Prognostic Predictor For Hepatocellular Carcinoma Research Articles

Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma.

Malic enzyme 1 (ME1) links the glycolytic and citric acid cycles and is important for NADPH production, glutamine metabolism, and lipogenesis. Recently, its deregulation has been implicated in the progression of various cancers. However, the role of ME1 in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we utilized short hairpin RNA-mediated gene silencing to investigate the biological effects of ME1 depletion in HCC and determined its prognostic significance in HCC. ME1 expression was examined by real-time (RT)-PCR and Western blot using five HCC cell lines and one normal liver cell line. We used polyethylenimine nanoparticles to deliver a short hairpin RNA to induce cessation of ME1 expression in HCC cells. Changes in NADPH production and reactive oxygen species (ROS) production were studied. Metastatic potentials of HCC cells were evaluated in vitro. Furthermore, we evaluated the protein level of ME1 in para-tumor and cancerous tissues of 65 HCC patients with detailed clinical, pathological, and clinical follow-up data. Patients' survivals were further assessed as well. Upregulated ME1 expression was observed in HCC cell lines. Downregulation of ME1 attenuated NADPH production and stimulated ROS production. Silencing ME1 was noted to inhibit migratory and invasive properties of HCC cells by inducing the E-cadherin expression and decreasing of N-cadherin and vimentin expression in a ROS-dependent pathway. Overexpression of ME1 was observed in a major fraction of HCC samples. Higher level of ME1 in tumors was significantly associated with reduced overall survival (Kaplan-Meier analysis, P = 0.024) and reduced progression-free survival (Kaplan-Meier analysis, P = 0.011). Inhibition of ME1 expression decreases HCC metastasis via suppression of epithelial-mesenchymal transition (EMT) processes in ROS-induced pathways. ME1 overexpression associates with unfavorable prognoses in patients with HCC, suggesting that ME1 is a poor prognostic predictor of hepatocellular carcinoma.

DEP domain containing 1 is a novel diagnostic marker and prognostic predictor for hepatocellular carcinoma.

This study was conducted to determine DEPDC1 expression in hepatocelluar carcinomas (HCCs) and to reveal its potential role in diagnosis and prognosis of affected patients. DEPDC1 expression at the mRNA level was detected by quantitative real-time PCR (qRT-PCR) in 205 cases of HCC and paired adjacent normal liver tissues, and by semi-quantitative RT-PCR in 20 cases. Survival curves were obtained by using Kaplan-Meier method and Log-rank test. Independent predictors associated with regard to disease free survival (DFS) and overall survival (OS) were identified using the Cox proportional hazard model. High DEPDC1 mRNA levels were detected in 144 out of 205 cases (70.24%) of HCC, significantly associated with clinicopathological parameters, including tumor size (≥4cm), alpha-fetoprotein (≥100ng/ml), B-C of BCLC stage and recurrence. Kaplan-Meier survival analysis revealed that HCC patients with high DEPDC1 expression had poor OS and DFS. Multivariate analysis demonstrated that high DEPDC1 expression was an independent predictor of OS (HR=1.651; 95% 95%CI, 1.041- 2.617; p=0.033) and DFS (HR=1.583; 95%CI, 1.01- 2.483; p=0.045). Our results indicate DEPDC1 might be a novel diagnostic marker and an independent prognostic predictor for HCC patients.

Tissue biomarkers of prognostic significance in hepatocellular carcinoma.

Despite major advancements in the clinical management of hepatocellular carcinoma (HCC), the natural history of this disease is characterized by an invariably poor prognosis. However, there are significant interindividual variations in the biologic behavior of this tumor and this combined with the confounding effect of liver function on patient survival makes prognostic prediction particularly difficult. Several studies have attempted to investigate the prognostic role of tissue biomarkers to better understand the molecular basis of HCC progression. These studies have looked at several aspects of cancer biology including proliferative potential, invasive capacity, and angiogenic promotion utilizing different methodologies. The aim of this review is to summarize the role of tissue biomarkers in the prognostic prediction of HCC and to outline questions and strategies in the prognostic assessment of HCC.

Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence.

Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan-Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.

Alpha-1-fucosidase as a prognostic indicator for hepatocellular carcinoma following hepatectomy: a large-scale, long-term study

Background:Preoperative alpha-L-fucosidase (AFU) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its role as a prognostic predictor after partial hepatectomy has not been well defined. The study aimed to investigate the prognostic significance of preoperative serum AFU for HCC patients after hepatic resection.Methods:A retrospective training data set and a prospective validation data set were used to evaluate the prognosis of HCC after partial hepatectomy. A total of 669 patients with histopathologically confirmed HCC were enrolled. Univariate and multivariate analyses were used to identify the prognostic significance of preoperative serum AFU.Results:The retrospective training data set showed a preoperative AFU>35 u l−1 should be used. The prospective validation data set showed preoperative AFU was an independent prognostic factor of overall survival (OS) (P=0.008; hazard ratio: 2.333; 95% confidence interval: 1.249–4.369). Patients with a preoperative AFU>35 u l−1 had a lower recurrence-free survival rate and an OS rate than those with AFU⩽35 u l−1, and they have a higher tendency to form macrovascular invasion. Furthermore, the prognostic significance of AFU>35 u l−1 could also be applied to patients with alpha-fetoprotein levels of ⩽400 ng ml−1.Conclusions:Preoperative serum AFU is a prognostic predictor of HCC.

Evaluation of Individual and Combined Applications of Serum Biomarkers for Diagnosis of Hepatocellular Carcinoma: A Meta-Analysis

The clinical value of Serum alpha-fetoprotein (AFP) to detect early hepatocellular carcinoma (HCC) has been questioned due to its low sensitivity and specificity found in recent years. Other than AFP, several new serum biomarkers including the circulating AFP isoform AFP-L3, des-gamma-carboxy prothrombin (DCP) and Golgi protein-73 (GP73) have been identified as useful HCC markers. In this investigation, we review the current knowledge about these HCC-related biomarkers, and sum up the results of our meta-analysis on studies that have addressed the utility of these biomarkers in early detection and prognostic prediction of HCC. A systematic search in PubMed, Web of Science, and the Cochrane Library was performed for articles published in English from 1999 to 2012, focusing on serum biomarkers for HCC detection. Data on sensitivity and specificity of tests were extracted from 40 articles that met the inclusion criteria, and the summary receiver operating characteristic curve (sROC) was obtained. A meta-analysis was carried out in which the area under the curve (AUC) for each biomarker or biomarker combinations (AFP, DCP, GP73, AFP-L3, AFP + DCP, AFP + AFP-L3, and AFP + GP73) was used to compare the diagnostic accuracy of different biomarker tests. The AUC of AFP, DCP, GP73, AFP-L3, AFP + DCP, AFP + AFP-L3, and AFP + GP73 are 0.835, 0.797, 0.914, 0.710, 0.874, 0.748, and 0.932 respectively. A combination of AFP + GP73 is superior to AFP in detecting HCC and differentiating HCC patients from non-HCC patients, and may prove to be a useful marker in the diagnosis and screening of HCC. In addition, the AUC of GP73, AFP + DCP and AFP + GP73 are better than that of AFP. The clinical value of GP73, AFP + DCP, or AFP + GP73 as serological markers for HCC diagnosis needs to be addressed further in future studies.

Prognostic value of preoperative peripheral neutrophil-to-lymphocyte ratio in patients with HBV-associated hepatocellular carcinoma after radical hepatectomy

Neutrophil-to-lymphocyte ratio (NLR), an inflammation index, is considered a prognostic predictor of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic value of preoperative peripheral NLR in patients with hepatitis B virus (HBV)-associated HCC after radical hepatectomy. Clinical data were collected from patients with HBV-associated HCC who underwent radical hepatectomy. NLR was calculated from lymphocyte and neutrophil counts on preoperative routine blood tests. Demographics, laboratory analyses, and histopathological data were analyzed. A total of 282 patients were selected and divided by the cutoff NLR value of 2. Multivariate analysis showed that NLR > 2 was an independent prognostic predictor of poor disease-free survival [hazard ratio (HR) = 1.362; 95% confidence interval (CI) 1.025-1.811; P = 0.033] and overall survival (HR = 1.434; 95% CI 1.044-1.970; P = 0.023). NLR had a good predictive value for prognosis in patients with HBV-associated HCC who had normal serum AFP level. These results suggested that NLR is an independent indicator of both disease-free survival and overall survival in patients with HBV-associated HCC after radical hepatectomy, including AFP-normal patients.

The expression of chitinase 3-like 1: a novel prognostic predictor for hepatocellular carcinoma

Chitinase 3-like 1 (CHI3L1) is associated with poor prognosis of various human cancers. However, the clinical and prognostic significance of CHI3L1 in hepatocellular carcinoma (HCC) is largely unknown. The aim of the present study is to investigate the expression of CHI3L1 in human HCC cell lines, clinical HCC specimens and its association with expressions of phosphorylated-Akt (p-Akt), E-cadherin and prognostic significance. The protein level of CHI3L1 in HCC cell lines was evaluated by western blot. The mRNA and protein levels of CHI3L1 in 19 self-paired HCC specimens were assessed by RT-PCR and western blot assays. The clinical and prognostic significance of CHI3L1 in 70 cases of HCC patients was determined by immunohistochemistry. In addition, expressions of p-Akt and E-cadherin were also assessed. The protein level of CHI3L1 paralleled with increased malignant potential of HCC cell lines (P < 0.05). The mRNA and protein levels of CHI3L1 in HCC tissues were up-regulated compared with those in adjacent peritumoral tissues and further increased in tumors with metastasis (P < 0.05). Clinicopathological analysis showed that positive CHI3L1 expression was significantly associated with larger tumor size, capsular invasion, advanced TNM stages and status of metastasis (P = 0.035, 0.003, 0.023 and 0.003, respectively). Furthermore, CHI3L1 expression was positively correlated with high level of p-Akt (r = 0.293, P = 0.014), but inversely correlated with expression of E-cadherin (r = -0.267, P = 0.026). Additionally, Kaplan-Meier survival analysis showed that HCC patients with positive CHI3L1 expression had a worse overall survival and disease-free survival compared with those with negative CHI3L1 expression (P < 0.001, respectively). Multivariate analysis identified CHI3L1 as an independent prognostic predictor for overall survival and disease-free survival of HCC patients (P = 0.044 and 0.031, respectively). CHI3L1 plays an essential role in HCC malignancies and may be served as a valuable prognostic biomarker for HCC patients.

Metadherin is a prognostic predictor of hepatocellular carcinoma after curative hepatectomy.

Background/AimsThe prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rate of recurrence. Thus, it is crucial to identify patients with a high risk of recurrence after curative hepatectomy and to develop more effective and targeted treatment strategies to improve disease outcomes. In this study, we investigated the roles of metadherin (MTDH) in the prognosis of HCC.MethodsWe investigated MTDH expression using immunohistochemistry in tumor tissue microarrays of 288 primary HCC patients who underwent curative surgical resection.ResultsHigh MTDH expression was observed in 138 of the 288 HCC cases (47.9%). High MTDH expression was associated with a younger age (p<0.001), higher Edmondson grade (p<0.001), microvascular invasion (p<0.001), higher American Joint Committee on Cancer T stage (p=0.001), and higher α-fetoprotein level (p=0.003). Multivariate analyses revealed that high MTDH expression (p=0.014), higher Barcelona-Clinic Liver Cancer (BCLC) stage (p<0.001), and Edmondson grade III (p=0.042) were independent predictors of shorter disease-free survival (DFS). Higher BCLC stage (p<0.001) and Edmondson grade III (p=0.047) were also independent predictors of shorter disease-specific survival.ConclusionsHigh MTDH expression may be a prognostic predictor of shorter DFS in HCC patients after curative hepatectomy.

Circulating cancer stem cells: a novel prognostic predictor of hepatocellular carcinoma.

Not only tumor progression but also metastasis are the major causes of mortality from a wide range of cancers, including hepatocellular carcinoma (HCC). In general, tumor cells frequently leave the primary tumor and form metastatic lesions in distant organs. It has been believed that tumor infiltration of blood vessels at the primary tumor site is responsible for the dissemination of tumor cells and the formation of metastatic lesions in distant organs.

Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization

Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3β and lead to β-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.

LOH analysis of genes around D4S2964 identifies ARD1B as a prognostic predictor of hepatocellular carcinoma

To investigate genes around the locus D4S2964 affected by loss of heterozygosity (LOH) and their clinical implications. Four hundred and forty single nucleotide polymorphisms (SNPs) located at 49 genes around D4S2964 were selected from the National Center for Biotechnology Information website for the SNPs microarray fabrication. LOH of SNPs markers in 112 cases of hepatocellular carcinoma (HCC) tissues and paired adjacent liver tissues were investigated by the SNPs microarray. The correlation between allelic losses with clinicopathological features and overall survival was analyzed. A fine map of LOH of SNPs in genes around D4S2964 was plotted. The average frequency of LOH in genes was 0.39. A correlation between cirrhosis and the FAL index (fractional allelic loss) was found (P = 0.0202). Larger tumor size was found to be significantly associated with LOH in genes ADP-ribosyltransferase 3 (ART3), nucleoporin 54 kDa (NUP54), scavenger receptor class B, member 2 (SCARB2) and coiled-coil domain containing 158 (CCDC158) (P = 0.043, P = 0.019, P = 0.001, P = 0.037, respectively). Kaplan-Meier analysis showed that patients with LOH in ARD1 homolog B (ARD1B) and septin 11 (SEPT11) had a significantly lower survival rate than those with retention (P = 0.021 and P = 0.004, respectively). A Cox regression model suggested that LOH in ARD1B and SEPT11, respectively, were predictors of the overall survival in HCC (P = 0.006 and P = 0.026, respectively). LOH in genes around D4S2964 may play an important role in HCC development and progression. LOH in ARD1B and SEPT11 could serve as novel prognostic predictors in HCC patients.

The MELD-Na is an independent short- and long-term prognostic predictor for hepatocellular carcinoma: A prospective survey

Serum sodium has been suggested to incorporate into the model for end-stage liver disease to enhance its prognostic ability for cirrhosis. A mathematical equation based on model for end-stage liver disease and sodium, known as "MELD-Na", was developed for outcome prediction for cirrhosis. The severity of liver cirrhosis is a key component to predict survival in patients with hepatocellular carcinoma. This study investigated the prognostic role of MELD-Na for hepatocellular carcinoma. A total of 535 unselected hepatocellular carcinoma patients were prospectively enrolled to evaluate the performance of MELD-Na. The MELD-Na was better than model for end-stage liver disease in predicting 6-month mortality by comparing the area under receiver operating characteristic curve (0.782 vs. 0.761, p=0.101). MELD-Na, but not model for end-stage liver disease, was an independent predictor associated with 6-month mortality in multivariate logistic regression analysis (odds ratio: 1.14, p=0.001). In the survival analysis, MELD-Na also independently predicted mortality, with an additional risk of 4.3% per unit increment of the score (p<0.001). Patients with MELD-Na scores between 10 and 20 and scores >20 had 2.1-fold (p<0.001) and 7.5-fold (p<0.001) risk of mortality, respectively, compared to patients with a score <10 in the Cox proportional hazard model. The MELD-Na score is a feasible and independent prognostic predictor for both short- and long-term outcome predictions in patients with hepatocellular carcinoma.

P53 as a prognostic predictor in hepatocellular carcinoma (HCC)

P53 as a prognostic predictor in hepatocellular carcinoma (HCC)