Survival Outcomes In Hepatocellular Carcinoma Patients Research Articles

Down-regulation of TIMP2 by HIF-1α/miR-210/HIF-3α regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma.

Cancer metastasis is a multistep process that involves a series of tumor‐stromal interaction, including extracellular matrix (ECM) remodeling, which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases (TIMP) 2 in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly down‐regulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.8%; 23 of 55) in human HCCs and was significantly associated with liver invasion and poorer survival outcomes of HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced cell invasive ability and ECM degradation associated with formation of invadopodia‐like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Using an orthotopic tumor xenograft model, we demonstrated that ectopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line, MHCC‐97L, significantly reduced HCC progression as well as pulmonary metastasis. Mechanistically, TIMP2 suppression, in a hypoxic environment, was induced through a regulatory feedback circuit consisting of hypoxia‐inducible factor (HIF) 1 alpha, microRNA‐210 (miR‐210), and HIF‐3α. Conclusion: TIMP2 is frequently down‐regulated in human HCCs and its down‐regulation is associated with aggressive tumor behavior and poorer patient outcome. Its suppression is under the regulation of a novel feedback circuit consisting of HIF‐1α/miR‐210/HIF‐3α. TIMP2 is an important regulator of ECM degradation and HCC metastasis. (Hepatology 2016;64:473‐487)

Nomogram prediction of survival in patients with brain metastases from hepatocellular carcinoma treated with whole-brain radiotherapy: a multicenter retrospective study.

The incidence of brain metastasis from hepatocellular carcinoma (HCC) is increasing because of the improved survival outcome of HCC patients, but the prognosis of these patients is extremely poor. HCC patients with brain metastasis were investigated to identify their prognostic factors for overall survival. Patients with brain metastasis from HCC who had been treated with whole-brain radiotherapy (WBRT) in five hospitals were enrolled in the study. The medical records of the patients were reviewed, and the clinical factors were analyzed to identify the prognostic factors for overall survival. Of the total of 97 patients who were enrolled in the study, 83 were male and the median age at the brain metastases was 56.6 years. Motor weakness (43.3 %) and headache (41.2 %) were common presenting symptoms. The median AFP level was 4180 ng/ml, and 81 patients were assessed as belonging to Child-Pugh classification A upon the diagnosis of brain metastasis. WBRT alone in 71 patients, surgery or radiosurgery combined with WBRT as the adjuvant setting in 18 patients, and WBRT as salvage treatment in 8 patients were performed. The median overall survival of the patients was 3.5 months. In the multivariate analysis, the ECOG performance status (PS), Child-Pugh classification, AFP, and treatment aim showed significant association with the overall survival of the patients. Based on these factors, a nomogram predicting the prognosis was developed. The concordance index of the nomogram was 0.74, and the prediction was well calibrated. In conclusion, the survival outcome of patients with brain metastasis from HCC can be predicted with the nomogram constructed from the ECOG PS, Child-Pugh classification, AFP, and treatment aim.

Low Expression of LDHB Correlates With Unfavorable Survival in Hepatocellular Carcinoma: Strobe-Compliant Article.

Lactate dehydrogenase B (LDHB) is widely expressed in adult somatic tissue and plays important roles in the development of human cancers. However, the association between LDHB expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is not well understood. The study was to detect the expression of LDHB in human HCC and investigate the association between its expression and the clinicopathological characteristics of HCC.Immunohistochemistry (IHC) analysis was performed to characterize the expression of LDHB in HCC and matched noncancerous tissues. Kaplan–Meier survival and Cox regression analyses were employed to evaluate the prognosis of 75 HCC patients.The results showed that the expression of LDHB in HCC was significantly lower than that in noncancerous tissues. Moreover, the expression level of the LDHB protein in HCC was correlated with pathological grade (P = 0.037), vascular invasion (P = 0.037), lymph node metastasis (P = 0.016), and tumor-node metastasis (TNM) stage (P = 0.007). Cox regression analysis further revealed that LDHB expression is an independent prognostic factor for disease-free survival (P = 0.045) and overall survival (P = 0.019).These data are the first to indicate that LDHB expression is a valuable prognostic biomarker for HCC and that low LDHB expression suggests unfavorable survival outcomes in HCC patients.

Abstract 533: S100A10 as a novel biomarker in hepatocellular carcinoma

Abstract Background and Objective: Hepatocellular carcinoma (HCC) is the dominant form of primary liver tumor and the second most lethal malignancy in worldwide. From transcriptome sequencing analysis, we observed that S100A10 was overexpressed in our cohort of 16 HCC patients. S100A10 is a calcium binding protein and accumulating studies have indicated that annexin A2- S100A10 heterotetramer on the cell surface is important for the conversion of plasminogen to plasmin, which promotes activation of matrix metalloproteinases and degradation of extracellular matrix. This enhances cancer invasion and migration. While annexin A2 overexpression has been documented in various malignancies and shows significant association with local invasion and metastasis, information regarding the expression of S100A10 in human cancers is scarce. Furthermore, how S100A10 was regulated remains unexplored. Hypoxia is a common phenomenon in HCC microenvironment and stabilizies transcription factors, hypoxia inducible factor (HIF)-1α and -2α, to initiate transcription of a wide repertoire of genes for cancer progression. The major aim of this study is to evaluate the possible clinical relevance and diagnostic value of S100A10 in HCC and study the molecular mechanism that drives S100A10 overexpression under the influence of hypoxia in HCC. Experimental Procedures: We evaluated S100A10 expression in human HCC and the corresponding non-tumorous liver (NT) tissues in a cohort of 67 HCC patients by RT-PCR. S100A10 expression was correlated with various HCC clinico-pathological features by Student's t-test and survival outcome of HCC patients by Kaplan-Meier plot followed by log rank test. Promoter of S100A10 was analyzed for potential hypoxia responsive elements -A/GCGTG- and confirmed by ChIP assay with HIF antibodies. To evaluate the impact of HIF on S100A10 expression, we knocked-down (shRNA) and knocked-out (TALEN) HIF-1/2α in a HCC cell line, MHCC97L and evaluated S100A10 mRNA and protein expression. Results: S100A10 was significantly upregulated (P = 0.001, Wilcoxon signed rank test) in HCC as compared to NT tissues. Overexpression of S100A10 (≥ 2 fold) was found in 50.746% (34/67) of HCC patients and was closely correlated with direct liver invasion (P = 0.038), tumor microsatellite formation (P = 0.050) and absence of tumor encapsulation (P = 0.048). More importantly, S100A10 overexpression was associated with poorer 5-year survival rate in HCC patients (P = 0.062). ROC analysis suggested that S100A10 could be a potential diagnostic marker for HCC detection (Area Under Curve = 0.685, P = 0.001). Hypoxia induced S100A10 mRNA and protein expression levels in multiple HCC cell lines and this was abolished in HIF-1/2α knockdown or knockout HCC cells. Conclusion: Our current data have presented evidence that S100A10 can be a potential diagnostic and prognostic marker in HCC and S100A10 is a transcriptional target of HIF. Citation Format: David Kung-Chun Chiu, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Aki Pui-Wah Tse. S100A10 as a novel biomarker in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 533. doi:10.1158/1538-7445.AM2015-533

Hepatoma-derived growth factor/nucleolin axis as a novel oncogenic pathway in liver carcinogenesis.

Hepatoma-derived growth factor (HDGF) overexpression is involved in liver fibrosis and carcinogenesis. However, the receptor(s) and signaling for HDGF remain unclear. By using affinity chromatography and proteomic techniques, nucleolin (NCL) was identified and validated as a HDGF-interacting membrane protein in hepatoma cells. Exogenous HDGF elicited the membrane NCL accumulation within 0.5 hour by protein stabilization and transcriptional NCL upregulation within 24 hours. Blockade of surface NCL by antibodies neutralization potently suppressed HDGF uptake and HDGF-stimulated phosphatidylinositol 3-kinase (PI3K)/Akt signaling in hepatoma cells. By using rescectd hepatocellular carcinoma (HCC) tissues, immunohistochemical analysis revealed NCL overexpression was correlated with tumour grades, vascular invasion, serum alpha-fetoprotein levels and the poor survival in HCC patients. Multivariate analysis showed NCL was an independent prognostic factor for survival outcome of HCC patients after surgery. To delineate the role of NCL in liver carcinogenesis, ectopic NCL overexpression promoted the oncogenic behaviours and induced PI3K/Akt activation in hepatoma cells. Conversely, NCL knockdown by RNA interference attenuated the oncogenic behaviours and PI3K/Akt signaling, which could be partially rescued by exogenous HDGF supply. In summary, this study provides the first evidence that surface NCL transmits the oncogenic signaling of HDGF and facilitates a novel diagnostic and therapeutic target for HCC.

Comparison of survival outcomes after anatomical resection and non-anatomical resection in patients with hepatocellular carcinoma.

Backgrounds/AimsLiver resection is a curative procedure performed worldwide for hepatocellular carcinoma (HCC). Deciding on the appropriate resection range for postoperative hepatic function preservation is an important surgical consideration. This study compares survival outcomes of HCC patients who underwent anatomical or non-anatomical resection, to determine which offers the best clinical survival benefit.MethodsOne hundred and thirty-one patients underwent liver resection with HCC, between January 2007 and February 2015, and were divided into two groups: those who underwent anatomical liver resection (n=88) and those who underwent non-anatomical liver resection (n=43). Kaplan-Meier survival analysis and Cox regressions were used to compare the disease-free survival (DFS) and overall survival (OS) rates between the groups.ResultsThe mean follow-up periods were 27 and 40 months in the anatomical and non-anatomical groups, respectively (p=0.229). The 3- and 5-year DFS rates were 70% and 60% in the anatomical group and 62% and 48% in the non-anatomical group, respectively. The 3 and 5-year OS rates were 94% and 78% in the anatomical group, and 86% and 80% in the non-anatomical group, respectively. The anatomical group tended to show better outcomes, but the findings were not significant. However, a relative risk of OS between the anatomical and non-anatomical group was 0.234 (95% CI, 0.061-0.896; p=0.034), which is statistically significant.ConclusionsAlthough statistical significance was not detected in survival curves, anatomical resection showed better results. In this respect, anatomical resection is more likely to perform in HCC patients with preserve liver function than non-anatomical resection.

High expression of MAGE-A9 correlates with unfavorable survival in hepatocellular carcinoma.

Melanoma-associated antigens (MAGE)-A9 has been reported to play important roles in the development of human cancers. However, the association between MAGE-A9 expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is not well understood. The study was to detect the expression of MAGE-A9 in human HCC and investigate the association between its expression and the clinicopathological characteristics of HCC. Reverse transcription-polymerase chain reaction (RT-PCR), one-step quantitative -PCR (qPCR) and immunohistochemistry (IHC) analyses were performed to characterize the expression of MAGE-A9 in HCC cell lines and tissues. Kaplan-Meier survival and Cox regression analyses were employed to evaluate the prognosis of 100 HCC patients. The results showed that the expression of MAGE-A9 in HCC was significantly higher than that in non-cancerous cells and tissues. Moreover, the expression level of the MAGE-A9 protein in HCC was related to the pathological grade (p = 0.003), portal vein invasion (p = 0.001), distant metastasis (p = 0.022) and TNM stage (p = 0.005). Cox regression analysis further revealed that MAGE-A9 expression is an independent prognostic factor for disease-free survival (p = 0.006) and overall survival (p = 0.022). These data are the first to indicate that MAGE-A9 expression is a valuable prognostic biomarker for HCC and that high MAGE-A9 expression suggests unfavorable survival outcomes in HCC patients.

Hepatitis B viral load affects prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a complex disease that is dually challenging to treat due to underlying chronic liver disease in addition to the cancer itself. The prognosis of patients with HCC is determined by intrahepatic tumor status and reserved hepatic function. Hepatitis B virus (HBV) is an established major risk factor of HCC development, and HBV viral load is being increasingly recognized as a prognostic factor in the presence of established HCC. High HBV viral load may affect the prognosis of HBV-related HCC patients in several ways. First, it is associated with more frequent recurrence of HBV-related HCC after treatment. Second, it is associated with more occurrence and severity of potentially life-threatening HBV reactivation. Last, it is associated with more worsened liver function, which limits the therapeutic options for HBV-related HCC. HBV, directly or indirectly, can induce hepatocarcinogenesis. In patients with a high HBV DNA level and subsequent active hepatitis, adhesion molecules expressed on the sinusoidal cells are up-regulated and may increase intrahepatic metastasis. HCC progression after treatment can lead to a poor prognosis by reducing number of normal functioning hepatocytes. Thus, high HBV viral load can affect the prognosis of patients with HCC by frequent recurrence after treatment for HCC and deterioration of hepatic function associated with HCC progression. Recent meta-analysis showed that antiviral treatment reduces HCC recurrence and liver-related mortality after curative therapy of HCC. Given the strong relationship between high HBV DNA load and poor survival outcome of HCC patients due to cancer progression, it is expected that long-term antiviral therapy results in the sustained HBV suppression, control of inflammation, reduction in HCC progression, and eventually in improved overall survival.

Interrelationships among genetic C677T polymorphism of 5,10‐methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic p53 oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma

Metabolic genotypes of 5,10-methylenetetrahydrofolate reductase (MTHFR) and folate status on oxidative DNA lesions in hepatocellular carcinoma (HCC) has not been elucidated. The aims of the study were to investigate the folate-polymorphic interactions on genetic oxidative damage in association with advanced HCC malignancy and prognosis. The study included 232 HCC patients with folate nutrition, MTHFR C677T polymorphic, p53 genetic and tumour pathological data collected and analyzed for their survivals after a 7.8-years following up. By adjustment for oxidative risk factors of HCC, the compound CT and TT genotypes in relative to the CC wild-type were associated with 83% reduced lymphocytic p53 oxidative lesions of HCC patients with RBC folate lower than 688ng/mL (OR: 0.17, 95%CI: 0.07-0.43). Such genetic protective effects by the CT/TT genotypes were 2-fold enhanced among those with high RBC folate (OR: 0.08, 95% CI: 0.03-0.21, P for interaction < 0.001). For those with non-folate-deficient status, the compound CT and TT vs. CC genotypes were associated with 80% reduced risks of advanced HCC stages (III&IV) (OR: 0.2, 95%CI: 0.08-0.56). Such protection was negated either by adjustment of lymphocytic p53 oxidative lesions or by 3-fold increased risks among those with high RBC status (OR: 0.6, 95%CI; 0.31-1.41, P for interaction = 0.009). Multivariate Cox proportional hazards analysis showed that the CT/TT genotypes vs. CC wild-type were the independent predictable factor for better survival outcome of HCC patients (HR: 0.48, CI = 0.30-0.79). For CC homozygote, the second vs. the bottom tertile levels of RBC status were associated with 2-fold increased mortality rate of HCC patients (HR: 2.05, CI = 1.0-4.1). Our data demonstrated that reduced MTHFR activities associated with the MTHFR T allele may interact with RBC folate as the risk modifiers of lymphocytic p53 oxidative lesions of HCC patients. The CT/TT genotypes correlated with lower risks of late-stage HCC and a favorable survival of HCC patients, depending on p53 oxidative lesions or RBC folate status.

Genetic C677T polymorphisms of methylenetetrahydrofolate reductase and one‐carbon metabolites as prognostic predictors for survival outcome of patients with hepatocellular carcinoma.

The aims of this study were to investigate the association between methylene‐ tetrahydrofolate reductase(MTHFR) C677T polymorphism, two thymidylate synthase(TS) polymorphylisms (a tandem‐repeat of 5′UTR and 6‐bp ins/del polymophylism on the 3′UTR), one carbon‐status and survival rates of patients with hepatocellular carcinoma (HCC). The cohort study included 232 HCC patients. MTHFR C677T and TS polymorphisms were analyzed by real‐time PCR. Survival outcome of HCC patients was analyzed by Kaplan–Meier method and Cox proportional hazard model. The results showed that Cox elevated serum AFP (&gt;;200 vs. &lt;20, HR=3.61, CI=1.99–6.55), vitB12(&gt;;1500 vs. &lt;699, HR=2.69, CI =1.24–5.84), RBC folate (&gt;;818 vs. &lt;566, HR=2.05, CI=1.11–3.78), overweight (&gt;;24 vs. &lt;18.5, HR=4.86, CI=1.11–21.17) and increase tumor size (5~10 vs. &lt;5, HR=1.97; CI=1.18–3.27) will elevate the hazard ratio of HCC death. MTHFR 677 CT or TT genotypes were associated with reduced hazard ratio of HCC death (CT/TT vs. CC, HR=0.48; CI=0.30–0.79). CC genotype in combination with high folate status (566–818 ng/mL) or with elevated vitamin B12 levels (699–1500 ng/ mL) were associated with increased HR (HR=2.02, 95%CI=1.00–4.11) for RBC; (HR=2.04, 95% CI=1.11–3.77) for vitamin B12. Taken together, folate, B12 and MTHFR C677T polymorphism serve as the potential predictors for survival outcome of HCC patients.