P53 In Hepatocellular Carcinoma Research Articles

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100mg/L) administration in the drinking water for 13 and 16weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5mg/kg/day) for 3weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16week control group may indicate a different metabolic status of HCC.

TRAF7 contributes to tumor progression by promoting ubiquitin-proteasome mediated degradation of P53 in hepatocellular carcinoma

It has been proved that TRAFs family proteins played malfunctioning roles in the development of human cancers. TRAF7 is the last one of TRAFs family proteins to be found, which was demonstrated to be involved in a serious of cancers development. In this study, we systematically investigated the molecular mechanisms of TRAF7 in facilitating hepatocellular carcinoma (HCC). We discovered that TRAF7 was overexpressed in tumor tissues and the increased TRAF7 expression was closely associated with tumor size, histologic grade, TNM stage and poor prognostication. TRAF7 overexpression repressed cell apoptosis and promoted cell proliferation, invasion and migration, whereas knockdown of TRAF7 in HCC cells had totally opposite effects. Besides, we identified the interaction between TRAF7 and P53 in HCC and demonstrated that TRAF7 promoted ubiquitin-proteasome mediated degradation of P53 at K48 site. The rescue assays further proved that the function of TRAF7 in inhibiting apoptosis and promoting tumor development was depended on P53 in HCC. Overall, this work identified that TARF7 promoted tumorigenesis by targeted degradation P53 for ubiquitin-mediated proteasome pathway. Targeting the TRAF7-P53 axis may provide new insights in the pathogenesis of HCC, and pave the way for developing novel strategies for HCC prevention and treatment.

Correlationship between Ki67, VEGF, and p53 and Hepatocellular Carcinoma Recurrence in Liver Transplant Patients

Background and Aims Patients with hepatocellular carcinoma (HCC) who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate the correlation between the expression of Ki67, VEGF, and p53 in HCC and clinicopathological characteristics of HCC patients, as well as their predictive value for HCC recurrence after OLT. Methods 60 patients who underwent OLT and were found to have HCC in the liver explant. The expression of Ki67, VEGF, and p53 in HCC was detected by immunohistochemistry. Results Ki67 was associated with the tumor number and the grade of differentiation at baseline. VEGF was associated with the diameter and number of tumors, tumor differentiation, and lymph node metastasis. p53 was associated with the tumor diameter and tumor encapsulation. The expression of Ki67, VEGF, and p53 in HCC was correlated with the tumor recurrence after OLT, respectively. Among them, VEGF was an independent predictor for tumor recurrence after OLT. Conclusion Ki67, VEGF, and p53 are associated with the recurrence of HCC after OLT. VEGF independently predicts the recurrence of HCC.

Correlation between CT features and liver function and p53 expression in hepatitis, cirrhosis and hepatocellular carcinoma.

This study aimed to investigate the correlation between CT features and liver function and p53 expression in hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Forty patients with HCC, 30 patients with cirrhosis and 30 patients with chronic hepatitis were enrolled between December, 2015 and December, 2016. At the same time, normal liver tissues collected from 30 patients with hepatic hemangioma were used as the normal control group. All the patients were scanned by CT. Average body surface area, left outer lobe and caudate lobe volume, and the proportions of left outer lobe and caudate lobe to the whole liver were calculated. Biochemical indexes of liver function were determined. The pathological tissues of all the subjects were analyzed. Compared with the control group, total liver volume of the HCC group was significantly reduced (P<0.05). Compared with the HCC group, the volume of the left outer lobe increased in the hepatitis group and the cirrhosis group. Compared with control group, caudate lobe volume increased significantly in the hepatitis group (P<0.05). Compared with the control group, the volume of the left outer lobe and the proportion of caudate lobe to the whole liver volume was significantly increased in all three groups (P<0.05). Liver function-related indicators in the HCC and cirrhosis groups were significantly different from those in the control group (P<0.05). The expression level of p53 in HCC was significantly higher than that in the control group (P<0.05). The accuracy of diagnosis by using both p53 and CT was higher than the use of p53 or CT alone. CT can accurately measure the volume of each lobe of the liver, and p53 has important clinical values in the diagnosis of liver diseases. Thus, the reasonable combination of the two can effectively improve the diagnostic accuracy.

Expression of PD-1/PD-L1 and P53 in hepatocellular carcinoma

Expression of PD-1/PD-L1 and P53 in hepatocellular carcinoma

Butein activates p53 in hepatocellular carcinoma cells via blocking MDM2-mediated ubiquitination.

IntroductionIn this study, we aimed to investigate the effect of butein on p53 in hepatocellular carcinoma (HCC) cells and the related molecular mechanisms by which p53 was activated.MethodsMTS assay and clonogenic survival assay were used to examine the antitumor activity of butein in vitro. Reporter gene assay was adopted to evaluate p53 transcriptional activity. Flow cytometry and western blotting were performed to study apoptosis induction and protein expression respectively. Xenograft model was applied to determine the in vivo efficacy and the expression of p53 in tumor tissue was detected by immunohistochemistry.ResultsHCC cell proliferation and clonogenic survival were significantly inhibited after butein treatment. With the activation of cleaved-PARP and capsase-3, butein induced apoptosis in HCC cells in a dose-dependent manner. The transcriptional activity of p53 was substantially promoted by butein, and the expression of p53-targeted gene was increased accordingly. Mechanism studies demonstrated that the interaction between MDM2 and p53 was blocked by butein and MDM2-mediated p53 ubiquitination was substantially decreased. Short-hairpin RNA experiment results showed that the sensitivity of HCC cells to butein was substantially impaired after p53 was knocked down and butein-induced apoptosis was dramatically decreased. In vivo experiments validated substantial antitumor efficacy of butein against HepG2 xenograft growth, and the expression of p53 in butein-treated tumor tissue was significantly increased.ConclusionButein demonstrated potent antitumor activities in HCC by activating p53, and butein or its analogs had therapeutic potential for HCC management.

WITHDRAWN: Autoimmune response of p53 and its regulator MDM2 in patients with hepatocellular carcinoma

// Li-Ping Dai 1,2,3,* , Ji-Tian Li 3,* , Xiao Wang 1,2,3 and Jian-Ying Zhang 1,2,3 1 Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China 2 Henan Key Laboratory for Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, China 3 Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA * Li-Ping Dai and Ji-Tian Li contributed equally to this work Correspondence to: Jian-Ying Zhang, email: jzhang@utep.edu Li-Ping Dai, email: lpdai@zzu.edu.cn Keywords : hepatocellular carcinoma (HCC); autoantibody; MDM2; p53 Received: July 13, 2017&nbsp;&nbsp;&nbsp;&nbsp; Accepted: October 30, 2017&nbsp;&nbsp;&nbsp;&nbsp; Epub: January 03, 2018 Abstract Purpose: The human homologue of the mouse double minute 2 (MDM2) is a transcriptional target and negative regulator of p53. This study aims to investigate the immune response of MDM2 and p53 in hepatocellular carcinoma (HCC). Methods: The autoantibodies were examined by immunoassay in individual sera from 160 HCC patients and 89 normal controls, as well as 76 sequential serum samples from an independent group of 16 HCC patients. The receiver operating characteristic (ROC) analysis was conducted for autoantibody for the distinguishing of HCC from controls. Results: Anti-MDM2 and anti-p53 autoantibodies could distinguish HCC patients from normal individuals in derivation set with area under curve (AUC) of 0.752 and 0.844, as well as in validation set with AUC of 0.658 and 0.703, respectively. The frequencies of anti-MDM2 (30.3%) and anti-p53 (32.9%) autoantibodies were significantly higher in HCC patients than that in normal individuals (10.1%). When anti-MDM2 and anti-p53 autoantibodies combined together, the positive frequency in HCC patients increased to 44.7% which was still significantly higher than that in normal individuals (18.0%). By using longitudinal preclinical samples, 62.5% of patients were observed with anti-MDM2 or anti-p53 autoantibody positive one year prior to diagnosis of HCC. Serum level of autoantibodies against these two TAAs were positively associated with each other ( r = 0.500, P &lt; 0.001). Conclusions: MDM2 and p53 are autoantigens that elicit autoimmune responses in HCC and can be the potential biomarkers for the early detection or predictor of HCC.

A promising chemosesitization role of inulin in management of experimentally induced hepatocellular carcinoma

Objectives Globally, hepatocellular carcinoma (HCC) is an important reason of death due to cancer. The present study investigates antioxidant and anti-inflammatory properties of inulin (IN) in HCC rat model.Methods Five groups of rats were treated for 4 months, a control group, received intra peritoneal saline daily, HCC group given freshly prepared thioacetamide (TAA) solution orally, twice weekly (200 mg/kg bw), cisplatin (CP) + TAA group (single intra peritoneal(IP) dose of CP, 7.5 mg/kg bw + TAA as mentioned), fourth group received oral doses of IN, 10 mg/kg bw, daily+TAA), the fifth group was given a single dose of CP + IN + TAA for 4 months.Results HCC exhibited periportal fibrosis, nuclear/cytoplasmic ratio increments, significant increase in alpha fetoprotein (AFP), malondialdehyde (MDA), protein carbonyl (PC), xanthine oxidase (XO) and aldehyde oxidase (AO) activity. Hepatic glutathione (GSH), total antioxidant capacity (TAC), super oxide dismutase (SOD) and catalase (CAT) activities, were decreased. Significant decrease in B-cell lymphoma 2 (Bcl2), while a significant increase in levels of tumor necrosis factor (TNF) and P53 in HCC group.Conclusions Treatment of HCC rats with CP or IN improved such effects. IN was more effective than CP, and the best effect was observed using both drugs. Conclusively, IN is a chemo-sensitizer to CP in the treatment of HCC through restoration of the antioxidant defense mechanism, anti-apoptotic and anti-inflammatory properties.

Relationship of the expression levels of XIAP and p53 genes in hepatocellular carcinoma and the prognosis of patients.

In this study, we measured mRNA and protein expression levels of X-linked inhibitor of apoptosis protein (XIAP) and p53 in hepatocellular carcinoma (HCC) and analyzed their relationships to clinicopathological parameters and the prognosis of the patients. Samples were obtained from tumors and tumor-adjacent normal tissues from 70 patients with HCC who were hospitalized in Weifang People's Hospital from January 2009 to December 2011. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were used to detect the mRNA and protein expression levels, respectively. The clinical data of patients who were followed for 5 years from the day of the tumor-resection surgery were collected in detailed clinical histories. Statistical analyses were used to find relationships between the XIAP and p53 levels and the clinical variables and 5-year survival of patients. Our qPCR results showed that the mRNA expression levels of XIAP and p53 in HCC tumors were significantly higher than those in tumor-adjacent normal tissues. At the same time, IHC results showed that the positive expression rates of XIAP and p53 in HCC in tumors were 81.4% (57/70) and 72.9% (51/70), respectively and their high expression was related to invasion, metastasis and tumor staging. The overall 5-year survival rate of the patients was 15.7% (11/70). Single factor survival analysis showed that both XIAP and p53 were influencing factors of the overall survival rate of patients with HCC (P<0.01). In conclusion, high expression levels of XIAP and p53 are closely related to clinicopathological parameters of patients with HCC, especially related to invasion, metastasis and tumor staging. XIAP and p53 levels can be used as reference values to guide the treatment of HCC and estimate the prognosis.

Effective co-delivery of nutlin-3a and p53 genes via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma.

The tumor suppressor protein p53 is the most frequently inactivated, mutated, or deleted transcriptional factor in tumor cells. Recent studies have shown that the negative regulation of p53 by the murine double minute 2 (MDM2) protein in human cells interrupts the p53 apoptotic pathway and causes tumorigenesis. Therefore, the disruption of the MDM2-p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells. This study aims to introduce a unique combined p53-based gene and chemotherapy approach using core-shell polymeric microparticles for the localized treatment of cancers. Core-shell microparticles were successfully fabricated in a single step using a modified electrohydrodynamic atomization (EHDA) technique, where the core and shell layers were loaded with nutlin-3a and β-cyclodextrin-g-chitosan/p53 nanoparticles, respectively. The grafting of β-cyclodextrin (β-CD) onto chitosan chains demonstrated remarkable cellular uptake (∼5-fold) compared to pure chitosan at N/P = 6, attributed to a strong interaction and temporary disruption of the lipid bilayer in the cell membrane by the synthesized copolymer. The therapeutic efficiencies of single- and dual-agent loaded microparticle formulations were also evaluated and compared against free-drug treatment in terms of cell viability and intracellular expression of p53, caspase 3, and MDM2 proteins via an MTS assay, an enzyme-linked immunosorbent assay, and an immunostaining assay. The results revealed that the controlled and sustained release of both agents from the microparticles synergistically enhanced the anti-proliferative efficacy of the agents via the continuous overexpression of p53 and caspase 3 proteins over 5 days. However, MDM2 protein expression remained at the basal level over that period. The findings also indicated that nutlin-3a could impose excessive oxidative stress on cancer cells, where the overproduction of reactive oxygen species (ROS) with irreversible destructive effects on subcellular organelles such as the nucleus (DNA) and mitochondria could be considered as a secondary apoptotic pathway induced by nutlin-3a. Inspired by the observations, the proposed drug delivery system can serve as a unique and powerful drug and gene delivery system with a far-reaching application in human cancer therapy.

Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner.

The development and progression of hepatocellular carcinoma (HCC) is accompanied with persistent oxidative stress, but the molecular basis is not well defined. Superoxide dismutase 2 (SOD2) is an important mitochondrial antioxidant and a key aging factor. Here we investigated the expression and clinical significance of SOD2 in a large cohort of HBV-positive HCC tumors. Both SOD2 mRNA and protein are reduced in human primary HCCs compared with matching liver tissues. Consistently, the SOD2 DNA copy numbers are decreased in HCCs, providing a genetic basis for the decrease in SOD2 mRNA expression. Reduced SOD2 expression in HCCs is correlated with older age, larger tumor size, multiple tumor nodules and tumor emboli, and cancer recurrence. Moreover, low SOD2 expression is strongly associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses indicates that SOD2 is an independent prognostic predictor for OS and RFS. Intriguingly, reduced SOD2 mRNA is strongly associated with poor survival in a separate cohort of HCC patients carrying mutant p53. Altogether, our results provide clinical evidence for the importance of SOD2 in tumor progression and mortality, and the close relationship of SOD2 and p53 in HCC.

Anticarcinogenic action of quercetin by downregulation of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) via induction of p53 in hepatocellular carcinoma (HepG2) cell line.

Protein kinase C (PKC) is a key regulator of cell growth and differentiation in mammalian cells and hyperactivation of PKC is believed to play an important role in tumor progression. PKC is downstream to signaling protein of phosphatidylinositol 3-Kinase (PI3K), a known up-regulator of cell proliferation and survival. Accumulation of reactive oxygen species (ROS) triggers oxidative stress in the tumor microenvironment, leading to the hyperactivation of various oxidative stress-stimulated signaling molecules. Quercetin (QUE) is a naturally occurring dietary flavonoid having antioxidant properties. QUE is reported to show antitumor activity both in vitro and in vivo; however, the molecular mechanism is yet to be thoroughly explored. HepG2 cells display cellular functions similar to the normal hepatocytes with high degree of morphological and functional differentiation, therefore HepG2 cell line is chosen as the suitable model for drug targeting. Present study is aimed to establish the signaling pathway involved in the anticarcinogenic action of QUE in HepG2 cell line. HepG2 cells were treated with different doses of QUE. Protein level and gene expression were analysed by Western blotting and RT-PCR, respectively. PKC activity was measured by non-radioactive-tagged phosphorylation. Results showed downregulation of expression of PI3K, PKC, COX-2 and ROS caused by QUE. Additionally, QUE enhanced the expression of p53 and BAX in HepG2 cells. Overall, results of the current study suggested that QUE elicited anticarcinogenic action by upregulation of p53 and BAX in HepG2 cells via downregulation of ROS, PKC, PI3K and COX-2, confirming our earlier report on the animal model.

Crosstalk between EGFR and p53 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, with a high mortality. Most patients present with late stage disease, when the treatment options are limited to systemic chemotherapy. The purpose of our study was to evaluate the significance of p53 and EGFR expression in HCC, and to determine whether these two markers correlate with conventional parameters of prognosis. Our study included a total of 45 patients, diagnosed histopathologically with HCC. Clinicopathological data including sex, age, tumor necrosis, tumor size, histologic grading, tumor stage, the presence of cirrhosis and chronic hepatitis, were recorded from the Institute database. Three independent microscopic fields were selected for each sample and all the tumor cells within each microscopic field were counted, and then the positive percent of p53 cells were calculated. Three staining patterns were recognized: diffuse, heterogenous and focal. The intensity of EGFR staining was scored on a scale of 0-3+: 0 no staining; 1+ when a weak membrane staining was observed; 2+ when membrane staining is more intense than in 1+, but less than 3+, and 3+ when intense dark brown staining delineated the membrane. To determine the relationship between EGFR expression and p53, we performed double staining in the same HCC specimens. By immunohistochemical staining, p53 protein was detected in tumor cell nuclei in 20 HCCs (44%). We found a significant correlation between the intensity of p53 expression and the histological grade (p=0.008). EGFR expression was detected in 17 (38%) cases, linked to histological grade (p=0.039). Moreover, the intensity of p53 expression was significantly correlated with EGFR intensity (p=0.014). Our results suggest that overexpression of p53 and EGFR plays an important role in hepatocarcinogenesis and contributes to more advanced disease. These markers are not only valuable predictors of prognosis in HCC, but they are also rational targets for new anti-tumor strategies.

Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma.

BackgroundArsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance.MethodsMutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms.ResultsThe acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung.ConclusionsAcquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.

Interference with the p53 family network contributes to the gain of oncogenic function of mutant p53 in hepatocellular carcinoma

Whereas the hallmark of wild-type p53 is its tumor suppressor activity, tumor-associated mutant p53 proteins can exert novel anti-apoptotic gain-of-function activities, which confer a selective advantage upon tumor cells harboring such mutations. We investigated the molecular mechanisms of mutant p53 gain-of-function in hepatocellular carcinoma with special emphasis on the interaction of mutant p53 gain-of-function proteins with the p53 family members p63 and p73. Mutant forms of p53, namely the hot-spot mutants p53R143A, p53R175D, p53R175H, p53R248W, and p53R273H, acquire anti-apoptotic gain-of-function in hepatocellular carcinoma by repressing the activity of genes regulating both, the extrinsic apoptosis pathway initiated by ligation of death receptors and the intrinsic/mitochondrial apoptosis pathway. In the presence of mutated p53, the CD95L-CD95 apoptotic pathway is markedly attenuated. This is due to repression of CD95 gene transcription by mutant p53. In addition, these mutants repress the expression of the Bax gene and attenuate mitochondria-mediated apoptosis signaling. Furthermore, and of clinical relevance, these gain-of-function mutants are anti-apoptotic due to their inhibitory interaction with the pro-apoptotic p53 family members TAp63 and TAp73. p53 gain-of-function mutants significantly decrease activation of pro-apoptotic target genes by wild-type p53, TAp63, and TAp73. This contributes to the ability of cancer cells to withstand DNA damage-induced apoptosis. Interference with the interaction of p53 gain-of-function mutants with TAp63 or TAp73 may thus sensitize hepatocellular carcinoma to elimination by therapy.

Expression of DNA repair gene apurinic/apyrimidinic endonuclease 1 and its correlation with the expression of mutant p53 in hepatocellular carcinoma

Objective To detect the expression of apurinic/apyrimidinic endonuclease 1 (APEI) and explore its correlation with the expression of mutant p53 in hepatocellular carcinoma (HCC). Methods The expression of APE1 and mutant p53 was detected by SP immunohistochemical method in 10 specimens of normal liver tissue, 40 specimens of liver cirrhosis tissue and 103 specimens of HCC tissue which were collected at the Department of Pathology of Daping Hospital from 1991 to 2004. All data were analyzed by chi-square test, correla-tion analysis and K Independent-Samples Tests. Results The expression rate of APE1 in HCC was 100.0%, which was significantly higher than that in normal liver tissue (40.0%) and liver cirrhosis tissue (82.5%) (χ~2= 47.852, P < 0.01). The expression of APE1 was only detected in the nucleus in normal liver tissue. Ectopic expression of APE1 in cytoplasm was detected in liver cirrhosis tissue and HCC tissue, with the rate of 20.0% and 53.4%, respectively (χ~2=20.757, P <0.01). There was statistical difference in clinical staging and pathological grading of HCC with different combinations of APE1 expression (intranuclear or ectopic expression) and mutant p53 expression (positive or negative expression) (χ~2=12.910, 14.481, P < 0.01), and HCC with ectopic expression of APE1 and positive expression of p53 had high malignant degree. Conclusion Overexpression and ectopic expression of APE1 in cytoplasm may play important roles in the genesis and progression of HCC, and the ectopic expression of APE1 and p53 mutation may have synergistic effect. Key words: Liver neoplasms; Apurinic/apyrimidinic endonuclease 1; Mutant p53

Interference with the p53 family network contributes to the gain of oncogenic function of mutant p53 in hepatocellular carcinoma (HCC)

Interference with the p53 family network contributes to the gain of oncogenic function of mutant p53 in hepatocellular carcinoma (HCC)

Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients

To elucidate the clinicopathological correlations among vascular endothelial growth factor (VEGF), microvessel density (MVD) and tumor suppressor gene p53 in hepatocellular carcinomas (HCCs), we adopted a new definition of "VEGF overexpression." The expressions of VEGF, MVD, and p53 in 113 HCC specimens were analyzed by immunohistochemistry. VEGF expression in surrounding liver tended to be stronger (VEGF overexpression, 31%) than, or similar to (57%) that in HCCs (P = 0.001). P53 positivity was noted in 42 cases (37.1%). MVD ranged from 22 to 201 microvessels/field determined for 5 high-power fields. VEGF expression in HCCs was positively correlated with MVD (P = 0.001). VEGF overexpression is positively correlated with young age (P = 0.008), male gender (P = 0.01), hepatitis B viremia (P = 0.013), high alpha-fetoprotein levels (P < 0.001), p53 (+) (P = 0.036), advanced-stage HCC (P = 0.015), and HCC dedifferentiation (P = 0.004). Survival analyses indicated that VEGF overexpression, high MVD, and advanced-stage HCC were independent poor prognostic factors for disease-free and overall survival. This study provides evidence of a positive association between parameters reflective of angiogenesis, and p53 expression in HCCs. VEGF overexpression exhibited a significant correlation with viremia and survival.

GEP associates with wild-type p53 in hepatocellular carcinoma

Granulin-epithelin precursor (GEP) is a novel growth factor whose up-regulation we previously reported in 72% of hepatocellular carcinoma (HCC). GEP expression has been reported to be associated with p53 protein accumulation in a breast cancer study, though the p53 mutation status was not revealed. We aim to investigate whether p53 protein and mutation status correlates with GEP expression in HCC. The statistical comparison of p53 and GEP data revealed an overall positive association between the two protein expression patterns (P<0.001). Upon detailed analysis, the association of p53 and GEP protein expression was found to be highly significant only in HCCs with wild-type p53 (P=0.001); there was no association in HCCs with p53 mutation (P=0.669). The GEP levels in the HepG2 hepatoma cell line with a wild-type p53 background were modulated by transfection experiments. Overexpression of the GEP protein resulted in an increased p53 protein level and suppression of the GEP protein resulted in a decreased p53 protein level in HepG2 cells. In summary, we demonstrated that p53 wild-type protein nuclei accumulation is associated with GEP protein expression in human HCC specimens, and GEP modulates p53 wild-type protein levels in vitro.

Evaluation of serum levels of p53 in hepatocellular carcinoma in Egypt

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-induced death. Somatic mutation of the p53 gene is the most common genetic abnormality so far described in human cancer and there is evidence that supports a high level of p53 alterations in HCC. The aim of this study was to investigate serum levels of p53 in Egyptian patients with HCC, and its relation to other prognostic factors such as tumor grade, alpha-fetoprotein (AFP), and liver function tests in an attempt to clarify their significance in the pathogenesis of the disease. Liver function tests were carried out and AFP and p53 levels were measured for all individuals studied. Our results show that detection of p53 increased the frequency of HCC prediction from 79.5% to 86.3%. Moreover, significant positive correlation between p53 and tumor size (cm) for tumor grade II and III was identified. In conclusion, serum concentration of p53 protein may be a convenient and useful non-invasive screening test for prediction of HCC.