRNA-130b promotes proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths owing to its high rate of postoperative recurrence and metastasis. New research is continuously identifying novel metastasis-associated oncogenes and tumor suppressor genes. miRNAs are noncoding RNAs that regulate protein synthesis post-translationally. miR-130b is one of several miRNAs involved in tumor metastasis. However, the role of miR-130b in HCC remains controversial. Here, we demonstrate that miR-130b is highly expressed in HCC and that it correlates with tumor number, vascular invasion, and TNM stage-important predictors of postoperative recurrence and metastases. Moreover, high levels of miR-130b predicted poor overall and disease-free survival of HCC patients, and in vitro and in vivo research revealed that knockdown or overexpression of miR-130b inhibited and promoted proliferation and metastasis of HCC cells, respectively. We identified PTEN as a direct functional target of miR-130b using miRNA databases and a dual luciferase report assay. Next, using a gain and loss assay and epithelial-mesenchymal transition (EMT) relative assays, we show that miR-130b may promote proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Collectively, our data suggests that miR-130b may have prognostic value in HCC. Additionally, the miR-130b/PTEN/p-AKT/HIF-1α axis identified in this study provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.

Surgical treatment for hepatocellular carcinoma with portal vein tumor thrombus: a novel classification.

BACKGROUND: The hepatic resection for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) which is not uncommon at clinic continues to be debated. Our study introduced a novel classification of HCC with PVTT and compared the outcomes of surgical treatment between different groups. METHODS: From January 2008 to December 2012, a total of 56 cases of HCC with PVTT underwent liver resection combined with thrombectomy. Clinical pathological features and surgical data of these patients were retrospectively studied. The patients were divided into two groups. Cumulative overall and disease-free survival curves of the patients were compared according to different groups. RESULTS: Sixteen patients (28.6%) belonging to group A were compared to 40 patients (71.4%) belonging to group B. The rates of capsular formation and tumor number showed differences between the two groups (P = 0.047, P = 0.032). Group A had more liver cirrhosis than group B (P = 0.047). The patients with large blood loss (≥1,000) were more in group A, as well. There was no significant difference in complications between the two groups except the ascites (P = 0.028). The 1-year overall survival rate of group A after liver resection was 31.5%. The 1-, 3-, and 5-year overall survival rates of group B were 62.3%, 16.1%, and 5.2%, respectively. For further study, group B had significantly better overall survival than group A (P = 0.033). Group A had significantly higher incidence of recurrence than group B (P = 0.021). CONCLUSIONS: Liver resection combined with thrombectomy for HCC with PVTT can get better outcome in the HCC patients with PVTT involving only one branch (left/right) of portal vein (group B) compared to patients with PVTT involving the main portal vein trunk or both the left and right portal veins (group A).

Reduced Histone H3 Acetylation in CD4(+) T Lymphocytes: Potential Mechanism of Latent Autoimmune Diabetes in Adults.

Aims. Latent autoimmune diabetes in adults (LADA) is the result of gene-environment interactions. Histone acetylation regulates gene expression and maybe interpret how environmental factors modify LADA. Hence, we studied the histone acetylation patterns in CD4(+) T lymphocytes from LADA patients. Methods. Blood CD4(+) T lymphocytes from 28 patients with LADA and 28 healthy controls were obtained to detect histone H3 acetylation and H4 acetylation. The gene expression of histone acetyltransferases (P300 and CREBBP) and histone deacetylases (HDAC1, HDAC2, and HDAC7) was measured by real-time polymerase chain reaction (RT-PCR). Results. Compared to healthy controls, reduced global H3 acetylation was observed in LADA patients' CD4(+) T lymphocytes (P < 0.05). Global level of H4 acetylation was not statistically different. Among LADA, CD4(+) T lymphocytes H3 acetylation was associated with glycosylated hemoglobin (HbA1c) and GADA titer. Compared to healthy controls, the expression of histone acetyltransferases CREBBP in LADA patients was downregulated, and the expression of histone deacetylases HDAC1 and HDAC7 was upregulated. Conclusion. A concerted downregulation of histone H3 acetylation was found in CD4(+) T lymphocytes of LADA patients, and this might provide evidence of a novel epigenetic explanation for the pathogenesis of LADA and its complications.

Liver resection for young patients with large hepatocellular carcinoma: a single center experience from China.

BACKGROUND: To investigate retrospectively the clinicopathological characteristics and outcomes of young patients with large hepatocellular carcinoma after hepatectomy. METHODS: From January 2003 to December 2012, a total of 153 patients with large hepatocellular carcinoma (HCC) who received liver resection were included in the study. The clinicopathological features were analyzed retrospectively. The perioperative data were compared between those aged <40 years (the young group) and those aged >40 years (the older group). Prognostic factors and long-term survival were evaluated. RESULTS: The young group had more hepatitis B virus-related HCC than the older group (87.2% vs 66.3%, P = 0.031). In the young group, 15 patients (21.5%) were overweight (body mass index 25 to 29.9 kg/m2) or obese (body mass index ≥30 kg/m2), and 38 patients (45.8%) were overweight or obese in the older group (P = 0.032). Other clinicopathological characteristics were similar between the two groups. The perioperative data showed that the older group had more pulmonary infection after hepatectomy. Vascular invasion and high Edmondson-Steiner grade were the independent prognostic factors for long-term survival. There was no statistical difference between the young group and the older group in overall survival and disease-free survival (P = 0.109 and P = 0.087, respectively). CONCLUSIONS: Liver resection for young patients with large HCC was safe and efficacious and should be recommended.

MicroRNA-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting PH domain and leucine-rich repeat protein phosphatase.

UNLABELLED: Hepatocellular carcinoma (HCC) is a highly invasive tumor with frequent intrahepatic or pulmonary metastasis, which is the main reason for high recurrence and poor survival of HCC after liver resection. However, the mechanisms for metastasis remain incompletely clear. Given that microRNAs (miRNAs) are implicated in HCC progression, we explored a potential role of miRNAs in metastasis by performing miRNA expression profiling in three subtypes of HCC with different metastatic potentials. We discovered miR-331-3p as one of most significantly overexpressed miRNAs and highly associated with metastasis of HCC. Increased expression of miR-331-3p was correlated with poor long-term survival of HCC. We provided both in vivo and in vitro evidence demonstrating that miR-331-3p promoted proliferation and metastasis of HCC cells. Using an integrated approach, we uncovered that PH domain and leucine-rich repeat protein phosphatase (PHLPP) was a novel target of miR-331-3p. Indeed, the miR-331-3p-mediated effects were antagonized by reexpression of PHLPP or mimicked by silencing of PHLPP. We further showed that miR-331-3p-mediated inhibition of PHLPP resulted in stimulation of protein kinase B (AKT) and subsequent epithelial mesenchymal transition (EMT). Finally, inhibition of miR-331-3p through a jetPEI-mediated delivery of anti-miR-331-3p vector resulted in marked inhibition of proliferation and metastasis of HCC in xenograft mice. CONCLUSION: miR-331-3p promotes proliferation and EMT-mediated metastasis of HCC through suppression of PHLPP-mediated dephosphorylation of AKT. Our work implicates miR-331-3p as a potential prognostic biomarker and a novel therapeutic target.