• Humans
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/mortality
• Liver Neoplasms/genetics
• Liver Neoplasms/surgery
• beta Catenin/genetics
• beta Catenin/metabolism
• Male
• Female
• Middle Aged
• Prospective Studies
• Prognosis
• Aged
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Disease-Free Survival
• Adult
• Hepatectomy
• Neutrophils/metabolism

In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.

• Hepatocellular carcinoma
• p53
• Tumour suppressor gene
• Murine double minute 2
• Chemoresistance

• Livercancer
• Nanocarriers
• Nanotechnology
• Repurposingdrug
• Wnt/βcateninpathway

• Humans
• beta Catenin/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Proliferation
• Drug Repositioning
• Liver Neoplasms/pathology
• Nanotechnology
• Tumor Necrosis Factors
• Wnt Signaling Pathway
• Wnt Proteins/metabolism

• epithelial-mesenchymal transition
• hepatocellular carcinoma
• mir-20a-5p
• runx3

Background: Anti-silencing function 1B (ASF1B), a histone H3-H4 chaperone, is crucial for S-phase progression and cell proliferation. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. However, the prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear.

Methods: We analyzed the expression of ASF1B and its prognostic value using The Cancer Genome Atlas (TCGA) database (as a training set) and other databases, and we validated the findings by immunohistochemistry in our clinical database, containing 141 HCC patients (as a validation set). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to probe the tumor-associated biological processes of ASF1B in HCC. The interrelationships between ASF1B expression and tumor immunological characteristics were analyzed by multiple databases. The Imvigor210 cohort was retrieved to assess the ability of ASF1B to predict immunotherapy efficacy.

Results: ASF1B was highly expressed in tumor tissue compared to paracancerous tissue. High ASF1B expression was associated with worse overall survival (OS) and progression-free survival (PFS) in the training set (p = 0.005, p < 0.001) and validation set (p < 0.001, p < 0.001). Multivariate analysis revealed that ASF1B was an independent prognostic factor associated with OS and PFS. GSEA and GSVA suggested that ASF1B was involved in tumor-associated biological processes, including the cell cycle, DNA replication, base excision repair, mismatch repair, RNA degradation, ubiquitin-mediated proteolysis, and nucleotide excision repair. Further analysis revealed that the levels of ASF1B were positively correlated with the immune cells infiltration of B cells, CD8⁺ T cells, CD4⁺ T cells, neutrophils, and dendritic cells. However, ASF1B was positively correlated with Treg cell infiltration and inhibitory immune checkpoints in exhausted T cells. Patients who received anti-PD-L1 immunotherapy with high ASF1B expression had a higher objective response.

Conclusion: The ASF1B level is an independent prognostic factor and may serve as a potential immunotherapeutic target.

• National Natural Science Foundation of China

• clinical
• liver cancer
• microRNA

• ELAV
• HCC
• HSC
• HuR

• cancer
• genetics
• molecular biology

• Adenomatous Polyposis Coli Protein/genetics
• Class I Phosphatidylinositol 3-Kinases/genetics
• DNA Mutational Analysis
• Gastrointestinal Neoplasms/genetics
• Humans
• MAP Kinase Signaling System/genetics
• Mutation
• Prevalence
• Proto-Oncogene Proteins p21(ras)/genetics
• Signal Transduction
• Wnt Signaling Pathway/genetics

• Iran University of Medical Sciences

• Diagnostic biomarkers
• HCC
• Micrornas
• lncRNA

• SPARC gene
• hepatocellular carcinoma
• single nucleotide polymorphisms
• survival
• susceptibility

• HBV, Hepatitis B Virus
• HCC, Hepatocellular Carcinoma
• HCV, Hepatitis B Virus
• NAFLD, Non-Alcoholic Fatty Liver Disease
• hepatocellular carcinoma
• immunomodulators
• signaling pathways
• systems biology

• HMGB1/RAGE axis
• genetic susceptibility
• haplotype
• hepatocellular carcinoma
• polymorphism

Mounting evidence suggests that human leukocyte antigen (HLA) plays a central role in anti-virus and tumor defense. To test whether genetic variation in HLA-DRB1 gene, a key component of HLA system, can predict its predisposition to hepatocellular carcinoma (HCC), we thereby conducted an association study by genotyping 8 nonsynonymous polymorphisms in HLA-DRB1 gene among 257 HCC patients and 264 controls.

All polymorphisms respected the Hardy-Weinberg equilibrium. The genotypes and alleles of rs17879599 differed significantly between patients and controls after Bonferroni correction (both P < 0.001), and the power to detect this significance was 94.4%. After adjusting for age, gender, smoking, drinking and hepatitis infection, the mutant allele of rs17879702 was significantly associated with an increased risk for HCC under additive (odds ratio [OR] = 2.12, 95% confidence interval [CI]: 1.20-4.02, P = 0.004) and dominant (OR = 2.51, 95% CI: 1.39–2.96, P = 0.004) models. Haplotype analysis indicated that haplotype A-T-C-T-G-C-T-A (alleles ordered by rs199514452, rs201540428, rs201614260, rs17879702, rs17880292, rs17879599, rs17424145 and rs35445101) was overrepresented in patients and enhanced predisposition to HCC (adjusted OR = 2.72, 95% CI: 1.24–5.78, P = 0.004). In cumulative analysis, carriers of 7–9 unfavorable alleles had a 2.41-fold (95% CI: 1.18–4.92, P = 0.016) increased risk for HCC after adjusting for confounding factors relative to those possessing 4 or less unfavorable alleles.

Genotypes were determined by ligase detection reaction. HCC patients were newly diagnosed, histopathologically confirmed or previously untreated and controls were cancer-free.

Our findings suggest an independent leading contribution of rs17879599 in the 2nd exon of HLA-DRB1 gene to HCC risk in Han Chinese.

• Han Chinese
• genetic predisposition
• hepatocellular carcinoma
• human leukocyte antigen
• non-synonymous polymorphism

• BIRC5
• CCNE1
• CDKN2A
• E2F1
• Gene signatures
• Hepatocellular carcinoma
• Natural language processing
• Oncomine
• Pathways in cancer
• TCGA

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-Kras^G12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-catenin^S37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-β-catenin^S37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active β-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the β-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/β-catenin signaling pathway in pancreatic cancer cells. Nuclear β-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a β-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.

• g1–g6
• genomic
• hepatocellular carcinoma (hcc)
• inserm
• microvascular invasion
• transcriptomic classification

• Aged
• Carcinoma, Hepatocellular/classification
• Carcinoma, Hepatocellular/ethnology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/surgery
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Neoplasm
• Genotype
• Humans
• Liver Neoplasms/classification
• Liver Neoplasms/ethnology
• Liver Neoplasms/genetics
• Liver Neoplasms/surgery
• Male
• Middle Aged
• Neoplasm Invasiveness/genetics
• Phenotype
• Reverse Transcriptase Polymerase Chain Reaction
• Singapore

To analyse the expression profile of hepatocellular carcinoma compared with normal liver by using bioinformatics methods.

In this study, we analysed the microarray expression data of HCC and adjacent normal liver samples from the Gene Expression Omnibus (GEO) database to screen for differentially expressed genes. Then, functional analyses were performed using GenCLiP analysis, Gene Ontology categories, and aberrant pathway identification. In addition, we used the CMap database to identify small molecules that can induce HCC.

Overall, 2721 differentially expressed genes (DEGs) were identified. We found 180 metastasis-related genes and constructed co-occurrence networks. Several significant pathways, including the transforming growth factor β (TGF-β) signalling pathway, were identified as closely related to these DEGs. Some candidate small molecules (such as betahistine) were identified that might provide a basis for developing HCC treatments in the future.

Although we functionally analysed the differences in the gene expression profiles of HCC and normal liver tissues, our study is essentially preliminary, and it may be premature to apply our results to clinical trials. Further research and experimental testing are required in future studies.

• bioinformatics analysis
• differentially expressed genes
• functional analysis
• hepatocellular carcinoma

• HCC
• HMGB1
• SNP
• Susceptibility

• Cytotoxicity
• Hepatocellular carcinoma
• Human amniotic membrane
• Protein extracts
• hAMPE

• ADAMTS5
• Chinese
• Hepatocellular carcinoma
• SNP
• Susceptibility

• ADAMTS5 Protein/genetics
• ADAMTS5 Protein/metabolism
• Adult
• Aged
• Alleles
• Carcinoma, Hepatocellular/ethnology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Case-Control Studies
• China
• Disease Progression
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• Heterozygote
• Humans
• Liver Neoplasms/ethnology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Male
• Middle Aged
• Mutation, Missense
• Odds Ratio
• Polymorphism, Single Nucleotide

Hepatocellular carcinoma is a highly deadly malignancy, accounting for approximately 800,000 deaths worldwide every year. Mutation of the p53 tumor suppressor gene is a common genetic change in HCC, present in 30% of cases. p53^R175H (corresponding to p53^R172H in mice) is a hotspot for mutation that demonstrates “prometastatic” gain-of-function in other cancer models. Since the frequency of p53 mutation increases with tumor grade in HCC, we hypothesized that p53^R172H is a gain-of-function mutation in HCC that contributes to a decrease in tumor-free survival and an increase in metastasis. In an HCC mouse model, we found that p53^R172H/flox mice do not have decreased survival, increased tumor incidence, or increased metastasis, relative to p53^flox/flox littermates. Analysis of cell lines derived from both genotypes indicated that there are no differences in anchorage-independent growth and cell migration. However, shRNA-mediated knockdown of mutant p53 in p53^R172H-expressing HCC cell lines resulted in decreased cell migration and anchorage-independent growth. Thus, although p53 mutant-expressing cells and tumors do not have enhanced properties relative to their p53 null counterparts, p53^R172H-expressing HCC cells depend on this mutant for their transformation. p53 mutants have been previously shown to bind and inhibit the p53 family proteins p63 and p73. Interestingly, we find that the levels of p63 and p73 target genes are similar in p53 mutant and p53 null HCC cells. These data suggest that pathways regulated by these p53 family members are similarly impacted by p53^R172H in mutant expressing cells, and by alternate mechanisms in p53 null cells, resulting in equivalent phenotypes. Consistent with this, we find that p53 null HCC cell lines display lower levels of the TA isoforms of p63 and p73 and higher levels of ΔNp63. Taken together these data point to the importance of p63 and p73 in constraining HCC progression.

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Movement/genetics
• Disease Progression
• Genetic Predisposition to Disease
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Mice
• Mice, Transgenic
• Transcriptional Activation
• Tumor Suppressor Protein p53/genetics

• R01 CA121171 NCI NIH HHS
• R01CA121171 NCI NIH HHS

• sptbn1
• β-catenin
• stem cell
• wnt signaling
• hepatocellular carcinoma

• Animals
• Antigens, Neoplasm/metabolism
• Cadherins/metabolism
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/mortality
• Carrier Proteins/metabolism
• Cell Adhesion Molecules/metabolism
• Epithelial Cell Adhesion Molecule
• Female
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Liver Neoplasms/mortality
• Mice, Nude
• Microfilament Proteins/metabolism
• Neoplasm Recurrence, Local/metabolism
• Serpins/metabolism
• Vimentin/metabolism
• Wnt Proteins/metabolism
• beta Catenin/metabolism

• 5R01CA129813 NCI NIH HHS
• P01 CA130821 NCI NIH HHS
• NIH-P30 CA51008 NCI NIH HHS
• UL1 TR000101 NCATS NIH HHS
• 1P01CA130821 NCI NIH HHS
• P30 CA051008 NCI NIH HHS
• NCATS 8 UL1 TR000101 NCATS NIH HHS
• R01 CA129813 NCI NIH HHS

Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, and of its long-term complications. It is the most variable among DNA viruses, mostly because of its unique life cycle which includes the activity of error-prone enzyme, reverse transcriptase, and the very high virion production per day. In last two decades, numerous research studies have shown that the speed of disease progression, reliability of diagnostic methods and the success of antiviral therapy and immunization are all influenced by genetic variability of this virus. It was shown that mutations in specific regions of HBV genome could be responsible for unwanted clinical outcomes or evasion of detection by diagnostic tools, thus making the monitoring for these mutations a necessity in proper evaluation of patients. The success of the vaccination programs has now been challenged by the discovery of mutant viruses showing amino acid substitutions in hepatitis B surface antigen (HBsAg), which may lead to evasion of vaccine-induced immunity. However, the emergence of these mutations has not yet raised concern since it was shown that they develop slowly. Investigations of HBV genetic variability and clinical implications of specific mutations have resulted in significant advances over the past decade, particularly in regard to management of resistance to antiviral drugs. In the era of drugs with high genetic barrier for resistance, on-going monitoring for possible resistance is still essential since prolonged therapy is often necessary. Understanding the frequencies and clinical implications of viral mutations may contribute to improvement of diagnostic procedures, more proper planning of immunization programs and creating the most efficient therapeutic protocols.

• Hepatitis B virus
• Hepatitis B virus variability
• Mutation
• Drug resistance
• Vaccine escape

• Acute Disease
• Antiviral Agents/therapeutic use
• Drug Resistance, Viral/genetics
• Genotype
• Hepatitis B/diagnosis
• Hepatitis B/drug therapy
• Hepatitis B/virology
• Hepatitis B Antigens/genetics
• Hepatitis B virus/drug effects
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/virology
• Humans
• Mutation
• Phenotype
• Trans-Activators/genetics
• Treatment Outcome
• Viral Core Proteins/genetics
• Viral Regulatory and Accessory Proteins

• Adult
• Aged
• Angiogenic Proteins/metabolism
• Animals
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Caspase 3/metabolism
• Cisplatin/pharmacology
• Demography
• Down-Regulation/drug effects
• Female
• Gene Knockdown Techniques
• Hep G2 Cells
• Humans
• Liver Neoplasms/enzymology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Signal Transduction/drug effects
• Transfection
• Tumor Suppressor Protein p53/metabolism
• bcl-2-Associated X Protein/metabolism

• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/prevention & control
• Carcinoma, Hepatocellular/therapy
• Genetic Variation
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/prevention & control
• Liver Neoplasms/therapy
• Prognosis

• hepatocellular carcinoma
• single-nucleotide polymorphism
• vascular endothelial growth factor C

The current study examines the expression of molecular biomarkers in hepatocellular carcinoma (HCC) and whether these findings correlate with the clinicopathologic features of the disease and patient survival.

We analyzed the immunohistochemical expression of p53, mammalian target of rapamycin (mTOR), c-Met, and insulin-like growth factor 1 receptor (IGF-1R) heat shock protein 70 (HSP70) with the clinicopathologic features of 83 HCCs.

p53 expression was higher in the male patients with undifferentiated histological tumor grades, cirrhosis, and portal vein invasion. High 48 c-Met expression correlated with cirrhosis, and high mTOR expression correlated with the tumor grade and cirrhosis. High IGF-1R expression correlated with the tumor grade and cirrhosis. A multivariate analysis identified a significant relationship between the high expression of p53, tumor grade, and portal vein invasion. In addition, a high expression of mTOR was related to tumor grade and cirrhosis, and a high expression of HSP70 was related to portal vein invasion in a multivariate analysis. The Kaplan-Meier survival curve for patients with high versus low Edmondson grades and p53 expression was statistically significant.

p53, mTOR, and IGF-1R expression correlated with the Edmondson tumor grade in a univariate analysis, while p53 and mTOR correlated with the Edmondson tumor grade in a multivariate analysis. In addition, the tumor grade was found to predict survival. p53 was primarily related to the clinicopathologic features compared to other markers, and it is a poor prognostic factor of survival.

• Carcinoma, hepatocellular
• Receptor, IGF type 1
• c-Met
• mTOR
• p53

Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population.

We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis.

Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation.

Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.

• Adult
• Aged
• Cross-Sectional Studies
• Hepacivirus
• Hepatitis C, Chronic/genetics
• Humans
• Inflammation/genetics
• Liver Cirrhosis/genetics
• Male
• Middle Aged
• Polymorphism, Genetic
• Wnt Signaling Pathway/genetics

• P30 DK56338 NIDDK NIH HHS
• K24 DK04-107 NIDDK NIH HHS
• P30 DK056338 NIDDK NIH HHS
• K23 AI087821 NIAID NIH HHS
• K01 DK081736 NIDDK NIH HHS
• K23 AI 087821 NIAID NIH HHS
• R03 DK095082 NIDDK NIH HHS

• apoptosis
• diethylnitrosamine
• hepatocellular carcinoma
• miR-34
• p21

Although the mortality rate of endometrial cancer is comparatively low in gynecologic malignancies, a rising trend of this cancer has been observed for the past decade. The understanding of the molecular mechanism will favor for the clinical management of this disease. Aberrant activation of Wnt/β-catenin signaling pathway plays a major role in the pathogenesis of endometrioid adenocarcinoma including this cancer type. In this study, we reported that Sox7, one of Sox transcriptional factors, was frequently underexpressed in endometrial cancer and importantly, it was associated with dysregulation of the Wnt/β-catenin signaling activity. Immunohistochemical and quantitative RT-PCR analyses showed that Sox7 was underexpressed and was associated with high-grade tumor (P=0.021), increased expressions of β-catenin (P=0.038) and its downstream targets; CyclinD1 (P<0.001) and FGF9 (P<0.001). In addition, using HEK293T cell model, we found that Sox7 was able to inhibit TCF/LEF-1-dependent luciferase activity induced by Wnt-1. This was further proved by that Sox7 could significantly suppress the expressions of Wnt targets; Cyclin D1 and C-myc in endometrial cells. Immuno-fluorescent microscopy revealed that Sox7 was co-localizaed with either mutant β-catenin or TCF4 protein in nucleus, while co-immunopreciptation assay demonstrated that Sox7 could physically interact with not only wild-type but also mutant β-catenin, as well as TCF4 proteins. Functionally, enforced expression of Sox7 could significantly inhibit endometrial or endometrioid ovarian cancer cells (OEA) harboring either wild-type or mutant β-catenin. These data suggest Sox7 is a negative regulator of Wnt/β-catenin signaling pathway through impeding the transcriptional machinery of β-catenin/TCF/LEF-1 transcriptional complex, and the loss of expression may be involved in the pathogenesis of endometrial cancer.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells – ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.

The role of Pokemon (POK erythroid myeloid ontogenic actor), a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC) and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma) as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.

• Apoptosis
• Base Sequence
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Caspases/metabolism
• Cell Line, Tumor
• DNA Primers
• DNA-Binding Proteins/genetics
• Gene Silencing
• Humans
• In Situ Nick-End Labeling
• Liver Neoplasms/enzymology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mitochondria, Liver/metabolism
• Transcription Factors/genetics
• fas Receptor/metabolism

This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain ‘cellular memory’ by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell.

• HCC
• gene expression profile
• hepatocytes
• liver
• mathematical modeling
• network analysis
• proteomic