We used MCM3 to assess the proliferative poten- tial and the degree of malignancy of the tumour and its metastases. MCM3 staining was strong in the nuclei of cells. This protein is part of the minichro- mosomal maintenance complex that plays a key role in DNA replication during S phase (Musahl et al. 1998; Endl et al. 2001; Nowak et al. 2008). Our results may indicate a high grade of malignancy of the studied hepatocellularcarcinomas. The fast and infiltrative tumour growth and the presence of metastases in the studied organs, which also Table 1. Comparison of the results of the immunohisto-
Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regula- tion of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellularcarcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular inva- sion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genom- ics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers.
Abstract: Metastasis is the most important contributor to the mortality ofpatients with hepatocellularcarcinomas (HCCs), but the molecular basis for this is unknown. Previous studies had found that homeobox A9 (HOXA9) wasfre- quently methylated in HCCs; however, little is known about whether HOXA9 can influence the malignant properties of HCC cells and the exhaustive mechanisms in HCC progression. In a screen of 82 patients with HCCs, we found that HOXA9 protein expression was inversely correlated with invasion, lymphnode metastasis, and poor clinical out- comes. Silencing HOXA9 in HCC cells increased their neoplastic properties invitro and in vivo, markedly increasing the migratory, invasive, and metastatic capabilities of malignant cells. In contrast, ectopic expression of HOXA9 in HCC cells inhibited these processes. We also found that HOXA9 promoted the expression of E-cadherin and inhibited the expression of N-cadherin. These observations contribute to our understanding of the important roles of HOXA9 in HCC development and progression and HOXA9 could be a promising molecular target for the development of new diagnostic and therapeutic strategies for HCC.
up images (18-27 months, mean 19.2 months follow up time). Magnetic resonance images along with Diffusion weighted images with b = 800 s/mm 2 were evaluated by 2 radiologists. All imaging examinations were performed with 1.5 Tesla MR machine. Diffusion weighted images and ADC (apparent diffusion coefficient) mapping of lesions were evaluated and ADC values were calculated. The results were compared with conventional dynamic magnetic resonance images. Results: In our study 95% of 40 Hepatocellularcarcinomas demonstrated diffusion restriction. 52% of 25 RDN were isointense on diffusion-weighted images. The difference of the signal intensity distribution was statistically significant between two lesions (p<0.001). On quantitative analysis, we calculated ADC values of lesions and ADC ratio of lesion-to-liver values. The mean ADC values and ADC ratio of the RDN was higher than that of the hepatocellularcarcinomas, and there was a significant difference between 2 groups (p<0.001). When a cutoff value of 0.95 is considered for ADC ratio, on diffusion imaging with ADC mapping 97.5% sensitivity and 64% specificity can be calculated to differentiate hepatocellular carcinoma from RDN.
Human HCC (hepatocellularcarcinomas) is the common hepatic highly malignant tumor. Most patients, especially in China, present at diagnosis with a high stage. The etio- pathogenisis and developments of HCC are not well known. Deregulation of cell proliferation and cell apopto- sis underlies neoplastic initiation and development, which involves multiple gene alterations, and is regulated by complicated signal transduction pathways. It has become clear that deregulated apoptosis plays a pivotal role in tumorigenesis, malignancy and metastatic poten- tial .
Liver cancer is the leading cause of cancer death world- wide and is the second leading cause of cancer death in men . As hepatocellular carcinoma (HCC) is the most common liver malignancy, the molecular mechanism of its malignant phenotype has been a focus of intensive investigation. We previously reported the identification of prognostic factors for HCC, including glypican-3 (GPC3) [2, 3] and monocarboxylate transporter 4 (MCT4) . GPC3 is an oncofetal glycoprotein connected to the cell membrane via a glycosylphosphatidylinositol anchor  and regulates some signaling activities including canonical Wnt signaling . GPC3 is highly expressed
Cancer metastasis is a complex process, and the incidence of metastasis is influenced by many biological factors. Orosomucoid 2 (ORM2) is an important glycoprotein that is mainly biosynthesized and secreted by hepatocytes. As an acute-phase protein, ORM2 likely plays important roles in anti-inflammation, immunomodulation and drug delivery. However, little is known regarding the function of ORM2 in hepatocellular carcinoma (HCC). In this study, we determined that ORM2 expression in HCC tissues was negatively associated with intrahepatic metastasis and histological grade. Moreover, the ectopic overexpression of ORM2 decreased HCC cell migration and invasion in vitro and intrahepatic metastasis in vivo, whereas silencing ORM2 expression resulted in increased tumor cell migration and invasion in vitro. The CCAAT/enhancer binding protein β (C/EBPβ) upregulated ORM2 expression, while only the LAP1/2 (C/EBPβ isoforms) possessed transcription-promoting activity on the ORM2 promoter. Subsequently, we found that LAP1 repressed HCC cell migration and invasion via the induction of ORM2 expression. Consistently, the protein expression of C/EBPβ was negatively associated with histological grade and positively correlated with ORM2 protein expression in HCC tissues. Collectively, our findings indicate that ORM2 is a functional downstream target of C/EBPβ and functions as a tumor suppressor in HCC.
T cell surveillance is often effective against virus-associated tumors because of their high immunogenicity. It is not clear why surveillance occasionally fails, particularly against hepatitis B virus– or hepatitis C virus–asso- ciated hepatocellular carcinoma (HCC). We established a transgenic murine model of virus-induced HCC by hepatocyte-specific adenovirus-induced activation of the oncogenic SV40 large T antigen (TAg). Adenovirus infection induced cytotoxic T lymphocytes (CTLs) targeted against the virus and TAg, leading to clearance of the infected cells. Despite the presence of functional, antigen-specific T cells, a few virus-infected cells escaped immune clearance and progressed to HCC. These cells expressed TAg at levels similar to HCC isolated from neonatal TAg-tolerant mice, suggesting that CTL clearance does not select for cells with low immunogenicity. Virus-infected mice revealed significantly greater T cell infiltration in early-stage HCC compared with that in late-stage HCC, demonstrating progressive local immune suppression through inefficient T cell infiltration. Programmed cell death protein-1 (PD-1) and its ligand PD-L1 were expressed in all TAg-specific CD8 + T cells
Hepatocellular carcinoma (HCC) is one of the most fre- quently occurring malignant tumors worldwide . Risk factors of HCC are well recognized including gender, infection by hepatitis B virus or hepatitis C virus, cirrhosis, metabolism diseases, toxins, excess alcohol consumption, and smoking. HCC varies with wide geography, and is more prevalent in Asia, Africa, and southern Europe. It has been well defined that experiencing surgery for early HCC patients could achieve a higher curative resection
21. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, Yuen JC, Mizokami M, Lai CL: Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut 2008, 57:98-102.
Patients were included following institutional review board approval. Informed consent was waived in this retrospective analysis. Exclusion criteria were: (1) pres- ence of tumors >3 cm in average diameter, (2) extra- hepatic disease, (3) tumor invasion into the main or lobar portal vein. Diagnosis of HCC, as shown on CT or Mag- netic Resonance Imaging (MRI), was based on arterial hypervascularity in a lesion >1 cm with venous or de- layed phase washout in accordance with American Asso- ciation for the Study of Liver Diseases (AASLD), which takes the view that a lesion found incidentally or on screening in a patient with known hepatitis B or cirrhosis of other etiology is likely to be hepatocellular carcinoma .
Abstract: Autophagy is an intracellular lysosomal degradation process performed by the cells to maintain energy balance. The autophagy response plays an important role in the progression of liver disease due to hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC). An increased autophagy response also contributes to the pathogenesis of liver disease through modulation of innate and adaptive immune responses; a defective cellular autophagy response leads to the development of HCC. Recent progress in the field indicates that autophagy modulation provides a novel targeted therapy for human liver cancer. The purpose of this review is to update our understanding of how the cellular autophagy response impacts the pathophysiology of liver disease and HCC treatment. Keywords: hepatocellular carcinoma, macroautophagy, microautophagy, autophagy inhibitor, chloroquine, hydroxychloroquine, sorafenib
With regard to the prognostic impact of H3K27me3 in different human can- cers, some of the reported data are to- tally contradictory. It was documented that loss expression of H3K27me3 was linked to poor prognosis of patients with breast, ovarian and pancreatic cancers (16). In esophageal carcinomas, however, we and other groups found that high ex- pression of H3K27me3 was positively as- sociated with high invasiveness and/or poor survival (18). Considering that the mechanism by which EZH2-mediated H3K27 methylation leads to gene silenc- ing may vary among gene targets and among organisms (36), it is not very hard for us to understand that the function of Figure 5. ROC curve analysis for different clinicopathological features and H3K27me3 expression was performed to evaluate the survival status. (A) Sex (AUC = 0.539; P = 0.339), age (AUC = 0.504; P = 0.923), serum AFP (AUC = 0.678; P < 0.0001), hepatitis history (AUC = 0.510; P = 0.812), cirrhosis (AUC = 0.503; P = 0.942), tumor multiplicity (AUC = 0.687; P < 0.0001), tumor size (AUC = 0.699; P < 0.0001), differentiation (AUC = 0.597; P = 0.017) stage (AUC = 0.746; P < 0.0001), H3K27me3 expression (AUC = 0.733; P < 0.0001), vascular invasion (AUC = 0.764; P < 0.0001), and relapse (AUC = 0.664; P < 0.0001) implied statistical associations with survival in the testing cohort. (B) Sex (AUC = 0.508; P = 0.880), age (AUC = 0.521; P = 0.695), serum AFP (AUC = 0.702; P < 0.0001), hepatitis history (AUC = 0.504; P = 0.940), cirrhosis (AUC = 0.491; P = 0.868), tumor multiplicity (AUC = 0.710; P < 0.0001), tumor size (AUC = 0.715; P = 0.002), differentiation (AUC = 0.612; P = 0.036) stage (AUC = 0.761; P < 0.0001), H3K27me3 expression (AUC = 0.719; P < 0.0001), vascular invasion (AUC = 0.757; P < 0.0001) and relapse (AUC = 0.712; P < 0.0001) were used to test the survival status in validation cohort.