Glycolysis-related gene dihydrolipoamide acetyltransferase promotes poor prognosis in hepatocellular carcinoma through the Wnt/ß-catenin and PI3K/Akt signaling pathways.

Background: Recent research suggests that dihydrolipoamide acetyltransferase (DLAT), which is a copper-induced cell death-related gene, is involved in multiple biological events in tumors. This study sought to investigate the relationship between DLAT and hepatocellular carcinoma (HCC). Methods: In the Cancer Genome Atlas (TCGA) database, we first identified the differentially expressed gene (i.e., DLAT), then confirmed DLAT expression, and found a link between it and the prognosis of HCC patients. An internal validation nomogram was built based on a multivariate Cox regression analysis. Data from the Tumor Immune Estimation Resource (TIMER) database was used to examine the association between DLT and immunological cells. A gene set enrichment analysis (GSEA) was conducted to investigate the probable mechanism of action. Finally, in vitro cytological research was conducted to further examin the involvement of DLAT in HCC-related unfavorable biological events. Results: The database screenings showed that DLAT was a differentially expressed molecule; that is, DLAT was more highly expressed in the cancer tissues than normal tissues. TCGA results and Kaplan-Meier-plotter data sets showed that HCC patients with reduced DLAT expression had greater disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI). The prediction model had a concordance index of 0.659 (0.614-0.704), which indicates high accuracy. According to the TIMER database, tumor cells in the HCC microenvironment may be able to bypass the immune system due to the expression of DLAT. The in vitro cytological tests showed that DLAT knockdown significantly decreased the proliferation and invasion of the HCC cells. It also inhibited the activity of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) and Wnt/ß-catenin signaling pathways. Conclusions: Decreased DLAT expression significantly prolongs the OS, PFI, and DSS of HCC patients. DLAT may be employed as a new predictive biomarker for HCC, and may be linked to the immune system in HCC patients. The tumor microenvironment (TME) may have a significant effect on the ability of tumor cells to evade the immune system. The PI3K/Akt and Wnt/ß-catenin signaling pathways may affect the prognosis of HCC by interfering with DLAT. Given these findings, HCC may be an ideal target for the development of anti-cancer therapies.

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis.

Hepatocellular carcinoma (HCC) is a common malignant tumor in the clinic. Although there are increasing numbers of available treatment methods, their therapeutic effects are not satisfactory. The clinical indicators commonly used to predict the prognosis of HCC include tumor size, degree of cirrhosis, degree of tumor differentiation and tumor microvascular invasion; however, there are currently no molecular indicators that can predict the prognosis of HCC. Due to the differences in the progression of liver cancer among individuals, there is a growing need for prognostic biomarkers to accurately stratify patients for appropriate risk-adaptive treatment. The DNA topoisomerase 2-α (TOP2A) gene, which is located on human chromosome 17, encodes DNA topoisomerase IIα. Previous studies have demonstrated that TOP2A indicates a poor prognosis in patients with various types of tumors, but no such studies are currently available on HCC. By analyzing the differential expression of TOP2A in 50 pairs of tumor and paracancerous tissue samples in The Cancer Genome Atlas (TCGA) database, the present study revealed that the expression of TOP2A was significantly higher in tumor tissue compared with that in paracancerous tissue (P=6.319×10-16). In the collected clinical samples, the mRNA expression levels of TOP2A were significantly upregulated in HCC tumor tissues compared with those in the paracancerous tissues (P=6.40×10-3), suggesting that TOP2A was associated with the occurrence and development of liver cancer. In addition, the associations between TOP2A expression, clinicopathological features and prognosis were analyzed using a multi-center large sample dataset from TCGA database, and the results demonstrated that high expression of TOP2A was associated with a higher T stage, poorer clinical stage and higher histological grade compared with those in patients with low TOP2A expression. High expression of TOP2A was also identified to be associated with a poor prognosis of HCC, particularly in Asian populations. These results suggested that high expression of TOP2A in HCC tissues may be closely associated with tumor progression and metastasis, which may be used as a biological indicator to predict tumor prognosis in clinical practice.

Liposomal clodronate combined with Cisplatin or Sorafenib inhibits hepatocellular carcinoma cell proliferation, migration and invasion by suppressing FOXQ1 expression.

The purpose of this study was to investigate the effect of liposomal clodronate combined with Cisplatin or Sorafenib on the FOXQ1 expression and biological function of hepatocellular carcinoma cell lines.  The expression of FOXQ1 was determined in normal hepatic cell line and hepatocellular carcinoma cell lines using quantitative real-time polymerase chain reaction (qRT-PCR). HepG2 and MHCC97H cells were administered low, medium and high concentrations of cisplatin (3, 5 and 7 µg/ml) or Sorafenib (2, 7 and 20 µg/ml) in combination with liposomal clodronate (LC, 20µg/ml), and the expression of FOXQ1 in each group was determined. Cell migration, MTT and transwell assays were used to determine the effects of the treatments on biological functions of HepG2 and MHCC97H cells. qRT-PCR showed that the expression of FOXQ1 mRNA was higher in the four hepatocellular carcinoma cell lines than in normal cells, and the expression of FOXQ1 mRNA in HepG2 and MHCC97H cells were more dominant. All the tested doses of Cisplatin, but only high dose Sorafenib down-regulated the expression of FOXQ1. However, Sorafenib at low and medium concentrations had no significant effect on the expression of FOXQ1. When Cisplatin or Sorafenib was administered in combination with LC, the expression level of FOXQ1 was significantly reduced. Cell migration, MTT and transwell assays showed that proliferation, migration and invasion were inhibited when each drug was administered alone, but was stronger when the drugs were combined with liposomal clodronate.Liposomal clodronate combined with Cisplatin or Sorafenib down-regulates the expression of FOXQ1 in HepG2 and MHCC97H hepatoma cells, and inhibits their proliferation, migration and invasion.

High expression of TOP2A gene predicted poor prognosis of hepatocellular carcinoma after radical hepatectomy.

BACKGROUND: Topoisomerase (DNA) II alpha (TOP2A) is the up-regulated gene of the chromosome aggregation pathway. This gene encodes DNA topoisomerase, which can control and change the topological state of DNA during transcription and replication, participate in chromosome agglutination, separation, and relieve stress from kinking. Abnormally high expression of TOP2A is often associated with active cell proliferation. In studies of breast cancer, endometrial cancer, and adrenal cancer, it was found that high expression of TOP2A suggested a poor prognosis. METHODS: A total of 15 pairs of fresh hepatocellular carcinoma (HCC) specimens and adjacent tissues were assembled, and the difference of TOP2A mRNA and protein expression level between tumor and adjacent tissues was detected by RT-PCR and Western blotting analysis, respectively. A total of 84 HCC paraffin specimens were selected for routine pathological grading. TOP2A expression was detected by immunohistochemistry (IHC). The correlation between TOP2A expression and clinicopathological features and survival time was analyzed. RESULTS: The expression of TOP2A mRNA and protein in HCC tumor tissues was significantly higher than that in the adjacent tissues. IHC results indicated that the TOP2A positive rate in tumor tissues was significantly higher than that in adjacent tissues (84.52%, 71/84 vs. 8.33%, 7/84). High TOP2A expression was associated with poor tumor differentiation, significant cirrhosis, and larger tumor diameter. Among the patients whose survival time exceeded 60 m, 14 patients (37.84%, 14/37) had a high expression of TOP2A. Among the patients whose survival time was less than 60 m, the TOP2A expression was high in 37 cases (78.72%, 37/47). Kaplan-Meier survival analysis showed that the survival time of the group with low or no TOP2A expression was better than that of the group with high TOP2A expression (P=0.0011). Regression analysis of the clinical characteristics and 5-year survival follow-up data of 84 patients showed that cirrhosis and TOP2A high expression were the independent factors influencing the prognosis of HCC, while gender, age, tumor grade, hepatitis B virus (HBV) infection, and tumor size did not affect 5-year survival. CONCLUSIONS: The high expression of TOP2A is associated with the invasiveness and poor prognosis of HCC tumors, and, together with liver cirrhosis, can be a prognostic indicator of radical HCC resection.

Expression of leucine aminopeptidase 3 (LAP3) correlates with prognosis and malignant development of human hepatocellular carcinoma (HCC).

Leucine aminopeptidases (LAPs) were associated with tumor cell proliferation, invasion and/or angiogenesis. LAP3 is one important member of this family. However, its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. In the present study, we demonstrated that LAP3 expression was significantly up-regulated in HCC tissues as well as cells and was closely correlated with lower differentiation, positive lymph node metastasis and high Ki-67 expression, indicating a poor prognosis. Then cell viability assays, flow cytometry assays, wound-healing assays and matrigel invasion assays were performed to demonstrate that LAP3 promoted HCC cells proliferation by regulating G1/S checkpoint in cell cycle and advanced HCC cells migration. Furthermore, we discovered that knockdown LAP3 will enhance the sensitivity of HCC cells to cisplatin, thus promoting the cell death of HCC cells. Collectively, our results indicated that up-regulated expression of LAP3 might contribute to the proliferation and metastasis of HCC. Our data gains greater insight into the cancer-promoting role of LAP3 and its functions in HCC cells, possibly providing potential therapeutic strategies for clinical trials.

Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular carcinoma: a meta-analysis.

BACKGROUND AND OBJECTIVE: The impact of perioperative allogenenic blood transfusion (ABT) on clinical outcomes for hepatocellular carcinoma (HCC) is conflicting and unclear. The aim of this meta-analysis is to evaluate the association between ABT and HCC clinical outcomes. Outcomes evaluated were all-cause death, tumor recurrence and postoperative complications. METHODS: Relevant articles were identified through MEDLINE search (up to November 2012). Meta-analyses were performed by using the fixed or random effect models. Study heterogeneity was assessed by Q-test and I(2) test. Publication bias was evaluated by funnel plots, Egger's and Begg's test. RESULTS: A total of 5635 cases from 22 studies finally met our inclusion criteria. Meta-analysis indicated HCC patients with ABT had an increased risk of all-cause death at 3 and 5 years after surgery (respectively: OR = 1.92, 95% CI, 1.61-2.29,P<0.001; OR = 1.60, 95% CI, 1.47-1.73,P<0.001 ) compared with those without ABT. The risk of tumor recurrence was significantly higher for ABT cases at 1, 3 and 5 years (respectively: OR = 1.70, 95% CI, 1.38-2.10, P<0.001; OR = 1.22, 95% CI, 1.08-1.38, P<0.001; OR = 1.16, 95% CI, 1.08-1.24, P<0.001). The HCC cases with ABT significantly increased postoperative complications occurrence compared with non-ABT cases (OR = 1.78,95% CI, 1.34-2.37, P<0.001). CONCLUSIONS: The findings from the current meta-analysis demonstrated that ABT was associated with adverse clinical outcomes for HCC patients undergoing surgery, including increased death, recurrence and complications. Therefore, ABT should not be performed if possible.

[Combined three-dimensional conformal radiotherapy plus transcatheter arterial chemoembolization and surgical intervention for portal vein tumor thrombus in patients with hepatocellular carcinoma].

OBJECTIVE: To explore the clinical therapeutic efficacies of combined three-dimensional conformal radiotherapy (3DCRT) plus transcatheter arterial chemoembolization (TACE) for portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC). METHODS: A total of 145 HCC patients with tumor thrombus in portal vein were divided randomly into 2 groups. Group A (n = 64) was treated with surgical intervention alone while group B (n = 81) underwent 3DCRT plus TACE. The gross tumor volume (GTV) was defined as PVTT only. RESULTS: Survival rates of group A at year 1 and 2 were 40.3% and 21.9% with a mean survival time (MST) of 15.2 months while that of group B were 41.2% and 22.5% with a MST of 15.8 months. The total effective rates of groups A and B was 40.6% (28/64) and 44.4% (36/81) respectively. CONCLUSION: The therapeutic efficacy of 3DCRT plus TACE is similar to that of surgical intervention.